JP2009528977A - 慢性線維形成性疾患を治療するための物質および方法 - Google Patents
慢性線維形成性疾患を治療するための物質および方法 Download PDFInfo
- Publication number
- JP2009528977A JP2009528977A JP2008547405A JP2008547405A JP2009528977A JP 2009528977 A JP2009528977 A JP 2009528977A JP 2008547405 A JP2008547405 A JP 2008547405A JP 2008547405 A JP2008547405 A JP 2008547405A JP 2009528977 A JP2009528977 A JP 2009528977A
- Authority
- JP
- Japan
- Prior art keywords
- fibroblasts
- ccl21
- lung
- fibrosis
- ccr7
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 238000000034 method Methods 0.000 title claims abstract description 124
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 title claims abstract description 120
- 230000003352 fibrogenic effect Effects 0.000 title claims abstract description 42
- 230000001684 chronic effect Effects 0.000 title claims abstract description 31
- 201000010099 disease Diseases 0.000 title claims description 53
- 239000000126 substance Substances 0.000 title description 6
- 210000002950 fibroblast Anatomy 0.000 claims abstract description 415
- 101000713085 Homo sapiens C-C motif chemokine 21 Proteins 0.000 claims abstract description 237
- 102100036846 C-C motif chemokine 21 Human genes 0.000 claims abstract description 225
- 239000000203 mixture Substances 0.000 claims abstract description 103
- 102100036842 C-C motif chemokine 19 Human genes 0.000 claims abstract description 92
- 101000713106 Homo sapiens C-C motif chemokine 19 Proteins 0.000 claims abstract description 90
- 210000000630 fibrocyte Anatomy 0.000 claims abstract description 81
- 230000000694 effects Effects 0.000 claims abstract description 79
- 230000003176 fibrotic effect Effects 0.000 claims abstract description 70
- 230000003902 lesion Effects 0.000 claims abstract description 54
- 208000024891 symptom Diseases 0.000 claims abstract description 46
- 230000002401 inhibitory effect Effects 0.000 claims abstract description 26
- 241000124008 Mammalia Species 0.000 claims abstract description 17
- 210000004072 lung Anatomy 0.000 claims description 198
- 208000029523 Interstitial Lung disease Diseases 0.000 claims description 161
- 230000014509 gene expression Effects 0.000 claims description 142
- 230000004761 fibrosis Effects 0.000 claims description 99
- 206010016654 Fibrosis Diseases 0.000 claims description 98
- 239000003814 drug Substances 0.000 claims description 94
- 208000005069 pulmonary fibrosis Diseases 0.000 claims description 93
- 238000011282 treatment Methods 0.000 claims description 82
- 210000001519 tissue Anatomy 0.000 claims description 73
- 208000035475 disorder Diseases 0.000 claims description 63
- 229940079593 drug Drugs 0.000 claims description 62
- 239000003795 chemical substances by application Substances 0.000 claims description 52
- 108020004459 Small interfering RNA Proteins 0.000 claims description 51
- 102000019034 Chemokines Human genes 0.000 claims description 39
- 108010012236 Chemokines Proteins 0.000 claims description 39
- 230000004913 activation Effects 0.000 claims description 39
- 238000004519 manufacturing process Methods 0.000 claims description 27
- 230000000241 respiratory effect Effects 0.000 claims description 25
- 108010006654 Bleomycin Proteins 0.000 claims description 23
- 206010006448 Bronchiolitis Diseases 0.000 claims description 23
- 238000013508 migration Methods 0.000 claims description 23
- 108010037362 Extracellular Matrix Proteins Proteins 0.000 claims description 22
- 230000005012 migration Effects 0.000 claims description 22
- 102000010834 Extracellular Matrix Proteins Human genes 0.000 claims description 21
- 210000002744 extracellular matrix Anatomy 0.000 claims description 19
- 238000002347 injection Methods 0.000 claims description 19
- 239000007924 injection Substances 0.000 claims description 19
- 241001465754 Metazoa Species 0.000 claims description 17
- 206010035664 Pneumonia Diseases 0.000 claims description 17
- 238000001727 in vivo Methods 0.000 claims description 17
- 230000005855 radiation Effects 0.000 claims description 17
- 102000004428 CCR7 Receptors Human genes 0.000 claims description 16
- 108010017158 CCR7 Receptors Proteins 0.000 claims description 16
- 229960001561 bleomycin Drugs 0.000 claims description 16
- OYVAGSVQBOHSSS-UAPAGMARSA-O bleomycin A2 Chemical compound N([C@H](C(=O)N[C@H](C)[C@@H](O)[C@H](C)C(=O)N[C@@H]([C@H](O)C)C(=O)NCCC=1SC=C(N=1)C=1SC=C(N=1)C(=O)NCCC[S+](C)C)[C@@H](O[C@H]1[C@H]([C@@H](O)[C@H](O)[C@H](CO)O1)O[C@@H]1[C@H]([C@@H](OC(N)=O)[C@H](O)[C@@H](CO)O1)O)C=1N=CNC=1)C(=O)C1=NC([C@H](CC(N)=O)NC[C@H](N)C(N)=O)=NC(N)=C1C OYVAGSVQBOHSSS-UAPAGMARSA-O 0.000 claims description 16
- 230000036573 scar formation Effects 0.000 claims description 16
- 230000035755 proliferation Effects 0.000 claims description 15
- 208000019693 Lung disease Diseases 0.000 claims description 13
- 239000002552 dosage form Substances 0.000 claims description 13
- 206010007559 Cardiac failure congestive Diseases 0.000 claims description 12
- 206010019280 Heart failures Diseases 0.000 claims description 12
- 206010064911 Pulmonary arterial hypertension Diseases 0.000 claims description 12
- 201000004409 schistosomiasis Diseases 0.000 claims description 12
- ZPUCINDJVBIVPJ-LJISPDSOSA-N cocaine Chemical compound O([C@H]1C[C@@H]2CC[C@@H](N2C)[C@H]1C(=O)OC)C(=O)C1=CC=CC=C1 ZPUCINDJVBIVPJ-LJISPDSOSA-N 0.000 claims description 11
- 239000003246 corticosteroid Substances 0.000 claims description 11
- 238000001959 radiotherapy Methods 0.000 claims description 11
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 claims description 10
- 208000004248 Familial Primary Pulmonary Hypertension Diseases 0.000 claims description 10
- 206010025135 lupus erythematosus Diseases 0.000 claims description 9
- 201000008312 primary pulmonary hypertension Diseases 0.000 claims description 9
- 206010039073 rheumatoid arthritis Diseases 0.000 claims description 9
- 230000019305 fibroblast migration Effects 0.000 claims description 8
- 241001529453 unidentified herpesvirus Species 0.000 claims description 8
- 208000023275 Autoimmune disease Diseases 0.000 claims description 7
- 206010023330 Keloid scar Diseases 0.000 claims description 7
- 208000016604 Lyme disease Diseases 0.000 claims description 7
- 206010033645 Pancreatitis Diseases 0.000 claims description 7
- 239000003242 anti bacterial agent Substances 0.000 claims description 7
- 229940121363 anti-inflammatory agent Drugs 0.000 claims description 7
- 239000002260 anti-inflammatory agent Substances 0.000 claims description 7
- 229960001334 corticosteroids Drugs 0.000 claims description 7
- 201000002793 renal fibrosis Diseases 0.000 claims description 7
- 208000017520 skin disease Diseases 0.000 claims description 7
- 230000008685 targeting Effects 0.000 claims description 7
- BUJAGSGYPOAWEI-SECBINFHSA-N (2r)-2-amino-n-(2,6-dimethylphenyl)propanamide Chemical compound C[C@@H](N)C(=O)NC1=C(C)C=CC=C1C BUJAGSGYPOAWEI-SECBINFHSA-N 0.000 claims description 6
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 claims description 6
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 claims description 6
- GVGLGOZIDCSQPN-PVHGPHFFSA-N Heroin Chemical compound O([C@H]1[C@H](C=C[C@H]23)OC(C)=O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4OC(C)=O GVGLGOZIDCSQPN-PVHGPHFFSA-N 0.000 claims description 6
- 206010020751 Hypersensitivity Diseases 0.000 claims description 6
- UETNIIAIRMUTSM-UHFFFAOYSA-N Jacareubin Natural products CC1(C)OC2=CC3Oc4c(O)c(O)ccc4C(=O)C3C(=C2C=C1)O UETNIIAIRMUTSM-UHFFFAOYSA-N 0.000 claims description 6
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 claims description 6
- 206010030348 Open-Angle Glaucoma Diseases 0.000 claims description 6
- 206010051657 Ovarian fibrosis Diseases 0.000 claims description 6
- 206010046798 Uterine leiomyoma Diseases 0.000 claims description 6
- 208000026935 allergic disease Diseases 0.000 claims description 6
- 229960002092 busulfan Drugs 0.000 claims description 6
- 208000019425 cirrhosis of liver Diseases 0.000 claims description 6
- 229960004397 cyclophosphamide Drugs 0.000 claims description 6
- 230000003247 decreasing effect Effects 0.000 claims description 6
- 229960002069 diamorphine Drugs 0.000 claims description 6
- 239000000835 fiber Substances 0.000 claims description 6
- 239000003112 inhibitor Substances 0.000 claims description 6
- 201000010260 leiomyoma Diseases 0.000 claims description 6
- 229960000485 methotrexate Drugs 0.000 claims description 6
- OSTGTTZJOCZWJG-UHFFFAOYSA-N nitrosourea Chemical compound NC(=O)N=NO OSTGTTZJOCZWJG-UHFFFAOYSA-N 0.000 claims description 6
- 230000001717 pathogenic effect Effects 0.000 claims description 6
- NCEXYHBECQHGNR-QZQOTICOSA-N sulfasalazine Chemical compound C1=C(O)C(C(=O)O)=CC(\N=N\C=2C=CC(=CC=2)S(=O)(=O)NC=2N=CC=CC=2)=C1 NCEXYHBECQHGNR-QZQOTICOSA-N 0.000 claims description 6
- 229960001940 sulfasalazine Drugs 0.000 claims description 6
- NCEXYHBECQHGNR-UHFFFAOYSA-N sulfasalazine Natural products C1=C(O)C(C(=O)O)=CC(N=NC=2C=CC(=CC=2)S(=O)(=O)NC=2N=CC=CC=2)=C1 NCEXYHBECQHGNR-UHFFFAOYSA-N 0.000 claims description 6
- 229960002872 tocainide Drugs 0.000 claims description 6
- USSIQXCVUWKGNF-UHFFFAOYSA-N 6-(dimethylamino)-4,4-diphenylheptan-3-one Chemical compound C=1C=CC=CC=1C(CC(C)N(C)C)(C(=O)CC)C1=CC=CC=C1 USSIQXCVUWKGNF-UHFFFAOYSA-N 0.000 claims description 5
- APKFDSVGJQXUKY-KKGHZKTASA-N Amphotericin-B Natural products O[C@H]1[C@@H](N)[C@H](O)[C@@H](C)O[C@H]1O[C@H]1C=CC=CC=CC=CC=CC=CC=C[C@H](C)[C@@H](O)[C@@H](C)[C@H](C)OC(=O)C[C@H](O)C[C@H](O)CC[C@@H](O)[C@H](O)C[C@H](O)C[C@](O)(C[C@H](O)[C@H]2C(O)=O)O[C@H]2C1 APKFDSVGJQXUKY-KKGHZKTASA-N 0.000 claims description 5
- DJBNUMBKLMJRSA-UHFFFAOYSA-N Flecainide Chemical compound FC(F)(F)COC1=CC=C(OCC(F)(F)F)C(C(=O)NCC2NCCCC2)=C1 DJBNUMBKLMJRSA-UHFFFAOYSA-N 0.000 claims description 5
- DUGOZIWVEXMGBE-UHFFFAOYSA-N Methylphenidate Chemical compound C=1C=CC=CC=1C(C(=O)OC)C1CCCCN1 DUGOZIWVEXMGBE-UHFFFAOYSA-N 0.000 claims description 5
- CXOFVDLJLONNDW-UHFFFAOYSA-N Phenytoin Chemical compound N1C(=O)NC(=O)C1(C=1C=CC=CC=1)C1=CC=CC=C1 CXOFVDLJLONNDW-UHFFFAOYSA-N 0.000 claims description 5
- 208000019526 Schistosoma mansoni infectious disease Diseases 0.000 claims description 5
- 208000002848 Schistosomiasis mansoni Diseases 0.000 claims description 5
- 229940122803 Vinca alkaloid Drugs 0.000 claims description 5
- APKFDSVGJQXUKY-INPOYWNPSA-N amphotericin B Chemical compound O[C@H]1[C@@H](N)[C@H](O)[C@@H](C)O[C@H]1O[C@H]1/C=C/C=C/C=C/C=C/C=C/C=C/C=C/[C@H](C)[C@@H](O)[C@@H](C)[C@H](C)OC(=O)C[C@H](O)C[C@H](O)CC[C@@H](O)[C@H](O)C[C@H](O)C[C@](O)(C[C@H](O)[C@H]2C(O)=O)O[C@H]2C1 APKFDSVGJQXUKY-INPOYWNPSA-N 0.000 claims description 5
- 229960003942 amphotericin b Drugs 0.000 claims description 5
- 239000003416 antiarrhythmic agent Substances 0.000 claims description 5
- 229940088710 antibiotic agent Drugs 0.000 claims description 5
- OZVBMTJYIDMWIL-AYFBDAFISA-N bromocriptine Chemical compound C1=CC(C=2[C@H](N(C)C[C@@H](C=2)C(=O)N[C@]2(C(=O)N3[C@H](C(N4CCC[C@H]4[C@]3(O)O2)=O)CC(C)C)C(C)C)C2)=C3C2=C(Br)NC3=C1 OZVBMTJYIDMWIL-AYFBDAFISA-N 0.000 claims description 5
- 229960002802 bromocriptine Drugs 0.000 claims description 5
- FFGPTBGBLSHEPO-UHFFFAOYSA-N carbamazepine Chemical compound C1=CC2=CC=CC=C2N(C(=O)N)C2=CC=CC=C21 FFGPTBGBLSHEPO-UHFFFAOYSA-N 0.000 claims description 5
- 229960000623 carbamazepine Drugs 0.000 claims description 5
- 229960004630 chlorambucil Drugs 0.000 claims description 5
- JCKYGMPEJWAADB-UHFFFAOYSA-N chlorambucil Chemical compound OC(=O)CCCC1=CC=C(N(CCCl)CCCl)C=C1 JCKYGMPEJWAADB-UHFFFAOYSA-N 0.000 claims description 5
- 208000020832 chronic kidney disease Diseases 0.000 claims description 5
- 229960003920 cocaine Drugs 0.000 claims description 5
- 238000011161 development Methods 0.000 claims description 5
- 229960004943 ergotamine Drugs 0.000 claims description 5
- OFKDAAIKGIBASY-VFGNJEKYSA-N ergotamine Chemical compound C([C@H]1C(=O)N2CCC[C@H]2[C@]2(O)O[C@@](C(N21)=O)(C)NC(=O)[C@H]1CN([C@H]2C(C3=CC=CC4=NC=C([C]34)C2)=C1)C)C1=CC=CC=C1 OFKDAAIKGIBASY-VFGNJEKYSA-N 0.000 claims description 5
- XCGSFFUVFURLIX-UHFFFAOYSA-N ergotaminine Natural products C1=C(C=2C=CC=C3NC=C(C=23)C2)C2N(C)CC1C(=O)NC(C(N12)=O)(C)OC1(O)C1CCCN1C(=O)C2CC1=CC=CC=C1 XCGSFFUVFURLIX-UHFFFAOYSA-N 0.000 claims description 5
- 229960000449 flecainide Drugs 0.000 claims description 5
- 230000009610 hypersensitivity Effects 0.000 claims description 5
- 239000003018 immunosuppressive agent Substances 0.000 claims description 5
- 229960001924 melphalan Drugs 0.000 claims description 5
- SGDBTWWWUNNDEQ-LBPRGKRZSA-N melphalan Chemical compound OC(=O)[C@@H](N)CC1=CC=C(N(CCCl)CCCl)C=C1 SGDBTWWWUNNDEQ-LBPRGKRZSA-N 0.000 claims description 5
- 229960001797 methadone Drugs 0.000 claims description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 5
- 229960001344 methylphenidate Drugs 0.000 claims description 5
- 239000002480 mineral oil Substances 0.000 claims description 5
- 235000010446 mineral oil Nutrition 0.000 claims description 5
- 229960002036 phenytoin Drugs 0.000 claims description 5
- 229920001296 polysiloxane Polymers 0.000 claims description 5
- CPTBDICYNRMXFX-UHFFFAOYSA-N procarbazine Chemical compound CNNCC1=CC=C(C(=O)NC(C)C)C=C1 CPTBDICYNRMXFX-UHFFFAOYSA-N 0.000 claims description 5
- 229960000624 procarbazine Drugs 0.000 claims description 5
- 229940127291 Calcium channel antagonist Drugs 0.000 claims description 4
- 208000019532 Schistosoma japonicum infectious disease Diseases 0.000 claims description 4
- 208000009434 Schistosomiasis japonica Diseases 0.000 claims description 4
- 239000003146 anticoagulant agent Substances 0.000 claims description 4
- 229940127219 anticoagulant drug Drugs 0.000 claims description 4
- 239000003524 antilipemic agent Substances 0.000 claims description 4
- 239000000480 calcium channel blocker Substances 0.000 claims description 4
- 229940097217 cardiac glycoside Drugs 0.000 claims description 4
- 239000002368 cardiac glycoside Substances 0.000 claims description 4
- 239000002934 diuretic Substances 0.000 claims description 4
- 229960003444 immunosuppressant agent Drugs 0.000 claims description 4
- 238000000338 in vitro Methods 0.000 claims description 4
- 201000006675 intestinal schistosomiasis Diseases 0.000 claims description 4
- 239000002571 phosphodiesterase inhibitor Substances 0.000 claims description 4
- 150000003815 prostacyclins Chemical class 0.000 claims description 4
- 229930002534 steroid glycoside Natural products 0.000 claims description 4
- RZWIIPASKMUIAC-VQTJNVASSA-N thromboxane Chemical compound CCCCCCCC[C@H]1OCCC[C@@H]1CCCCCCC RZWIIPASKMUIAC-VQTJNVASSA-N 0.000 claims description 4
- 238000011200 topical administration Methods 0.000 claims description 4
- 229940124549 vasodilator Drugs 0.000 claims description 4
- 239000003071 vasodilator agent Substances 0.000 claims description 4
- 229940097420 Diuretic Drugs 0.000 claims description 3
- 238000012084 abdominal surgery Methods 0.000 claims description 3
- 231100000433 cytotoxic Toxicity 0.000 claims description 3
- 230000001472 cytotoxic effect Effects 0.000 claims description 3
- 230000001882 diuretic effect Effects 0.000 claims description 3
- 239000003149 muscarinic antagonist Substances 0.000 claims description 3
- LPMXVESGRSUGHW-HBYQJFLCSA-N ouabain Chemical compound O[C@@H]1[C@H](O)[C@@H](O)[C@H](C)O[C@H]1O[C@@H]1C[C@@]2(O)CC[C@H]3[C@@]4(O)CC[C@H](C=5COC(=O)C=5)[C@@]4(C)C[C@@H](O)[C@@H]3[C@@]2(CO)[C@H](O)C1 LPMXVESGRSUGHW-HBYQJFLCSA-N 0.000 claims description 3
- 229940124143 Endopeptidase inhibitor Drugs 0.000 claims description 2
- 102000002045 Endothelin Human genes 0.000 claims description 2
- 108050009340 Endothelin Proteins 0.000 claims description 2
- 229940099471 Phosphodiesterase inhibitor Drugs 0.000 claims description 2
- 239000005557 antagonist Substances 0.000 claims description 2
- 229940082638 cardiac stimulant phosphodiesterase inhibitors Drugs 0.000 claims description 2
- 239000002308 endothelin receptor antagonist Substances 0.000 claims description 2
- ZUBDGKVDJUIMQQ-UBFCDGJISA-N endothelin-1 Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(O)=O)NC(=O)[C@H]1NC(=O)[C@H](CC=2C=CC=CC=2)NC(=O)[C@@H](CC=2C=CC(O)=CC=2)NC(=O)[C@H](C(C)C)NC(=O)[C@H]2CSSC[C@@H](C(N[C@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)N[C@H](CC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(O)=O)C(=O)N2)=O)NC(=O)[C@@H](CO)NC(=O)[C@H](N)CSSC1)C1=CNC=N1 ZUBDGKVDJUIMQQ-UBFCDGJISA-N 0.000 claims description 2
- 230000001861 immunosuppressant effect Effects 0.000 claims description 2
- 208000028867 ischemia Diseases 0.000 claims description 2
- 239000000137 peptide hydrolase inhibitor Substances 0.000 claims description 2
- 239000000556 agonist Substances 0.000 claims 2
- 230000002980 postoperative effect Effects 0.000 claims 2
- 229940030606 diuretics Drugs 0.000 claims 1
- 229910052738 indium Inorganic materials 0.000 claims 1
- APFVFJFRJDLVQX-UHFFFAOYSA-N indium atom Chemical compound [In] APFVFJFRJDLVQX-UHFFFAOYSA-N 0.000 claims 1
- 150000008143 steroidal glycosides Chemical class 0.000 claims 1
- 208000036971 interstitial lung disease 2 Diseases 0.000 description 381
- 201000009794 Idiopathic Pulmonary Fibrosis Diseases 0.000 description 147
- 201000004071 non-specific interstitial pneumonia Diseases 0.000 description 125
- 241000699670 Mus sp. Species 0.000 description 113
- 210000004027 cell Anatomy 0.000 description 83
- 238000001574 biopsy Methods 0.000 description 76
- 108090000623 proteins and genes Proteins 0.000 description 74
- 238000004458 analytical method Methods 0.000 description 49
- 102000004169 proteins and genes Human genes 0.000 description 43
- 230000001965 increasing effect Effects 0.000 description 40
- 239000004055 small Interfering RNA Substances 0.000 description 40
- 238000012546 transfer Methods 0.000 description 39
- 102000008186 Collagen Human genes 0.000 description 37
- 108010035532 Collagen Proteins 0.000 description 37
- 229920001436 collagen Polymers 0.000 description 37
- 239000003446 ligand Substances 0.000 description 37
- 101000922348 Homo sapiens C-X-C chemokine receptor type 4 Proteins 0.000 description 34
- 230000001225 therapeutic effect Effects 0.000 description 34
- 102100031650 C-X-C chemokine receptor type 4 Human genes 0.000 description 33
- 241000699666 Mus <mouse, genus> Species 0.000 description 28
- 241001529936 Murinae Species 0.000 description 27
- 206010028980 Neoplasm Diseases 0.000 description 27
- 238000002474 experimental method Methods 0.000 description 25
- 230000004044 response Effects 0.000 description 25
- PMMYEEVYMWASQN-DMTCNVIQSA-N Hydroxyproline Chemical compound O[C@H]1CN[C@H](C(O)=O)C1 PMMYEEVYMWASQN-DMTCNVIQSA-N 0.000 description 24
- PMMYEEVYMWASQN-UHFFFAOYSA-N dl-hydroxyproline Natural products OC1C[NH2+]C(C([O-])=O)C1 PMMYEEVYMWASQN-UHFFFAOYSA-N 0.000 description 24
- 229960002591 hydroxyproline Drugs 0.000 description 24
- FGMPLJWBKKVCDB-UHFFFAOYSA-N trans-L-hydroxy-proline Natural products ON1CCCC1C(O)=O FGMPLJWBKKVCDB-UHFFFAOYSA-N 0.000 description 24
- 102000009410 Chemokine receptor Human genes 0.000 description 23
- 108050000299 Chemokine receptor Proteins 0.000 description 23
- 102000019149 MAP kinase activity proteins Human genes 0.000 description 23
- 108040008097 MAP kinase activity proteins Proteins 0.000 description 23
- 230000026731 phosphorylation Effects 0.000 description 23
- 238000006366 phosphorylation reaction Methods 0.000 description 23
- 239000000523 sample Substances 0.000 description 23
- 238000010186 staining Methods 0.000 description 23
- 101000738771 Homo sapiens Receptor-type tyrosine-protein phosphatase C Proteins 0.000 description 19
- 102100037422 Receptor-type tyrosine-protein phosphatase C Human genes 0.000 description 19
- 108020004445 glyceraldehyde-3-phosphate dehydrogenase Proteins 0.000 description 19
- 102000006602 glyceraldehyde-3-phosphate dehydrogenase Human genes 0.000 description 19
- 238000007634 remodeling Methods 0.000 description 19
- 102100031573 Hematopoietic progenitor cell antigen CD34 Human genes 0.000 description 18
- 101000777663 Homo sapiens Hematopoietic progenitor cell antigen CD34 Proteins 0.000 description 18
- 102000005962 receptors Human genes 0.000 description 18
- 108020003175 receptors Proteins 0.000 description 18
- 238000002560 therapeutic procedure Methods 0.000 description 18
- 102000004127 Cytokines Human genes 0.000 description 16
- 108090000695 Cytokines Proteins 0.000 description 16
- 102000043839 human CCR7 Human genes 0.000 description 15
- 238000011579 SCID mouse model Methods 0.000 description 14
- 230000009471 action Effects 0.000 description 14
- 230000002829 reductive effect Effects 0.000 description 14
- 101000716065 Homo sapiens C-C chemokine receptor type 7 Proteins 0.000 description 13
- 230000015572 biosynthetic process Effects 0.000 description 13
- 210000001185 bone marrow Anatomy 0.000 description 13
- 230000037361 pathway Effects 0.000 description 13
- 239000000243 solution Substances 0.000 description 13
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 12
- 238000002965 ELISA Methods 0.000 description 12
- 238000003556 assay Methods 0.000 description 12
- 102000043711 human CCL21 Human genes 0.000 description 12
- 210000000651 myofibroblast Anatomy 0.000 description 12
- 238000002360 preparation method Methods 0.000 description 12
- 230000009696 proliferative response Effects 0.000 description 12
- 101150049756 CCL6 gene Proteins 0.000 description 11
- 108090000176 Interleukin-13 Proteins 0.000 description 11
- 102100021669 Stromal cell-derived factor 1 Human genes 0.000 description 11
- 208000027418 Wounds and injury Diseases 0.000 description 11
- 230000008859 change Effects 0.000 description 11
- 238000002991 immunohistochemical analysis Methods 0.000 description 11
- 210000005087 mononuclear cell Anatomy 0.000 description 11
- 101000617130 Homo sapiens Stromal cell-derived factor 1 Proteins 0.000 description 10
- 229940124647 MEK inhibitor Drugs 0.000 description 10
- 102100031480 Dual specificity mitogen-activated protein kinase kinase 1 Human genes 0.000 description 9
- 101710146526 Dual specificity mitogen-activated protein kinase kinase 1 Proteins 0.000 description 9
- 108091054455 MAP kinase family Proteins 0.000 description 9
- 102000043136 MAP kinase family Human genes 0.000 description 9
- 108090000587 Matrix metalloproteinase-19 Proteins 0.000 description 9
- 102000004055 Matrix metalloproteinase-19 Human genes 0.000 description 9
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 9
- 230000008569 process Effects 0.000 description 9
- 241000282412 Homo Species 0.000 description 8
- 108010081690 Pertussis Toxin Proteins 0.000 description 8
- 206010052428 Wound Diseases 0.000 description 8
- 230000007423 decrease Effects 0.000 description 8
- 208000015181 infectious disease Diseases 0.000 description 8
- 238000001990 intravenous administration Methods 0.000 description 8
- 239000003550 marker Substances 0.000 description 8
- 230000002685 pulmonary effect Effects 0.000 description 8
- WUIABRMSWOKTOF-OYALTWQYSA-N 3-[[2-[2-[2-[[(2s,3r)-2-[[(2s,3s,4r)-4-[[(2s,3r)-2-[[6-amino-2-[(1s)-3-amino-1-[[(2s)-2,3-diamino-3-oxopropyl]amino]-3-oxopropyl]-5-methylpyrimidine-4-carbonyl]amino]-3-[(2r,3s,4s,5s,6s)-3-[(2r,3s,4s,5r,6r)-4-carbamoyloxy-3,5-dihydroxy-6-(hydroxymethyl)ox Chemical compound OS([O-])(=O)=O.N([C@H](C(=O)N[C@H](C)[C@@H](O)[C@H](C)C(=O)N[C@@H]([C@H](O)C)C(=O)NCCC=1SC=C(N=1)C=1SC=C(N=1)C(=O)NCCC[S+](C)C)[C@@H](O[C@H]1[C@H]([C@@H](O)[C@H](O)[C@H](CO)O1)O[C@@H]1[C@H]([C@@H](OC(N)=O)[C@H](O)[C@@H](CO)O1)O)C=1NC=NC=1)C(=O)C1=NC([C@H](CC(N)=O)NC[C@H](N)C(N)=O)=NC(N)=C1C WUIABRMSWOKTOF-OYALTWQYSA-N 0.000 description 7
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 7
- 108091007433 antigens Proteins 0.000 description 7
- 102000036639 antigens Human genes 0.000 description 7
- 229960004395 bleomycin sulfate Drugs 0.000 description 7
- 238000006243 chemical reaction Methods 0.000 description 7
- 230000001419 dependent effect Effects 0.000 description 7
- 238000011081 inoculation Methods 0.000 description 7
- 230000003993 interaction Effects 0.000 description 7
- 210000000056 organ Anatomy 0.000 description 7
- 238000003753 real-time PCR Methods 0.000 description 7
- 238000011160 research Methods 0.000 description 7
- 229940124597 therapeutic agent Drugs 0.000 description 7
- 241000283707 Capra Species 0.000 description 6
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 6
- 102000002274 Matrix Metalloproteinases Human genes 0.000 description 6
- 108010000684 Matrix Metalloproteinases Proteins 0.000 description 6
- 230000002159 abnormal effect Effects 0.000 description 6
- 238000010171 animal model Methods 0.000 description 6
- 239000000427 antigen Substances 0.000 description 6
- 210000000038 chest Anatomy 0.000 description 6
- 238000001514 detection method Methods 0.000 description 6
- 238000003500 gene array Methods 0.000 description 6
- 150000007523 nucleic acids Chemical group 0.000 description 6
- 239000008194 pharmaceutical composition Substances 0.000 description 6
- 239000002953 phosphate buffered saline Substances 0.000 description 6
- 230000002062 proliferating effect Effects 0.000 description 6
- 208000002815 pulmonary hypertension Diseases 0.000 description 6
- 150000003839 salts Chemical class 0.000 description 6
- 210000003491 skin Anatomy 0.000 description 6
- 239000011780 sodium chloride Substances 0.000 description 6
- 238000003786 synthesis reaction Methods 0.000 description 6
- 238000001262 western blot Methods 0.000 description 6
- 102100026802 72 kDa type IV collagenase Human genes 0.000 description 5
- 101710151806 72 kDa type IV collagenase Proteins 0.000 description 5
- 208000026310 Breast neoplasm Diseases 0.000 description 5
- 102100037362 Fibronectin Human genes 0.000 description 5
- 108010067306 Fibronectins Proteins 0.000 description 5
- 101000797762 Homo sapiens C-C motif chemokine 5 Proteins 0.000 description 5
- 201000003838 Idiopathic interstitial pneumonia Diseases 0.000 description 5
- 206010061218 Inflammation Diseases 0.000 description 5
- 210000001744 T-lymphocyte Anatomy 0.000 description 5
- 239000004480 active ingredient Substances 0.000 description 5
- 230000009286 beneficial effect Effects 0.000 description 5
- 201000011510 cancer Diseases 0.000 description 5
- 230000006378 damage Effects 0.000 description 5
- 230000004069 differentiation Effects 0.000 description 5
- 239000006185 dispersion Substances 0.000 description 5
- 239000003937 drug carrier Substances 0.000 description 5
- 230000002055 immunohistochemical effect Effects 0.000 description 5
- 230000004054 inflammatory process Effects 0.000 description 5
- 230000035772 mutation Effects 0.000 description 5
- 230000007115 recruitment Effects 0.000 description 5
- 201000000306 sarcoidosis Diseases 0.000 description 5
- 239000006228 supernatant Substances 0.000 description 5
- 238000012384 transportation and delivery Methods 0.000 description 5
- 108091008927 CC chemokine receptors Proteins 0.000 description 4
- 101150044533 CCL19 gene Proteins 0.000 description 4
- 101150040382 CCL21 gene Proteins 0.000 description 4
- 102000005674 CCR Receptors Human genes 0.000 description 4
- 101150037720 CCR7 gene Proteins 0.000 description 4
- 241000282472 Canis lupus familiaris Species 0.000 description 4
- DLGOEMSEDOSKAD-UHFFFAOYSA-N Carmustine Chemical compound ClCCNC(=O)N(N=O)CCCl DLGOEMSEDOSKAD-UHFFFAOYSA-N 0.000 description 4
- 108090000611 Cathepsin E Proteins 0.000 description 4
- 102000004178 Cathepsin E Human genes 0.000 description 4
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 4
- 101100005546 Homo sapiens CCL19 gene Proteins 0.000 description 4
- 108010055717 JNK Mitogen-Activated Protein Kinases Proteins 0.000 description 4
- 108010015302 Matrix metalloproteinase-9 Proteins 0.000 description 4
- 102100030412 Matrix metalloproteinase-9 Human genes 0.000 description 4
- 102100039364 Metalloproteinase inhibitor 1 Human genes 0.000 description 4
- 108091028043 Nucleic acid sequence Proteins 0.000 description 4
- 238000010222 PCR analysis Methods 0.000 description 4
- 241000700159 Rattus Species 0.000 description 4
- 206010039710 Scleroderma Diseases 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- 102100040247 Tumor necrosis factor Human genes 0.000 description 4
- 230000000844 anti-bacterial effect Effects 0.000 description 4
- -1 antibiotic Substances 0.000 description 4
- 239000011324 bead Substances 0.000 description 4
- 210000004204 blood vessel Anatomy 0.000 description 4
- 239000000872 buffer Substances 0.000 description 4
- 229960005243 carmustine Drugs 0.000 description 4
- 239000002299 complementary DNA Substances 0.000 description 4
- 150000001875 compounds Chemical class 0.000 description 4
- 210000004443 dendritic cell Anatomy 0.000 description 4
- 230000018109 developmental process Effects 0.000 description 4
- 238000003745 diagnosis Methods 0.000 description 4
- 239000002612 dispersion medium Substances 0.000 description 4
- 230000006870 function Effects 0.000 description 4
- 230000036541 health Effects 0.000 description 4
- 210000002865 immune cell Anatomy 0.000 description 4
- 230000006698 induction Effects 0.000 description 4
- 230000002757 inflammatory effect Effects 0.000 description 4
- 238000010253 intravenous injection Methods 0.000 description 4
- 210000003734 kidney Anatomy 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 210000004185 liver Anatomy 0.000 description 4
- 210000002540 macrophage Anatomy 0.000 description 4
- 230000001617 migratory effect Effects 0.000 description 4
- 238000007479 molecular analysis Methods 0.000 description 4
- 210000001616 monocyte Anatomy 0.000 description 4
- NXFQHRVNIOXGAQ-YCRREMRBSA-N nitrofurantoin Chemical compound O1C([N+](=O)[O-])=CC=C1\C=N\N1C(=O)NC(=O)C1 NXFQHRVNIOXGAQ-YCRREMRBSA-N 0.000 description 4
- 229960000564 nitrofurantoin Drugs 0.000 description 4
- 239000002773 nucleotide Substances 0.000 description 4
- 125000003729 nucleotide group Chemical group 0.000 description 4
- 230000001575 pathological effect Effects 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 238000001356 surgical procedure Methods 0.000 description 4
- 230000004083 survival effect Effects 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- MZOFCQQQCNRIBI-VMXHOPILSA-N (3s)-4-[[(2s)-1-[[(2s)-1-[[(1s)-1-carboxy-2-hydroxyethyl]amino]-4-methyl-1-oxopentan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-3-[[2-[[(2s)-2,6-diaminohexanoyl]amino]acetyl]amino]-4-oxobutanoic acid Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CC(O)=O)NC(=O)CNC(=O)[C@@H](N)CCCCN MZOFCQQQCNRIBI-VMXHOPILSA-N 0.000 description 3
- 206010000050 Abdominal adhesions Diseases 0.000 description 3
- 102000007469 Actins Human genes 0.000 description 3
- 108010085238 Actins Proteins 0.000 description 3
- 206010002091 Anaesthesia Diseases 0.000 description 3
- 241000283690 Bos taurus Species 0.000 description 3
- 206010006187 Breast cancer Diseases 0.000 description 3
- 102100032367 C-C motif chemokine 5 Human genes 0.000 description 3
- 241001647372 Chlamydia pneumoniae Species 0.000 description 3
- 241000283086 Equidae Species 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- 241000282326 Felis catus Species 0.000 description 3
- 108091006027 G proteins Proteins 0.000 description 3
- 102000034286 G proteins Human genes 0.000 description 3
- 108091000058 GTP-Binding Proteins 0.000 description 3
- 102100037850 Interferon gamma Human genes 0.000 description 3
- 108010074328 Interferon-gamma Proteins 0.000 description 3
- 241000283973 Oryctolagus cuniculus Species 0.000 description 3
- 108091000080 Phosphotransferase Proteins 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 241000288906 Primates Species 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 238000012228 RNA interference-mediated gene silencing Methods 0.000 description 3
- 102000007056 Recombinant Fusion Proteins Human genes 0.000 description 3
- 108010008281 Recombinant Fusion Proteins Proteins 0.000 description 3
- 206010039580 Scar Diseases 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 241000282887 Suidae Species 0.000 description 3
- 108010031374 Tissue Inhibitor of Metalloproteinase-1 Proteins 0.000 description 3
- 108091023040 Transcription factor Proteins 0.000 description 3
- 102000040945 Transcription factor Human genes 0.000 description 3
- 108060008682 Tumor Necrosis Factor Proteins 0.000 description 3
- 230000003213 activating effect Effects 0.000 description 3
- 230000037005 anaesthesia Effects 0.000 description 3
- 229940121375 antifungal agent Drugs 0.000 description 3
- 239000003429 antifungal agent Substances 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 208000006673 asthma Diseases 0.000 description 3
- 229960002170 azathioprine Drugs 0.000 description 3
- LMEKQMALGUDUQG-UHFFFAOYSA-N azathioprine Chemical compound CN1C=NC([N+]([O-])=O)=C1SC1=NC=NC2=C1NC=N2 LMEKQMALGUDUQG-UHFFFAOYSA-N 0.000 description 3
- 238000012742 biochemical analysis Methods 0.000 description 3
- 230000012292 cell migration Effects 0.000 description 3
- 230000007881 chronic fibrosis Effects 0.000 description 3
- 238000000576 coating method Methods 0.000 description 3
- 238000002648 combination therapy Methods 0.000 description 3
- 230000007547 defect Effects 0.000 description 3
- 239000000428 dust Substances 0.000 description 3
- 230000007705 epithelial mesenchymal transition Effects 0.000 description 3
- 239000007789 gas Substances 0.000 description 3
- 230000009368 gene silencing by RNA Effects 0.000 description 3
- 208000035474 group of disease Diseases 0.000 description 3
- 230000012010 growth Effects 0.000 description 3
- 210000003958 hematopoietic stem cell Anatomy 0.000 description 3
- 238000003364 immunohistochemistry Methods 0.000 description 3
- 239000003547 immunosorbent Substances 0.000 description 3
- 239000004615 ingredient Substances 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- 230000000977 initiatory effect Effects 0.000 description 3
- 208000014674 injury Diseases 0.000 description 3
- 239000007951 isotonicity adjuster Substances 0.000 description 3
- 230000004199 lung function Effects 0.000 description 3
- 238000005399 mechanical ventilation Methods 0.000 description 3
- 230000001404 mediated effect Effects 0.000 description 3
- 108020004999 messenger RNA Proteins 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 210000003205 muscle Anatomy 0.000 description 3
- 108010068338 p38 Mitogen-Activated Protein Kinases Proteins 0.000 description 3
- 102000002574 p38 Mitogen-Activated Protein Kinases Human genes 0.000 description 3
- 230000008506 pathogenesis Effects 0.000 description 3
- 230000007170 pathology Effects 0.000 description 3
- 210000005259 peripheral blood Anatomy 0.000 description 3
- 239000011886 peripheral blood Substances 0.000 description 3
- 230000002688 persistence Effects 0.000 description 3
- 102000020233 phosphotransferase Human genes 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 229960004618 prednisone Drugs 0.000 description 3
- XOFYZVNMUHMLCC-ZPOLXVRWSA-N prednisone Chemical compound O=C1C=C[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 XOFYZVNMUHMLCC-ZPOLXVRWSA-N 0.000 description 3
- 230000002206 pro-fibrotic effect Effects 0.000 description 3
- 230000008439 repair process Effects 0.000 description 3
- 230000029058 respiratory gaseous exchange Effects 0.000 description 3
- 230000004043 responsiveness Effects 0.000 description 3
- 210000002966 serum Anatomy 0.000 description 3
- 239000013595 supernatant sample Substances 0.000 description 3
- 239000004094 surface-active agent Substances 0.000 description 3
- 208000011580 syndromic disease Diseases 0.000 description 3
- 230000036962 time dependent Effects 0.000 description 3
- 231100000331 toxic Toxicity 0.000 description 3
- 230000002588 toxic effect Effects 0.000 description 3
- 238000001890 transfection Methods 0.000 description 3
- 238000009423 ventilation Methods 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- 102000040650 (ribonucleotides)n+m Human genes 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- 206010067484 Adverse reaction Diseases 0.000 description 2
- 241000272517 Anseriformes Species 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 241000894006 Bacteria Species 0.000 description 2
- 206010004485 Berylliosis Diseases 0.000 description 2
- 238000009010 Bradford assay Methods 0.000 description 2
- 102100032366 C-C motif chemokine 7 Human genes 0.000 description 2
- 102000001902 CC Chemokines Human genes 0.000 description 2
- 108010040471 CC Chemokines Proteins 0.000 description 2
- 102000005600 Cathepsins Human genes 0.000 description 2
- 108010084457 Cathepsins Proteins 0.000 description 2
- 208000002330 Congenital Heart Defects Diseases 0.000 description 2
- 241000702421 Dependoparvovirus Species 0.000 description 2
- 241000196324 Embryophyta Species 0.000 description 2
- 108010043121 Green Fluorescent Proteins Proteins 0.000 description 2
- 102000004144 Green Fluorescent Proteins Human genes 0.000 description 2
- WZUVPPKBWHMQCE-UHFFFAOYSA-N Haematoxylin Chemical compound C12=CC(O)=C(O)C=C2CC2(O)C1C1=CC=C(O)C(O)=C1OC2 WZUVPPKBWHMQCE-UHFFFAOYSA-N 0.000 description 2
- XLYOFNOQVPJJNP-ZSJDYOACSA-N Heavy water Chemical compound [2H]O[2H] XLYOFNOQVPJJNP-ZSJDYOACSA-N 0.000 description 2
- 101000797758 Homo sapiens C-C motif chemokine 7 Proteins 0.000 description 2
- 101100005556 Homo sapiens CCL21 gene Proteins 0.000 description 2
- 101100005656 Homo sapiens CCR7 gene Proteins 0.000 description 2
- 102000013462 Interleukin-12 Human genes 0.000 description 2
- 108010065805 Interleukin-12 Proteins 0.000 description 2
- 108090000744 Mitogen-Activated Protein Kinase Kinases Proteins 0.000 description 2
- 102000004232 Mitogen-Activated Protein Kinase Kinases Human genes 0.000 description 2
- 208000004221 Multiple Trauma Diseases 0.000 description 2
- 241001494479 Pecora Species 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- 238000002123 RNA extraction Methods 0.000 description 2
- 241000700584 Simplexvirus Species 0.000 description 2
- 230000003187 abdominal effect Effects 0.000 description 2
- 239000003070 absorption delaying agent Substances 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 238000009825 accumulation Methods 0.000 description 2
- 230000002411 adverse Effects 0.000 description 2
- 230000006838 adverse reaction Effects 0.000 description 2
- 239000000443 aerosol Substances 0.000 description 2
- 230000000172 allergic effect Effects 0.000 description 2
- 230000003321 amplification Effects 0.000 description 2
- 230000003110 anti-inflammatory effect Effects 0.000 description 2
- 230000000692 anti-sense effect Effects 0.000 description 2
- 238000013459 approach Methods 0.000 description 2
- 239000010425 asbestos Substances 0.000 description 2
- 208000010668 atopic eczema Diseases 0.000 description 2
- 210000003719 b-lymphocyte Anatomy 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 229940124748 beta 2 agonist Drugs 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 238000004113 cell culture Methods 0.000 description 2
- 230000003915 cell function Effects 0.000 description 2
- 230000010261 cell growth Effects 0.000 description 2
- 238000001516 cell proliferation assay Methods 0.000 description 2
- 230000001413 cellular effect Effects 0.000 description 2
- 230000005754 cellular signaling Effects 0.000 description 2
- 238000012512 characterization method Methods 0.000 description 2
- OSASVXMJTNOKOY-UHFFFAOYSA-N chlorobutanol Chemical compound CC(C)(O)C(Cl)(Cl)Cl OSASVXMJTNOKOY-UHFFFAOYSA-N 0.000 description 2
- 208000028831 congenital heart disease Diseases 0.000 description 2
- 210000002808 connective tissue Anatomy 0.000 description 2
- 210000001151 cytotoxic T lymphocyte Anatomy 0.000 description 2
- 229940127089 cytotoxic agent Drugs 0.000 description 2
- 239000002254 cytotoxic agent Substances 0.000 description 2
- 230000008021 deposition Effects 0.000 description 2
- 238000010586 diagram Methods 0.000 description 2
- 238000002651 drug therapy Methods 0.000 description 2
- 230000007613 environmental effect Effects 0.000 description 2
- 230000002255 enzymatic effect Effects 0.000 description 2
- 210000002919 epithelial cell Anatomy 0.000 description 2
- 210000000981 epithelium Anatomy 0.000 description 2
- 238000011156 evaluation Methods 0.000 description 2
- 230000003328 fibroblastic effect Effects 0.000 description 2
- 230000009791 fibrotic reaction Effects 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 239000012634 fragment Substances 0.000 description 2
- 230000030279 gene silencing Effects 0.000 description 2
- 238000012226 gene silencing method Methods 0.000 description 2
- 239000005090 green fluorescent protein Substances 0.000 description 2
- 210000002443 helper t lymphocyte Anatomy 0.000 description 2
- 102000045341 human CCL5 Human genes 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- 238000011534 incubation Methods 0.000 description 2
- 108700016226 indium-bleomycin Proteins 0.000 description 2
- 230000002458 infectious effect Effects 0.000 description 2
- 239000010954 inorganic particle Substances 0.000 description 2
- 238000007918 intramuscular administration Methods 0.000 description 2
- 238000007912 intraperitoneal administration Methods 0.000 description 2
- 230000005865 ionizing radiation Effects 0.000 description 2
- 210000004731 jugular vein Anatomy 0.000 description 2
- 230000007774 longterm Effects 0.000 description 2
- 210000005265 lung cell Anatomy 0.000 description 2
- 208000020816 lung neoplasm Diseases 0.000 description 2
- 208000037841 lung tumor Diseases 0.000 description 2
- 210000001165 lymph node Anatomy 0.000 description 2
- 239000012139 lysis buffer Substances 0.000 description 2
- 201000001441 melanoma Diseases 0.000 description 2
- 239000012528 membrane Substances 0.000 description 2
- 206010061289 metastatic neoplasm Diseases 0.000 description 2
- 244000005700 microbiome Species 0.000 description 2
- 238000010232 migration assay Methods 0.000 description 2
- 238000010172 mouse model Methods 0.000 description 2
- RTGDFNSFWBGLEC-SYZQJQIISA-N mycophenolate mofetil Chemical compound COC1=C(C)C=2COC(=O)C=2C(O)=C1C\C=C(/C)CCC(=O)OCCN1CCOCC1 RTGDFNSFWBGLEC-SYZQJQIISA-N 0.000 description 2
- 229960004866 mycophenolate mofetil Drugs 0.000 description 2
- 210000000822 natural killer cell Anatomy 0.000 description 2
- 238000003199 nucleic acid amplification method Methods 0.000 description 2
- 102000039446 nucleic acids Human genes 0.000 description 2
- 108020004707 nucleic acids Proteins 0.000 description 2
- 239000011146 organic particle Substances 0.000 description 2
- 239000007800 oxidant agent Substances 0.000 description 2
- 230000001590 oxidative effect Effects 0.000 description 2
- 238000007911 parenteral administration Methods 0.000 description 2
- 238000002823 phage display Methods 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 230000008488 polyadenylation Effects 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 238000003752 polymerase chain reaction Methods 0.000 description 2
- 238000000575 proteomic method Methods 0.000 description 2
- 208000014731 pulmonary artery disease Diseases 0.000 description 2
- 210000004879 pulmonary tissue Anatomy 0.000 description 2
- 238000002601 radiography Methods 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- 210000002345 respiratory system Anatomy 0.000 description 2
- 238000003757 reverse transcription PCR Methods 0.000 description 2
- 229910052895 riebeckite Inorganic materials 0.000 description 2
- 208000037812 secondary pulmonary hypertension Diseases 0.000 description 2
- 108091006024 signal transducing proteins Proteins 0.000 description 2
- 102000034285 signal transducing proteins Human genes 0.000 description 2
- 230000019491 signal transduction Effects 0.000 description 2
- 239000000377 silicon dioxide Substances 0.000 description 2
- 210000002460 smooth muscle Anatomy 0.000 description 2
- 241000894007 species Species 0.000 description 2
- 210000000952 spleen Anatomy 0.000 description 2
- 239000008174 sterile solution Substances 0.000 description 2
- 238000003860 storage Methods 0.000 description 2
- 210000002536 stromal cell Anatomy 0.000 description 2
- 238000007920 subcutaneous administration Methods 0.000 description 2
- 230000009885 systemic effect Effects 0.000 description 2
- 230000000451 tissue damage Effects 0.000 description 2
- 231100000827 tissue damage Toxicity 0.000 description 2
- 230000017423 tissue regeneration Effects 0.000 description 2
- 238000002054 transplantation Methods 0.000 description 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- 210000004881 tumor cell Anatomy 0.000 description 2
- 230000003827 upregulation Effects 0.000 description 2
- 239000013598 vector Substances 0.000 description 2
- QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical compound O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-N 0.000 description 1
- LJRDOKAZOAKLDU-UDXJMMFXSA-N (2s,3s,4r,5r,6r)-5-amino-2-(aminomethyl)-6-[(2r,3s,4r,5s)-5-[(1r,2r,3s,5r,6s)-3,5-diamino-2-[(2s,3r,4r,5s,6r)-3-amino-4,5-dihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-6-hydroxycyclohexyl]oxy-4-hydroxy-2-(hydroxymethyl)oxolan-3-yl]oxyoxane-3,4-diol;sulfuric ac Chemical compound OS(O)(=O)=O.N[C@@H]1[C@@H](O)[C@H](O)[C@H](CN)O[C@@H]1O[C@H]1[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](N)C[C@@H](N)[C@@H]2O)O[C@@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)N)O[C@@H]1CO LJRDOKAZOAKLDU-UDXJMMFXSA-N 0.000 description 1
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 1
- ZKRFOXLVOKTUTA-KQYNXXCUSA-N 9-(5-phosphoribofuranosyl)-6-mercaptopurine Chemical compound O[C@@H]1[C@H](O)[C@@H](COP(O)(O)=O)O[C@H]1N1C(NC=NC2=S)=C2N=C1 ZKRFOXLVOKTUTA-KQYNXXCUSA-N 0.000 description 1
- 208000030507 AIDS Diseases 0.000 description 1
- 206010052747 Adenocarcinoma pancreas Diseases 0.000 description 1
- ITPDYQOUSLNIHG-UHFFFAOYSA-N Amiodarone hydrochloride Chemical compound [Cl-].CCCCC=1OC2=CC=CC=C2C=1C(=O)C1=CC(I)=C(OCC[NH+](CC)CC)C(I)=C1 ITPDYQOUSLNIHG-UHFFFAOYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 208000002267 Anti-neutrophil cytoplasmic antibody-associated vasculitis Diseases 0.000 description 1
- 101100114861 Arabidopsis thaliana CRK21 gene Proteins 0.000 description 1
- 206010003757 Atypical pneumonia Diseases 0.000 description 1
- 241000271566 Aves Species 0.000 description 1
- 208000035143 Bacterial infection Diseases 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- 101710112622 C-C motif chemokine 19 Proteins 0.000 description 1
- 102100021943 C-C motif chemokine 2 Human genes 0.000 description 1
- 102100025248 C-X-C motif chemokine 10 Human genes 0.000 description 1
- 102100025277 C-X-C motif chemokine 13 Human genes 0.000 description 1
- 102100039398 C-X-C motif chemokine 2 Human genes 0.000 description 1
- 102100036170 C-X-C motif chemokine 9 Human genes 0.000 description 1
- 102000018202 CC chemokine receptor 4 Human genes 0.000 description 1
- 108010017317 CCR4 Receptors Proteins 0.000 description 1
- 101150067717 CXCL12 gene Proteins 0.000 description 1
- FVLVBPDQNARYJU-XAHDHGMMSA-N C[C@H]1CCC(CC1)NC(=O)N(CCCl)N=O Chemical compound C[C@H]1CCC(CC1)NC(=O)N(CCCl)N=O FVLVBPDQNARYJU-XAHDHGMMSA-N 0.000 description 1
- BQENDLAVTKRQMS-SBBGFIFASA-L Carbenoxolone sodium Chemical compound [Na+].[Na+].C([C@H]1C2=CC(=O)[C@H]34)[C@@](C)(C([O-])=O)CC[C@]1(C)CC[C@@]2(C)[C@]4(C)CC[C@@H]1[C@]3(C)CC[C@H](OC(=O)CCC([O-])=O)C1(C)C BQENDLAVTKRQMS-SBBGFIFASA-L 0.000 description 1
- 208000031229 Cardiomyopathies Diseases 0.000 description 1
- 241000700198 Cavia Species 0.000 description 1
- 108010008951 Chemokine CXCL12 Proteins 0.000 description 1
- 102000006573 Chemokine CXCL12 Human genes 0.000 description 1
- 206010053567 Coagulopathies Diseases 0.000 description 1
- 102000012422 Collagen Type I Human genes 0.000 description 1
- 108010022452 Collagen Type I Proteins 0.000 description 1
- 208000029147 Collagen-vascular disease Diseases 0.000 description 1
- 206010010099 Combined immunodeficiency Diseases 0.000 description 1
- 206010010356 Congenital anomaly Diseases 0.000 description 1
- 206010054002 Congenital syphilitic osteochondritis Diseases 0.000 description 1
- 241000699800 Cricetinae Species 0.000 description 1
- 241000447938 Cyrtacanthacris tatarica Species 0.000 description 1
- 241000255581 Drosophila <fruit fly, genus> Species 0.000 description 1
- 101100210287 Drosophila melanogaster wech gene Proteins 0.000 description 1
- 102100023274 Dual specificity mitogen-activated protein kinase kinase 4 Human genes 0.000 description 1
- 102100023401 Dual specificity mitogen-activated protein kinase kinase 6 Human genes 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 208000005189 Embolism Diseases 0.000 description 1
- 241000991587 Enterovirus C Species 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 241000588724 Escherichia coli Species 0.000 description 1
- 206010015548 Euthanasia Diseases 0.000 description 1
- 206010051841 Exposure to allergen Diseases 0.000 description 1
- 206010073306 Exposure to radiation Diseases 0.000 description 1
- 108010007457 Extracellular Signal-Regulated MAP Kinases Proteins 0.000 description 1
- 102000007665 Extracellular Signal-Regulated MAP Kinases Human genes 0.000 description 1
- 206010015866 Extravasation Diseases 0.000 description 1
- 208000027445 Farmer Lung Diseases 0.000 description 1
- 206010053172 Fatal outcomes Diseases 0.000 description 1
- 102000009109 Fc receptors Human genes 0.000 description 1
- 108010087819 Fc receptors Proteins 0.000 description 1
- 241000233866 Fungi Species 0.000 description 1
- 241000287828 Gallus gallus Species 0.000 description 1
- 208000015872 Gaucher disease Diseases 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 206010064571 Gene mutation Diseases 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 208000024869 Goodpasture syndrome Diseases 0.000 description 1
- 108091006067 Goα proteins Proteins 0.000 description 1
- 108010017213 Granulocyte-Macrophage Colony-Stimulating Factor Proteins 0.000 description 1
- 102100039620 Granulocyte-macrophage colony-stimulating factor Human genes 0.000 description 1
- 206010018691 Granuloma Diseases 0.000 description 1
- 206010072579 Granulomatosis with polyangiitis Diseases 0.000 description 1
- 208000005176 Hepatitis C Diseases 0.000 description 1
- 101000897480 Homo sapiens C-C motif chemokine 2 Proteins 0.000 description 1
- 101000858088 Homo sapiens C-X-C motif chemokine 10 Proteins 0.000 description 1
- 101000858064 Homo sapiens C-X-C motif chemokine 13 Proteins 0.000 description 1
- 101000889128 Homo sapiens C-X-C motif chemokine 2 Proteins 0.000 description 1
- 101000947172 Homo sapiens C-X-C motif chemokine 9 Proteins 0.000 description 1
- 101001115395 Homo sapiens Dual specificity mitogen-activated protein kinase kinase 4 Proteins 0.000 description 1
- 101000624426 Homo sapiens Dual specificity mitogen-activated protein kinase kinase 6 Proteins 0.000 description 1
- 101000669513 Homo sapiens Metalloproteinase inhibitor 1 Proteins 0.000 description 1
- 101000946889 Homo sapiens Monocyte differentiation antigen CD14 Proteins 0.000 description 1
- 241000725303 Human immunodeficiency virus Species 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- 206010021143 Hypoxia Diseases 0.000 description 1
- 208000024934 IgG4-related mediastinitis Diseases 0.000 description 1
- 108060003951 Immunoglobulin Proteins 0.000 description 1
- 206010062016 Immunosuppression Diseases 0.000 description 1
- 206010061216 Infarction Diseases 0.000 description 1
- 208000022559 Inflammatory bowel disease Diseases 0.000 description 1
- 108090000978 Interleukin-4 Proteins 0.000 description 1
- 102000004388 Interleukin-4 Human genes 0.000 description 1
- PWKSKIMOESPYIA-BYPYZUCNSA-N L-N-acetyl-Cysteine Chemical compound CC(=O)N[C@@H](CS)C(O)=O PWKSKIMOESPYIA-BYPYZUCNSA-N 0.000 description 1
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 description 1
- 108010021099 Lamin Type A Proteins 0.000 description 1
- 102000008201 Lamin Type A Human genes 0.000 description 1
- 201000005099 Langerhans cell histiocytosis Diseases 0.000 description 1
- 206010049694 Left Ventricular Dysfunction Diseases 0.000 description 1
- 241000713666 Lentivirus Species 0.000 description 1
- GDBQQVLCIARPGH-UHFFFAOYSA-N Leupeptin Natural products CC(C)CC(NC(C)=O)C(=O)NC(CC(C)C)C(=O)NC(C=O)CCCN=C(N)N GDBQQVLCIARPGH-UHFFFAOYSA-N 0.000 description 1
- 239000012097 Lipofectamine 2000 Substances 0.000 description 1
- GQYIWUVLTXOXAJ-UHFFFAOYSA-N Lomustine Chemical compound ClCCN(N=O)C(=O)NC1CCCCC1 GQYIWUVLTXOXAJ-UHFFFAOYSA-N 0.000 description 1
- 208000004852 Lung Injury Diseases 0.000 description 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- 102000001291 MAP Kinase Kinase Kinase Human genes 0.000 description 1
- 108060006687 MAP kinase kinase kinase Proteins 0.000 description 1
- 229940126560 MAPK inhibitor Drugs 0.000 description 1
- 101150018665 MAPK3 gene Proteins 0.000 description 1
- 102000043131 MHC class II family Human genes 0.000 description 1
- 108091054438 MHC class II family Proteins 0.000 description 1
- 208000002805 Mediastinal fibrosis Diseases 0.000 description 1
- 206010027476 Metastases Diseases 0.000 description 1
- 229930192392 Mitomycin Natural products 0.000 description 1
- 208000011682 Mitral valve disease Diseases 0.000 description 1
- 102100035877 Monocyte differentiation antigen CD14 Human genes 0.000 description 1
- NWIBSHFKIJFRCO-WUDYKRTCSA-N Mytomycin Chemical compound C1N2C(C(C(C)=C(N)C3=O)=O)=C3[C@@H](COC(N)=O)[C@@]2(OC)[C@@H]2[C@H]1N2 NWIBSHFKIJFRCO-WUDYKRTCSA-N 0.000 description 1
- 208000009905 Neurofibromatoses Diseases 0.000 description 1
- 208000014060 Niemann-Pick disease Diseases 0.000 description 1
- 239000000020 Nitrocellulose Substances 0.000 description 1
- 206010061876 Obstruction Diseases 0.000 description 1
- 108091034117 Oligonucleotide Proteins 0.000 description 1
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 1
- 206010033799 Paralysis Diseases 0.000 description 1
- 102000035195 Peptidases Human genes 0.000 description 1
- 108091005804 Peptidases Proteins 0.000 description 1
- 241000286209 Phasianidae Species 0.000 description 1
- 241000233870 Pneumocystis Species 0.000 description 1
- 239000004698 Polyethylene Substances 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 108010026552 Proteome Proteins 0.000 description 1
- 208000031467 Pulmonary capillary hemangiomatosis Diseases 0.000 description 1
- 206010061924 Pulmonary toxicity Diseases 0.000 description 1
- 208000014777 Pulmonary venoocclusive disease Diseases 0.000 description 1
- 241000238711 Pyroglyphidae Species 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Natural products OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 1
- 238000011529 RT qPCR Methods 0.000 description 1
- 102000018120 Recombinases Human genes 0.000 description 1
- 108010091086 Recombinases Proteins 0.000 description 1
- 208000004756 Respiratory Insufficiency Diseases 0.000 description 1
- 102000009738 Ribosomal Protein S6 Kinases Human genes 0.000 description 1
- 108010034782 Ribosomal Protein S6 Kinases Proteins 0.000 description 1
- 241000283984 Rodentia Species 0.000 description 1
- 241000242677 Schistosoma japonicum Species 0.000 description 1
- 206010072170 Skin wound Diseases 0.000 description 1
- 101710088580 Stromal cell-derived factor 1 Proteins 0.000 description 1
- 102000019197 Superoxide Dismutase Human genes 0.000 description 1
- 108010012715 Superoxide dismutase Proteins 0.000 description 1
- 241000282898 Sus scrofa Species 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 108010017842 Telomerase Proteins 0.000 description 1
- 102100032938 Telomerase reverse transcriptase Human genes 0.000 description 1
- 208000001435 Thromboembolism Diseases 0.000 description 1
- 208000007536 Thrombosis Diseases 0.000 description 1
- IQFYYKKMVGJFEH-XLPZGREQSA-N Thymidine Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](O)C1 IQFYYKKMVGJFEH-XLPZGREQSA-N 0.000 description 1
- 108010005246 Tissue Inhibitor of Metalloproteinases Proteins 0.000 description 1
- 102000005876 Tissue Inhibitor of Metalloproteinases Human genes 0.000 description 1
- 108700019146 Transgenes Proteins 0.000 description 1
- 206010069363 Traumatic lung injury Diseases 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- 239000013504 Triton X-100 Substances 0.000 description 1
- 229920004890 Triton X-100 Polymers 0.000 description 1
- 102000004142 Trypsin Human genes 0.000 description 1
- 108090000631 Trypsin Proteins 0.000 description 1
- 208000026911 Tuberous sclerosis complex Diseases 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- JLCPHMBAVCMARE-UHFFFAOYSA-N [3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-hydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methyl [5-(6-aminopurin-9-yl)-2-(hydroxymethyl)oxolan-3-yl] hydrogen phosphate Polymers Cc1cn(C2CC(OP(O)(=O)OCC3OC(CC3OP(O)(=O)OCC3OC(CC3O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c3nc(N)[nH]c4=O)C(COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3CO)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cc(C)c(=O)[nH]c3=O)n3cc(C)c(=O)[nH]c3=O)n3ccc(N)nc3=O)n3cc(C)c(=O)[nH]c3=O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)O2)c(=O)[nH]c1=O JLCPHMBAVCMARE-UHFFFAOYSA-N 0.000 description 1
- 230000001594 aberrant effect Effects 0.000 description 1
- 230000005856 abnormality Effects 0.000 description 1
- 229960000583 acetic acid Drugs 0.000 description 1
- 229960004308 acetylcysteine Drugs 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 210000005006 adaptive immune system Anatomy 0.000 description 1
- 230000004721 adaptive immunity Effects 0.000 description 1
- 239000012670 alkaline solution Substances 0.000 description 1
- 208000028004 allergic respiratory disease Diseases 0.000 description 1
- 230000007815 allergy Effects 0.000 description 1
- 208000033571 alveolar capillary dysplasia with misalignment of pulmonary veins Diseases 0.000 description 1
- 229960005174 ambroxol Drugs 0.000 description 1
- JBDGDEWWOUBZPM-XYPYZODXSA-N ambroxol Chemical compound NC1=C(Br)C=C(Br)C=C1CN[C@@H]1CC[C@@H](O)CC1 JBDGDEWWOUBZPM-XYPYZODXSA-N 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 229960005260 amiodarone Drugs 0.000 description 1
- 239000000908 ammonium hydroxide Substances 0.000 description 1
- 230000033115 angiogenesis Effects 0.000 description 1
- 208000010123 anthracosis Diseases 0.000 description 1
- 230000001745 anti-biotin effect Effects 0.000 description 1
- 230000003510 anti-fibrotic effect Effects 0.000 description 1
- 229940124599 anti-inflammatory drug Drugs 0.000 description 1
- 238000009175 antibody therapy Methods 0.000 description 1
- 229940034982 antineoplastic agent Drugs 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 206010002906 aortic stenosis Diseases 0.000 description 1
- 239000012736 aqueous medium Substances 0.000 description 1
- 239000012131 assay buffer Substances 0.000 description 1
- 230000002238 attenuated effect Effects 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 208000022362 bacterial infectious disease Diseases 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 230000008512 biological response Effects 0.000 description 1
- 239000000090 biomarker Substances 0.000 description 1
- 208000015440 bird fancier lung Diseases 0.000 description 1
- OWMVSZAMULFTJU-UHFFFAOYSA-N bis-tris Chemical compound OCCN(CCO)C(CO)(CO)CO OWMVSZAMULFTJU-UHFFFAOYSA-N 0.000 description 1
- 210000003969 blast cell Anatomy 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 208000015294 blood coagulation disease Diseases 0.000 description 1
- 230000036765 blood level Effects 0.000 description 1
- 210000001124 body fluid Anatomy 0.000 description 1
- 239000010839 body fluid Substances 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- GJPICJJJRGTNOD-UHFFFAOYSA-N bosentan Chemical compound COC1=CC=CC=C1OC(C(=NC(=N1)C=2N=CC=CN=2)OCCO)=C1NS(=O)(=O)C1=CC=C(C(C)(C)C)C=C1 GJPICJJJRGTNOD-UHFFFAOYSA-N 0.000 description 1
- 229960003065 bosentan Drugs 0.000 description 1
- 210000000481 breast Anatomy 0.000 description 1
- 229940124630 bronchodilator Drugs 0.000 description 1
- 238000013276 bronchoscopy Methods 0.000 description 1
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 description 1
- 239000000920 calcium hydroxide Substances 0.000 description 1
- 229910001861 calcium hydroxide Inorganic materials 0.000 description 1
- 230000003185 calcium uptake Effects 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 230000022131 cell cycle Effects 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 239000006285 cell suspension Substances 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 230000023385 chemokine (C-C motif) ligand 5 production Effects 0.000 description 1
- 230000014564 chemokine production Effects 0.000 description 1
- 230000003399 chemotactic effect Effects 0.000 description 1
- 239000005482 chemotactic factor Substances 0.000 description 1
- 230000035605 chemotaxis Effects 0.000 description 1
- 235000013330 chicken meat Nutrition 0.000 description 1
- 229960004926 chlorobutanol Drugs 0.000 description 1
- 230000006020 chronic inflammation Effects 0.000 description 1
- 210000003040 circulating cell Anatomy 0.000 description 1
- 230000004186 co-expression Effects 0.000 description 1
- 230000008045 co-localization Effects 0.000 description 1
- 230000009852 coagulant defect Effects 0.000 description 1
- 230000015271 coagulation Effects 0.000 description 1
- 238000005345 coagulation Methods 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 230000037319 collagen production Effects 0.000 description 1
- 230000024203 complement activation Effects 0.000 description 1
- 238000002591 computed tomography Methods 0.000 description 1
- 208000018631 connective tissue disease Diseases 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000037029 cross reaction Effects 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 230000037416 cystogenesis Effects 0.000 description 1
- 231100000599 cytotoxic agent Toxicity 0.000 description 1
- 230000002498 deadly effect Effects 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 230000006735 deficit Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 230000001934 delay Effects 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 230000000249 desinfective effect Effects 0.000 description 1
- UGMCXQCYOVCMTB-UHFFFAOYSA-K dihydroxy(stearato)aluminium Chemical compound CCCCCCCCCCCCCCCCCC(=O)O[Al](O)O UGMCXQCYOVCMTB-UHFFFAOYSA-K 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 238000012137 double-staining Methods 0.000 description 1
- 230000002222 downregulating effect Effects 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- 210000005069 ears Anatomy 0.000 description 1
- 235000006694 eating habits Nutrition 0.000 description 1
- 238000001962 electrophoresis Methods 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 230000013020 embryo development Effects 0.000 description 1
- 210000001671 embryonic stem cell Anatomy 0.000 description 1
- 210000002257 embryonic structure Anatomy 0.000 description 1
- 210000002889 endothelial cell Anatomy 0.000 description 1
- 210000003038 endothelium Anatomy 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 210000000222 eosinocyte Anatomy 0.000 description 1
- 201000009580 eosinophilic pneumonia Diseases 0.000 description 1
- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 239000003172 expectorant agent Substances 0.000 description 1
- 230000036251 extravasation Effects 0.000 description 1
- 210000000744 eyelid Anatomy 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 229960004887 ferric hydroxide Drugs 0.000 description 1
- 239000012894 fetal calf serum Substances 0.000 description 1
- 230000000893 fibroproliferative effect Effects 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 238000000799 fluorescence microscopy Methods 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 239000003517 fume Substances 0.000 description 1
- 230000002538 fungal effect Effects 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 238000001476 gene delivery Methods 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 230000001434 glomerular Effects 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 239000003102 growth factor Substances 0.000 description 1
- 230000003394 haemopoietic effect Effects 0.000 description 1
- 230000035876 healing Effects 0.000 description 1
- 230000011132 hemopoiesis Effects 0.000 description 1
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 1
- 238000010562 histological examination Methods 0.000 description 1
- 230000007768 histopathological growth pattern Effects 0.000 description 1
- 229940046533 house dust mites Drugs 0.000 description 1
- 102000043803 human CCL19 Human genes 0.000 description 1
- 102000053523 human CXCR4 Human genes 0.000 description 1
- 210000005260 human cell Anatomy 0.000 description 1
- 238000011577 humanized mouse model Methods 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 230000007954 hypoxia Effects 0.000 description 1
- 208000036260 idiopathic disease Diseases 0.000 description 1
- 230000005934 immune activation Effects 0.000 description 1
- 230000001900 immune effect Effects 0.000 description 1
- 239000012642 immune effector Substances 0.000 description 1
- 230000028993 immune response Effects 0.000 description 1
- 230000037451 immune surveillance Effects 0.000 description 1
- 210000000987 immune system Anatomy 0.000 description 1
- 238000012760 immunocytochemical staining Methods 0.000 description 1
- 238000003365 immunocytochemistry Methods 0.000 description 1
- 230000002163 immunogen Effects 0.000 description 1
- 102000018358 immunoglobulin Human genes 0.000 description 1
- 229940072221 immunoglobulins Drugs 0.000 description 1
- 238000011532 immunohistochemical staining Methods 0.000 description 1
- 229940121354 immunomodulator Drugs 0.000 description 1
- 230000001506 immunosuppresive effect Effects 0.000 description 1
- 229940125721 immunosuppressive agent Drugs 0.000 description 1
- 238000002650 immunosuppressive therapy Methods 0.000 description 1
- 238000009169 immunotherapy Methods 0.000 description 1
- 238000002513 implantation Methods 0.000 description 1
- 230000008676 import Effects 0.000 description 1
- 230000001976 improved effect Effects 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 239000000411 inducer Substances 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 230000007574 infarction Effects 0.000 description 1
- 230000004968 inflammatory condition Effects 0.000 description 1
- 230000028709 inflammatory response Effects 0.000 description 1
- 230000004941 influx Effects 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 238000013383 initial experiment Methods 0.000 description 1
- 239000007972 injectable composition Substances 0.000 description 1
- 230000015788 innate immune response Effects 0.000 description 1
- 239000002054 inoculum Substances 0.000 description 1
- 150000007529 inorganic bases Chemical group 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 238000007913 intrathecal administration Methods 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- IEECXTSVVFWGSE-UHFFFAOYSA-M iron(3+);oxygen(2-);hydroxide Chemical compound [OH-].[O-2].[Fe+3] IEECXTSVVFWGSE-UHFFFAOYSA-M 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 description 1
- 238000002372 labelling Methods 0.000 description 1
- 108010025821 lamin C Proteins 0.000 description 1
- 108010057670 laminin 1 Proteins 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 229940067606 lecithin Drugs 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- 230000032820 leukocyte apoptotic process Effects 0.000 description 1
- GDBQQVLCIARPGH-ULQDDVLXSA-N leupeptin Chemical compound CC(C)C[C@H](NC(C)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@H](C=O)CCCN=C(N)N GDBQQVLCIARPGH-ULQDDVLXSA-N 0.000 description 1
- 108010052968 leupeptin Proteins 0.000 description 1
- 244000144972 livestock Species 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 230000004807 localization Effects 0.000 description 1
- 229960002247 lomustine Drugs 0.000 description 1
- 201000005202 lung cancer Diseases 0.000 description 1
- 231100000515 lung injury Toxicity 0.000 description 1
- 230000001926 lymphatic effect Effects 0.000 description 1
- 210000004698 lymphocyte Anatomy 0.000 description 1
- 210000003563 lymphoid tissue Anatomy 0.000 description 1
- 239000006166 lysate Substances 0.000 description 1
- 210000004962 mammalian cell Anatomy 0.000 description 1
- 229960002510 mandelic acid Drugs 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 238000013160 medical therapy Methods 0.000 description 1
- 210000004379 membrane Anatomy 0.000 description 1
- 210000002901 mesenchymal stem cell Anatomy 0.000 description 1
- 208000030159 metabolic disease Diseases 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 230000009401 metastasis Effects 0.000 description 1
- 230000001394 metastastic effect Effects 0.000 description 1
- MYWUZJCMWCOHBA-VIFPVBQESA-N methamphetamine Chemical compound CN[C@@H](C)CC1=CC=CC=C1 MYWUZJCMWCOHBA-VIFPVBQESA-N 0.000 description 1
- 230000000813 microbial effect Effects 0.000 description 1
- 229960004857 mitomycin Drugs 0.000 description 1
- 230000004660 morphological change Effects 0.000 description 1
- 229940066491 mucolytics Drugs 0.000 description 1
- 210000004400 mucous membrane Anatomy 0.000 description 1
- 239000000472 muscarinic agonist Substances 0.000 description 1
- 210000004237 neck muscle Anatomy 0.000 description 1
- 201000004931 neurofibromatosis Diseases 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 230000003472 neutralizing effect Effects 0.000 description 1
- 208000004235 neutropenia Diseases 0.000 description 1
- 210000000440 neutrophil Anatomy 0.000 description 1
- 229920001220 nitrocellulos Polymers 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 238000011275 oncology therapy Methods 0.000 description 1
- 238000001543 one-way ANOVA Methods 0.000 description 1
- 210000000287 oocyte Anatomy 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 238000012261 overproduction Methods 0.000 description 1
- 201000002094 pancreatic adenocarcinoma Diseases 0.000 description 1
- 201000002528 pancreatic cancer Diseases 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 230000007918 pathogenicity Effects 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 229960001639 penicillamine Drugs 0.000 description 1
- 229950000964 pepstatin Drugs 0.000 description 1
- 108010091212 pepstatin Proteins 0.000 description 1
- FAXGPCHRFPCXOO-LXTPJMTPSA-N pepstatin A Chemical compound OC(=O)C[C@H](O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)C[C@H](O)[C@H](CC(C)C)NC(=O)[C@H](C(C)C)NC(=O)[C@H](C(C)C)NC(=O)CC(C)C FAXGPCHRFPCXOO-LXTPJMTPSA-N 0.000 description 1
- 229960003742 phenol Drugs 0.000 description 1
- DHRLEVQXOMLTIM-UHFFFAOYSA-N phosphoric acid;trioxomolybdenum Chemical compound O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.OP(O)(O)=O DHRLEVQXOMLTIM-UHFFFAOYSA-N 0.000 description 1
- 230000010118 platelet activation Effects 0.000 description 1
- 201000000317 pneumocystosis Diseases 0.000 description 1
- 231100000374 pneumotoxicity Toxicity 0.000 description 1
- 229920005862 polyol Polymers 0.000 description 1
- 150000003077 polyols Chemical class 0.000 description 1
- 238000010837 poor prognosis Methods 0.000 description 1
- 230000032361 posttranscriptional gene silencing Effects 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 244000144977 poultry Species 0.000 description 1
- 235000013594 poultry meat Nutrition 0.000 description 1
- 229960005205 prednisolone Drugs 0.000 description 1
- OIGNJSKKLXVSLS-VWUMJDOOSA-N prednisolone Chemical compound O=C1C=C[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 OIGNJSKKLXVSLS-VWUMJDOOSA-N 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 230000001023 pro-angiogenic effect Effects 0.000 description 1
- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 1
- 229960004919 procaine Drugs 0.000 description 1
- 238000004393 prognosis Methods 0.000 description 1
- 230000000770 proinflammatory effect Effects 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 235000019833 protease Nutrition 0.000 description 1
- 238000002731 protein assay Methods 0.000 description 1
- 229940121649 protein inhibitor Drugs 0.000 description 1
- 239000012268 protein inhibitor Substances 0.000 description 1
- 239000012474 protein marker Substances 0.000 description 1
- 201000009732 pulmonary eosinophilia Diseases 0.000 description 1
- 230000007047 pulmonary toxicity Effects 0.000 description 1
- 210000003492 pulmonary vein Anatomy 0.000 description 1
- 208000037813 pulmonary venous hypertension Diseases 0.000 description 1
- 239000002510 pyrogen Substances 0.000 description 1
- 230000002285 radioactive effect Effects 0.000 description 1
- 230000006798 recombination Effects 0.000 description 1
- 238000005215 recombination Methods 0.000 description 1
- 230000008263 repair mechanism Effects 0.000 description 1
- 201000004193 respiratory failure Diseases 0.000 description 1
- 208000023504 respiratory system disease Diseases 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 238000010839 reverse transcription Methods 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 210000003705 ribosome Anatomy 0.000 description 1
- 238000011808 rodent model Methods 0.000 description 1
- 239000012723 sample buffer Substances 0.000 description 1
- 229960003440 semustine Drugs 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 208000002491 severe combined immunodeficiency Diseases 0.000 description 1
- 230000001568 sexual effect Effects 0.000 description 1
- 208000007056 sickle cell anemia Diseases 0.000 description 1
- 230000011664 signaling Effects 0.000 description 1
- 230000007781 signaling event Effects 0.000 description 1
- 229910052710 silicon Inorganic materials 0.000 description 1
- 239000010703 silicon Substances 0.000 description 1
- 208000023608 silo filler disease Diseases 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 238000002415 sodium dodecyl sulfate polyacrylamide gel electrophoresis Methods 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 238000012453 sprague-dawley rat model Methods 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 238000007619 statistical method Methods 0.000 description 1
- 210000000130 stem cell Anatomy 0.000 description 1
- 238000011146 sterile filtration Methods 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 239000000021 stimulant Substances 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 238000011477 surgical intervention Methods 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 230000009897 systematic effect Effects 0.000 description 1
- 238000012385 systemic delivery Methods 0.000 description 1
- 201000000596 systemic lupus erythematosus Diseases 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 238000011287 therapeutic dose Methods 0.000 description 1
- RTKIYNMVFMVABJ-UHFFFAOYSA-L thimerosal Chemical compound [Na+].CC[Hg]SC1=CC=CC=C1C([O-])=O RTKIYNMVFMVABJ-UHFFFAOYSA-L 0.000 description 1
- 229940033663 thimerosal Drugs 0.000 description 1
- 210000000115 thoracic cavity Anatomy 0.000 description 1
- 230000007838 tissue remodeling Effects 0.000 description 1
- 210000003371 toe Anatomy 0.000 description 1
- 239000002341 toxic gas Substances 0.000 description 1
- 239000003053 toxin Substances 0.000 description 1
- 231100000765 toxin Toxicity 0.000 description 1
- 108700012359 toxins Proteins 0.000 description 1
- 210000003437 trachea Anatomy 0.000 description 1
- 238000013518 transcription Methods 0.000 description 1
- 230000035897 transcription Effects 0.000 description 1
- 230000002103 transcriptional effect Effects 0.000 description 1
- 230000037317 transdermal delivery Effects 0.000 description 1
- 230000000472 traumatic effect Effects 0.000 description 1
- JREYOWJEWZVAOR-UHFFFAOYSA-N triazanium;[3-methylbut-3-enoxy(oxido)phosphoryl] phosphate Chemical group [NH4+].[NH4+].[NH4+].CC(=C)CCOP([O-])(=O)OP([O-])([O-])=O JREYOWJEWZVAOR-UHFFFAOYSA-N 0.000 description 1
- 230000001960 triggered effect Effects 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- IHIXIJGXTJIKRB-UHFFFAOYSA-N trisodium vanadate Chemical compound [Na+].[Na+].[Na+].[O-][V]([O-])([O-])=O IHIXIJGXTJIKRB-UHFFFAOYSA-N 0.000 description 1
- 239000012588 trypsin Substances 0.000 description 1
- 229960001322 trypsin Drugs 0.000 description 1
- 208000009999 tuberous sclerosis Diseases 0.000 description 1
- 241000701161 unidentified adenovirus Species 0.000 description 1
- 241001430294 unidentified retrovirus Species 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 230000009677 vaginal delivery Effects 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
- 239000013603 viral vector Substances 0.000 description 1
- 230000000007 visual effect Effects 0.000 description 1
- 239000011534 wash buffer Substances 0.000 description 1
- 230000010388 wound contraction Effects 0.000 description 1
- 230000029663 wound healing Effects 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/18—Drugs for disorders of the alimentary tract or the digestive system for pancreatic disorders, e.g. pancreatic enzymes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/08—Bronchodilators
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/04—Drugs for skeletal disorders for non-specific disorders of the connective tissue
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
- A61P27/06—Antiglaucoma agents or miotics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/20—Antivirals for DNA viruses
- A61P31/22—Antivirals for DNA viruses for herpes viruses
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
- A61P33/10—Anthelmintics
- A61P33/12—Schistosomicides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P41/00—Drugs used in surgical methods, e.g. surgery adjuvants for preventing adhesion or for vitreum substitution
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/24—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against cytokines, lymphokines or interferons
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
- C07K16/2866—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against receptors for cytokines, lymphokines, interferons
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
- C12N15/09—Recombinant DNA-technology
- C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
- C12N15/113—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing
- C12N15/1138—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing against receptors or cell surface proteins
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
- C12N5/10—Cells modified by introduction of foreign genetic material
- C12N5/12—Fused cells, e.g. hybridomas
- C12N5/16—Animal cells
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
- C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
- C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2310/00—Structure or type of the nucleic acid
- C12N2310/10—Type of nucleic acid
- C12N2310/14—Type of nucleic acid interfering N.A.
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- C12Q2525/00—Reactions involving modified oligonucleotides, nucleic acids, or nucleotides
- C12Q2525/10—Modifications characterised by
- C12Q2525/207—Modifications characterised by siRNA, miRNA
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- General Health & Medical Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Genetics & Genomics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Immunology (AREA)
- Molecular Biology (AREA)
- Biomedical Technology (AREA)
- Biochemistry (AREA)
- Zoology (AREA)
- Biotechnology (AREA)
- Wood Science & Technology (AREA)
- Biophysics (AREA)
- General Engineering & Computer Science (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Microbiology (AREA)
- Cardiology (AREA)
- Physics & Mathematics (AREA)
- Plant Pathology (AREA)
- Ophthalmology & Optometry (AREA)
- Virology (AREA)
- Heart & Thoracic Surgery (AREA)
- Dermatology (AREA)
- Rheumatology (AREA)
- Oncology (AREA)
- Communicable Diseases (AREA)
- Pulmonology (AREA)
- Physical Education & Sports Medicine (AREA)
- Urology & Nephrology (AREA)
Abstract
Description
本発明は、慢性線維形成性障害を治療するための方法及び組成物に関する。特に本発明は、慢性線維形成性障害の免疫療法による介入に関する。
炎症は、組織の損傷や感染に対する協調反応である。炎症は、化学走性因子の局所的放出、血小板の活性化、並びに凝固及び補体経路の開始から始まる。これらの事象は、局所的内皮を刺激し、好中球及び単球の管外遊出を促進する。炎症の第二段階は、細胞組織への適応免疫系(リンパ球を含む)の流入を特徴とする。続く消炎段階は、過剰な白血球のアポトーシスや組織マクロファージによる貪食が起こる場合、間質細胞(例えば線維芽細胞)による損傷組織の修復を特徴とする。
Green,Overview of pulmonary fibrosis.Chest 2002;122(suppl.6):334S−9S Nicholason Am.J.Resp.Crit.Car Med/2000:162:2213−7 Chapman J.Clin.,Invest.,2004;113:148−57 Flahertyら、Am.J.Med.,110:278−282(2001) Lynchら、Curr.Opin.Pulm.Med.,7:298−308(2001) Flahertyら、Thorax,58:143−148(2003) Kingら、Am.J.Respir.Crit.Care Med.,164:1025−1032(2001) van den Blinkら、Arch.Immunol.Ther.Exp.(Warsz),48:539−545(2000) Nagiraら、J.Biol.Chem.,272:19518−19524(1997) Forsterら、J.Immunol.,160:1522−1531(1998) Kimら、J.Leukoc.Biol.,66:455−461(1999) Kimら、J.Clin.Invest.,108:1331−1339(2001) Sallustoら、Eur.J.Immunol.,29:1617−1625(1999) Randolphら、Science,286:2159−2162(1999) Hammadら、J.Immunol.,169:1524−1534(2002) Wardら、Biochem.J.,333:457−470(1998) Gonzaloら、J.Immunol.,165:499−508(2000) Mullerら、Nature,410:50−56(2001) Murakamiら、J.Dermatol.Sci.,36:71−78(2004) Tavorら、Cancer Res.,64:2817−2824(2004) Ghobrialら、Mayo Clin.Proc.,79:318−325(2004)
本発明は、上述した線維形成性障害を治療するための方法及び組成物に関する。特に本発明が明らかにするところは、CCL21の活性を単独で又はCCL19とともに阻害するか又は減少させることが、線維症の病変の存在を減らすこと及び線維形成性障害の症状を改善することに効果的であるということである。
線維症は、線維細胞の抑制されていない増殖と分化を伴う。線維細胞は、末梢血単球に由来する別個の線維芽細胞状の細胞群であり、それは、通常、損傷組織の部位に入って新脈管形成及び傷の治癒を促進する。本発明において明らかなことは、線維症の病変に存在する線維細胞及び/又は線維芽細胞中のCCL21の存在又は活性を減少させることによって、線維症病巣の存在が減らされる、及び/又は、線維症病巣の形成が阻害される、及び/又は線維症の1つ以上の症状が改善されることによる線維症治療の有益な結果がもたらされるということである。
臨床的所見、生理学的所見、放射線写真撮影による所見、及び病理学的所見を総合して、IIPの疑いがある患者を決定した(Flahertyら、Am.J.Med.,110:278−282(2001)、Flahertyら、Curr.Opin.Pulm.Med.,6:404−410(2000)、Kazerooniら、AJR Am.J.Roentgenol.,169:977−983(1997)、American Thoracic Society,European Respiratory Society(ATS/ERS)、Am.J.Respir.Crit.Care Med.,165:277−304(2002)。本研究に登録されたどの患者も、以前に生検外科手術を受けたことがなく、また、IIPの治療を受けたことがなかった。SLBは、2000年5月〜2004年8月の間に、線維性肺疾患の病理生物学における評価の一部として、the University of Michigan Specialized Center of Researchで行われた。疾患の病理学的形跡がない組織学的に正常な肺の生検試料は、肺癌に対して胸部切除術を受けている患者の切除標本の遠位縁から得た。各SLBは別々に、層流フード内において無菌の手法により処理され、分子分析、タンパク質分析、及び免疫組織化学分析のため処理された(下記を参照)。
IIP及び正常縁のSLBにおけるCCR7、CXCR4、CCL19、CCL21、及びCXCL12のSuperArray分析。IIP及び正常縁のSLBにおけるCCR7及びCXCR4の存在を、特定のSuperArray GEArrayを用いて調べた。これは定性的であり、定量的な手法でなかったが、CCR7(図1A)及びCXCR4(図1B)の発現をGAPDHの発現に対して正規化し、その値を両受容体について示している。CCR7及びCXCR4の最も高い相対的発現は、UIP患者群(n=7)からの上葉及び下葉の生検試料において見られた。NSIP(n=6)、RBILD(n=6)、及び正常縁(n=5)腫瘍患者群からの下葉及び上葉の生検試料も同様に分析した。有意差は認められなかったが、全体的にみて、両ケモカイン受容体の相対的発現は、UIP、NSIP、RBILD、正常縁のように、病気の重篤さの順番に従っているようであった。これまでに特定されている2つのCCR7のリガンドは、CCL19(Yoshidaら、J.Biol.Chem.,272:13803−13809(1997))とCCL21(Campbellら、J.Cell Biol.,141:1053−1059(1998))である。CCL19(すなわちELC、エキソダス(exodus)−3、及びCKb−1134)は、リンパ節のT細胞領域及び輸入リンパ上皮において構成的に発現されるため、その主な役割は、樹状細胞及びT細胞をそれらの免疫部位に遊走させることにあると考えられている(Sallustoら、Eur.J.Immunol.,29:1617−1625(1999))。同時に行われた研究は、CCL21(すなわちSLC、エキソダス−2、TCA−4、及びCKb−99)が類似の機能及び類似の発現パターンを有していることを明らかにした。33。しかし、両ケモカインは、肺で検出され(Gunnら、Proc.Natl.Acad.Sci.USA,95:258−263(1998))、そして腎臓で検出された(Banasら、J.Immunol.,168:4301−4307(2002))。このことは、それらが免疫監視機構の外で役割をもっている可能性を示唆している。CCL19の相対的転写発現の分析により、UIPの上葉及び下葉の生検試料においてこのCCR7のリガンドの量がより高くなっていることが明らかになった(図2A)。同様の量のCCL19転写物が、NSIP及びRBILDの生検試料から検出され、最も低い量が正常縁の生検試料で見られた。しかし、明瞭なパターンのCCL21(図2B)及びCXCL12(図2C)の転写物発現は、IIP及び正常縁の生検試料の中で認められなかった。
この実施例は、肺の慢性線維症においてCCL19及び/又はCCL21を標的にする新たな可能性について詳しく説明する。既知の特発性の原因による慢性肺線維症は、極めて大きな臨床上の難問であり、それに対して選択可能な治療は、有効性が限られていたり、毒性が見られるものである(Flahertyら、Am.J.Med.,110:278−282(2001)、Hamptonら、Am.J.Respir.Crit.Care Med.,149:A878(1994))。また、診断後の平均生存率はほとんど変わらなかった(Ryuら、Mayo Clin.Proc.,73:1085−1101(1998)、Laskyら、Environ.Health Perspect.,108 Suppl 4:751−762(2000))。既知の前線維化をもたらす刺激には、放射線、無機物及び有機物の粒子の吸入、酸化性物質の気体、薬剤、及び感染性生物があり、これに対し、議論は、特発性間質性肺炎(IIP)の臨床病理を引き起こす病因の特定に関するものに固執している。IIPは、遠位の肺実質を巻き込む多様な群の疾患であり、それらは、多くの特徴が共通している一方、それぞれ別個の疾患として特定するのが妥当なほど十分に異なった印象を与えるものである(Travisら、Am.J.Surg.Path.,24:19−33(2000))。それらの病因は依然としてはっきりしていないが、肺に対する1つの傷(又は複数の傷)が中心になっていると考えられ、従ってその傷を治癒させる試みが行われる。線維芽細胞の病巣(活発に増殖する線維芽細胞の小さな集塊)は、組織化された傷の前病巣であると考えられ、線維形成が活発で進行中であることを示すものであると考えられている。目下の仮説は、CCL19及びCCL21へのヒト線維芽細胞の応答は(それらによるCCR7のアップレギュレーションのため)、それらの細胞の不適切な活性化をもたらし、それによってIIPに見られる過剰な線維形成反応が生じるということである。
本実施例の目的は、IPF/UIPの肺外科生検試料及び正常な肺外科生検試料から増殖した一次線維芽細胞のCCR7発現について機能的重要性及びシグナル伝達上の重要性を調べることである。IPF/UIP患者及び正常な患者から得られた肺の生検試料から一次線維芽細胞を培養した。CCケモカインリガンド(CCL)21で処理した線維芽細胞又は処理しなかった線維芽細胞を、免疫細胞化学分析、遺伝子アレイ、タックマンリアルタイムPCR、移動、増殖、及びウェスタンブロットアッセイにより、機能的差、転写物差、及びプロテオーム差について分析した。
Claims (48)
- 哺乳動物の慢性線維形成性障害を治療する方法であって、該線維形成性障害の線維性病変に存在する線維細胞及び/又は線維芽細胞においてCCL21の存在又は活性を減少させることを包含する、方法。
- 前記線維形成性障害に関連する線維芽細胞においてCCL19の存在又は活性を減少させることをさらに包含する、請求項1に記載の方法。
- 前記CCL21の存在又は活性を減少させることは、CCL21を該線維芽細胞から除去する薬剤を、該慢性線維形成性障害の1つ以上の症状を軽減するのに有効な量で、該哺乳動物に接触させることをさらに包含する、請求項1に記載の方法。
- 前記薬剤は、CCL21に対して特異的に免疫反応性である抗体である、請求項3に記載の方法。
- 前記抗体は、CCL21上のエピトープを他のケモカインよりも優先的に認識するものである、請求項4に記載の方法。
- 前記CCL21の存在又は活性を減少させることは、前記線維芽細胞におけるCCL21の発現を減少させる薬剤を、前記慢性線維形成性障害の1つ以上の症状を軽減するのに有効な量で、前記哺乳動物に接触させることを包含する、請求項1に記載の方法。
- 前記薬剤は、CCL21に対するsiRNA分子である、請求項6に記載の方法。
- 前記線維形成性障害は、肺線維症、慢性閉塞性肺疾患、肝臓線維症、関節リウマチ、うっ血性心不全、慢性腎臓疾患、過敏性肺炎、呼吸細気管支炎/間質性肺疾患、マンソン住血吸虫感染、叢状病変により引き起こされる原発性肺高血圧症、肺で発現するヘルペスウイルス関連疾患、皮膚で発現するヘルペスウイルス関連疾患、ケロイド瘢痕、狼瘡、腎性線維形成性皮膚障害、日本住血吸虫感染に伴う線維形成性病変、自己免疫疾患、病原性線維形成、ライム病、膵炎及び間質線維症における間質の再構築、子宮類線維腫、卵巣線維症、角膜線維症、うっ血性心不全及び他の虚血後の症状、腹部の外科手術後の瘢痕形成、広角度緑内障線維柱帯切開術の術後瘢痕形成、並びにそれらの任意の組合せからなる群から選択される、請求項1に記載の方法。
- 前記線維形成性障害は慢性肺線維症である、請求項8に記載の方法。
- 前記薬剤を線維形成性病変の部位に局所投与することを包含する、請求項3又は6に記載の方法。
- 前記線維形成性病変は肺中にあり、かつ前記組成物は前記病変に局所的に接触させられる、請求項10に記載の方法。
- 前記薬剤は、線維形成性病変の部位に該薬剤を特異的に配置するための標的化部分を含む、請求項3又は6に記載の方法。
- 前記線維形成性病変は肺中にあり、かつ前記組成物は前記病変に局所的に接触させられる、請求項12に記載の方法。
- 前記抗体は、局所投与、注射、吸入、デポ剤若しくはポンプによる連続的放出、又はそれらの任意の組合せからなる群から選択される投与形態を用いて投与される、請求項3に記載の方法。
- 線維芽細胞及び/又は線維細胞の増殖を阻害する方法であって、抗CCL21抗体又はCCL21に対して設計したsiRNA分子を含む組成物を該線維芽細胞及び/又は該線維細胞に接触させることを包含する、方法。
- 抗CCL19抗体又はCCL19に対して設計したsiRNA分子を含む組成物を前記線維芽細胞に接触させることをさらに包含する、請求項15に記載の方法。
- 抗CCR7抗体又はCCR7受容体に対して設計したsiRNA分子を含む組成物を前記線維芽細胞に接触させることをさらに包含する、請求項15又は16に記載の方法。
- 前記線維細胞及び/又は線維芽細胞はインビトロで存在する、請求項15に記載の方法。
- 前記線維細胞及び/又は線維芽細胞はインビボで存在する、請求項15に記載の方法。
- 前記線維細胞及び/又は線維芽細胞は、肺組織中にインビボで存在する、請求項15に記載の方法。
- 線維細胞の移動及び/又は線維芽細胞の活性化を阻害する方法であって、CCL21の活性を阻害する組成物を該線維細胞及び/又は該線維芽細胞に接触させることを包含する、方法。
- 前記線維細胞は哺乳動物においてインビボで存在し、かつ前記方法は、該哺乳動物において線維細胞の肺組織への移動を阻害し、それによって細胞外マトリックスの過剰な生産を防止する、請求項21に記載の方法。
- 前記線維芽細胞は、哺乳動物の肺組織に存在する常在性肺線維芽細胞であり、かつ前記方法は、該哺乳動物の肺組織にある該線維芽細胞の活性化を阻害し、それによって細胞外マトリックスの過剰な生産を防止する、請求項21に記載の方法。
- 肺線維症を治療する方法であって、線維症性の肺疾患にかかっている哺乳動物の肺組織に存在する常在性肺線維芽細胞の活性化及び/又は線維細胞の移動を、該線維芽細胞及び/又は該線維細胞におけるCCL21の活性又は発現を阻害することにより阻害し、それにより、細胞外マトリックスの過剰な生産を防止しかつ肺線維症の症状を改善することを包含する、方法。
- 対象において、放射線により誘発される肺板炎症及び/又は放射線により誘発される肺線維症の治療をする又はその発症を阻害する方法であって、該対象の肺組織にある線維細胞及び/又は線維芽細胞におけるCCL21の存在又は活性を減少させる薬剤を、該対象に投与することを備え、ここで該薬剤は、放射線治療の前、及び/又は、放射線治療中、及び/又は放射線治療後に投与される、方法。
- 該線維形成性障害に関連する線維芽細胞においてCCL19の存在又は活性を減少させる薬剤を投与することをさらに包含する、請求項25に記載の方法。
- 対象において、薬により誘発される肺線維症の治療をするか又はその発症を阻害する方法であって、該対象の肺組織にある線維細胞及び/又は線維芽細胞におけるCCL21の存在又は活性を減少させる薬剤を、該対象に投与することを備え、ここで該薬剤は、該薬の投与前、及び/又は、該薬の投与中、及び/又は該薬の投与後に投与される、方法。
- 該線維形成性障害に関連する線維芽細胞においてCCL19の存在又は活性を減少させる薬剤を投与することをさらに包含する、請求項27に記載の方法。
- 前記薬が、細胞傷害性薬剤、抗生物質、抗不整脈剤、抗炎症剤、及び違法薬物からなる群から選択される、請求項27に記載の方法。
- 前記薬が、アンホテリシンB、ブレオマイシン、ブロモクリプチン、ブスルファン、カルバマゼピン、クロラムブシル、コカイン、シクロホスファミド、ジフェニルヒダントイン、エルゴタミン、フレカイニド、ヘロイン、メルファラン、メタドン、メトトレキサート、メチルフェニデート、メチルセルジド、鉱油、ニトロフラントイン、ニトロソウレア、プロカルバジン、シリコーン、スルファサラジン、トカイニド、及びビンカアルカロイド類の薬剤からなる群から選択される、請求項27に記載の方法。
- 該薬剤が、コルチコステロイド、免疫抑制剤、抗凝血薬、利尿薬、強心配糖体、カルシウムチャネル遮断薬、血管拡張薬、プロスタサイクリン類似体、エンドセリン拮抗薬、ホスホジエステラーゼ阻害剤、β−2アゴニスト、抗ムスカリン剤、エンドペプチダーゼ阻害剤、脂質低下剤、及びトロンボキサン阻害剤、又はそれらの組合せと併用で投与される、請求項24〜30のいずれか1項に記載の方法。
- 線維性病変に存在する線維細胞及び/又は線維芽細胞におけるCCL21の存在又は活性を減少させる薬剤の、必要に応じて、線維性病変に存在する線維細胞及び/又は線維芽細胞におけるCCL19の存在又は活性を減少させる薬剤と併用した、哺乳動物において慢性線維形成性障害を治療するための医薬の製造のための使用。
- 前記薬剤は、CCL21に対して特異的に免疫反応性である抗体である、請求項32に記載の使用。
- 該抗体は、CCL21上のエピトープを他のケモカインよりも優先的に認識するものである、請求項33に記載の使用。
- 該薬剤は、CCL21に対するsiRNA分子である、請求項32に記載の使用。
- 該線維形成性障害は、肺線維症、慢性閉塞性肺疾患、肝臓線維症、関節リウマチ、うっ血性心不全、慢性腎臓疾患、過敏性肺炎、呼吸細気管支炎/間質性肺疾患、マンソン住血吸虫感染、叢状病変により引き起こされる原発性肺高血圧症、肺で発現するヘルペスウイルス関連疾患、皮膚で発現するヘルペスウイルス関連疾患、ケロイド瘢痕、狼瘡、腎性線維形成性皮膚障害、日本住血吸虫感染に伴う線維形成性病変、自己免疫疾患、病原性線維形成、ライム病、膵炎及び間質線維症における間質の再構築、子宮類線維腫、卵巣線維症、角膜線維症、うっ血性心不全及び他の虚血後の症状、腹部の外科手術後の瘢痕形成、広角度緑内障線維柱帯切開術の術後の瘢痕形成、並びにそれらの任意の組合せからなる群から選択される、請求項32に記載の使用。
- 該線維形成性障害は慢性肺線維症である、請求項36に記載の使用。
- 該薬剤は、局所投与、注射、吸入、デポ剤若しくはポンプによる連続的放出、又はそれらの任意の組合せからなる群から選択される投与形態用に処方される、請求項1の使用。
- 抗CCL21抗体又はCCL21に対して設計したsiRNA分子を、必要に応じて、抗CCL19又はCCL19に対して設計したsiRNA分子とともに含む組成物の、線維芽細胞及び/又は線維細胞の増殖を阻害するための医薬の製造のための使用。
- 該使用が、抗CCR7抗体又はCCR7受容体に対して設計したsiRNA分子を含む組成物の、線維芽細胞及び/又は線維細胞の増殖を阻害するための医薬の製造のための使用をさらに含む、請求項39に記載の使用。
- CCL21の活性を阻害する組成物の、線維芽細胞の移動及び/又は線維芽細胞の活性化を阻害するための医薬の製造のための使用。
- 線維細胞におけるCCL21の活性若しくは発現及び/又は常在性肺線維芽細胞の活性化を阻害する組成物の、細胞外マトリックスの過剰な生産を妨げかつ肺線維症の症状を改善することにより肺線維症を治療する医薬の製造のための使用。
- 肺組織にある線維細胞及び/又は線維芽細胞におけるCCL21の存在又は活性を減少させる薬剤の、必要に応じて、肺組織にある線維細胞及び/又は線維芽細胞におけるCCL19の存在又は活性を減少させる薬剤と併用した、放射線により誘発される肺板炎症及び/又は放射線により誘発される肺線維症を治療するための医薬の製造のための使用。
- 肺組織にある線維細胞及び/又は線維芽細胞におけるCCL21の存在又は活性を減少させる薬剤の、必要に応じて、肺組織にある線維細胞及び/又は線維芽細胞におけるCCL19の存在又は活性を減少させる薬剤と併用した、薬により誘発される肺線維症を治療するための医薬の製造のための使用。
- 前記薬は、細胞傷害性薬剤、抗生物質、抗不整脈剤、抗炎症剤、及び違法薬物からなる群から選択されるものである、請求項43又は44に記載の使用。
- 前記薬は、アンホテリシンB、ブレオマイシン、ブロモクリプチン、ブスルファン、カルバマゼピン、クロラムブシル、コカイン、シクロホスファミド、ジフェニルヒダントイン、エルゴタミン、フレカイニド、ヘロイン、メルファラン、メタドン、メトトレキサート、メチルフェニデート、メチルセルジド、鉱油、ニトロフラントイン、ニトロソウレア、プロカルバジン、シリコーン、スルファサラジン、トカイニド、及びビンカアルカロイド類の薬からなる群から選択される、請求項43又は44に記載の使用。
- 前記医薬は、コルチコステロイド、免疫抑制剤、抗凝血薬、利尿薬、強心配糖体、カルシウムチャネル遮断薬、血管拡張薬、プロスタサイクリン類似体、エンドセリン拮抗薬、ホスホジエステラーゼ阻害剤、β−2アゴニスト、抗ムスカリン剤、エンドペプチダーゼ阻害剤、脂質低下剤、及びトロンボキサン阻害剤、又はそれらの組合せと併用される、請求項32〜46のいずれか1項に記載の使用。
- 前記線維細胞及び/又は線維芽細胞においてCCL21及びCCL19の存在又は活性を減少させることは、CCL21及びCCL19を該線維細胞及び/又は線維芽細胞から除去する薬剤を、該慢性線維形成性障害の1つ以上の症状を軽減するのに有効な量で、該哺乳動物に接触させることをさらに包含する、請求項2に記載の方法。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US75364705P | 2005-12-23 | 2005-12-23 | |
PCT/US2006/048282 WO2007075592A2 (en) | 2005-12-23 | 2006-12-19 | Materials and methods for treating chronic fibrotic disease |
Publications (2)
Publication Number | Publication Date |
---|---|
JP2009528977A true JP2009528977A (ja) | 2009-08-13 |
JP2009528977A5 JP2009528977A5 (ja) | 2011-02-10 |
Family
ID=38218516
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2008547405A Pending JP2009528977A (ja) | 2005-12-23 | 2006-12-19 | 慢性線維形成性疾患を治療するための物質および方法 |
Country Status (16)
Country | Link |
---|---|
US (1) | US8795668B2 (ja) |
EP (1) | EP1963492A4 (ja) |
JP (1) | JP2009528977A (ja) |
KR (1) | KR20080081069A (ja) |
CN (1) | CN101351545A (ja) |
BR (1) | BRPI0619638A2 (ja) |
CA (1) | CA2633641A1 (ja) |
MA (1) | MA31060B1 (ja) |
MX (1) | MX2008008238A (ja) |
NO (1) | NO20082434L (ja) |
NZ (1) | NZ568991A (ja) |
RU (1) | RU2446825C2 (ja) |
TN (1) | TNSN08277A1 (ja) |
TW (1) | TW200733974A (ja) |
WO (1) | WO2007075592A2 (ja) |
ZA (1) | ZA200804294B (ja) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2012043533A1 (ja) | 2010-09-28 | 2012-04-05 | 積水化学工業株式会社 | 抗ヒトccr7抗体、ハイブリドーマ、核酸、ベクター、細胞、医薬組成物、並びに、抗体固定化担体 |
WO2015147335A1 (ja) * | 2014-03-27 | 2015-10-01 | 国立大学法人大阪大学 | 脳マラリアの診断および治療 |
Families Citing this family (16)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP5337405B2 (ja) * | 2007-09-17 | 2013-11-06 | ザ・ホスピタル・フォー・シック・チルドレン | ゴーシェ病の治療方法 |
EP2279267A4 (en) * | 2008-03-27 | 2012-01-18 | Vascular Biosciences Inc | METHOD FOR IDENTIFICATION OF NEW THERAPEUTIC CANDIDATES VIA GENE EXPRESSION ANALYSIS IN VASCULAR DISEASES |
WO2010062640A1 (en) * | 2008-10-28 | 2010-06-03 | Gilead Colorado, Inc. | Methods for treating idiopathic pulmonary fibrosis and associated complications |
JP5801202B2 (ja) * | 2009-09-29 | 2015-10-28 | 学校法人慶應義塾 | 抗腫瘍剤およびそのスクリーニング方法 |
WO2011047287A1 (en) * | 2009-10-15 | 2011-04-21 | Immuneregen Biosciences, Inc. | Methods of treating inflammatory and fibrotic lung diseases with substance p analogs |
WO2011080050A2 (en) * | 2009-12-11 | 2011-07-07 | Novartis Ag | Binding molecules |
BR112013019803A2 (pt) * | 2011-02-02 | 2019-06-11 | Excaliard Pharmaceuticals Inc | método de tratar quelóides ou cicatrizes hipertróficas usando os compostos anti-sentido objetivando fator de desenvolvimento de tecido conjuntivo (ctgf) |
GB201118840D0 (en) * | 2011-11-01 | 2011-12-14 | Univ Sheffield | Pulmonary hypertension II |
CN102526114A (zh) * | 2011-12-27 | 2012-07-04 | 苏州人本药业有限公司 | 物理改性后的眼镜蛇蛇毒在制备治疗肺纤维化药物中的用途 |
GB201315486D0 (en) * | 2013-08-30 | 2013-10-16 | Ucb Pharma Sa | Antibodies |
US20170035703A1 (en) * | 2015-10-29 | 2017-02-09 | Hans M. Albertsen | Method of Treating Adhesion by Altering an Epithelial to Mesenchymal Transition |
CN116836977A (zh) * | 2017-03-29 | 2023-10-03 | 中国医学科学院基础医学研究所 | 小rna及其用于预防和/或治疗纤维增生性病症和/或综合征 |
WO2018195392A1 (en) * | 2017-04-20 | 2018-10-25 | Thomas Jefferson University | Trametinib prevents mesothelial-mesenchymal transition and ameliorates abdominal adhesion and pulmonary fibrosis formation |
CN112236445A (zh) * | 2017-12-14 | 2021-01-15 | 芝加哥大学 | 用基因工程化的巨噬细胞治疗纤维化 |
CN108524912A (zh) * | 2018-04-26 | 2018-09-14 | 高常青 | 一种肺纤维化动物模型的构建方法 |
RU2735054C1 (ru) * | 2020-02-27 | 2020-10-27 | Федеральное государственное бюджетное учреждение "Национальный медицинский исследовательский центр кардиологии" Министерства здравоохранения Российской Федерации | Способ профилактики развития реперфузионного поражения ткани легкого с помощью неинвазивной искусственной вентиляции лёгких постоянным положительным давлением у неоперабельных больных с хронической тромбоэмболической легочной гипертензией после транслюминальной баллонной ангиопластики легочной артерии |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2004531265A (ja) * | 2001-06-04 | 2004-10-14 | サイトカイン・ファーマサイエンシズ・インコーポレーテッド | 末梢血線維細胞の分化経路及び創傷部位への遊走 |
Family Cites Families (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
IL95031A (en) * | 1989-07-18 | 2007-03-08 | Amgen Inc | A method of producing a recombinant human necrotic factor absorber |
DK0567566T4 (da) * | 1991-01-18 | 2007-10-22 | Amgen Inc | Fremgangsmåder til behandling af tumornekrosefaktor-medierede sygdomme |
US6495129B1 (en) * | 1994-03-08 | 2002-12-17 | Human Genome Sciences, Inc. | Methods of inhibiting hematopoietic stem cells using human myeloid progenitor inhibitory factor-1 (MPIF-1) (Ckbeta-8/MIP-3) |
AU708558B2 (en) * | 1994-08-23 | 1999-08-05 | Human Genome Sciences, Inc. | Human chemokine beta-9 |
US6139832A (en) * | 1995-02-08 | 2000-10-31 | Human Genome Sciences, Inc. | Leukocyte adhesion inhibitor-1 (LAI-1) Polypeptides |
PT1504764E (pt) * | 1997-08-08 | 2009-01-14 | Univ California | Tratamento da fibrose hepática com anticorpos contra integrina alfa-v-beta 6 |
US20020168358A1 (en) * | 2001-04-30 | 2002-11-14 | Gladue Ronald P. | Treatment of T-cell mediated diseases |
KR20150043568A (ko) * | 2002-07-19 | 2015-04-22 | 애브비 바이오테크놀로지 리미티드 | TNFα 관련 질환의 치료 |
AU2003300266B2 (en) * | 2002-12-23 | 2009-10-08 | William Marsh Rice University | Methods and compositions for suppressing fibrocyte differentiation |
CA2512672A1 (en) * | 2003-01-09 | 2004-07-29 | Arizeke Pharmaceuticals Inc. | Methods of treating lung diseases |
US20050008639A1 (en) * | 2003-02-14 | 2005-01-13 | Chervonsky Alexander V. | Methods of modulating homing of T cell by interruption of chemokine/chemokine receptor signaling |
-
2006
- 2006-12-18 US US11/641,465 patent/US8795668B2/en not_active Expired - Fee Related
- 2006-12-19 KR KR1020087018174A patent/KR20080081069A/ko not_active Application Discontinuation
- 2006-12-19 BR BRPI0619638-1A patent/BRPI0619638A2/pt not_active IP Right Cessation
- 2006-12-19 ZA ZA200804294A patent/ZA200804294B/xx unknown
- 2006-12-19 CA CA002633641A patent/CA2633641A1/en not_active Abandoned
- 2006-12-19 MX MX2008008238A patent/MX2008008238A/es not_active Application Discontinuation
- 2006-12-19 NZ NZ568991A patent/NZ568991A/en not_active IP Right Cessation
- 2006-12-19 WO PCT/US2006/048282 patent/WO2007075592A2/en active Application Filing
- 2006-12-19 RU RU2008130410/15A patent/RU2446825C2/ru not_active IP Right Cessation
- 2006-12-19 EP EP06848920A patent/EP1963492A4/en not_active Withdrawn
- 2006-12-19 CN CNA2006800483424A patent/CN101351545A/zh active Pending
- 2006-12-19 JP JP2008547405A patent/JP2009528977A/ja active Pending
- 2006-12-22 TW TW095148606A patent/TW200733974A/zh unknown
-
2008
- 2008-05-27 NO NO20082434A patent/NO20082434L/no not_active Application Discontinuation
- 2008-06-20 TN TNP2008000277A patent/TNSN08277A1/en unknown
- 2008-07-18 MA MA31135A patent/MA31060B1/fr unknown
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2004531265A (ja) * | 2001-06-04 | 2004-10-14 | サイトカイン・ファーマサイエンシズ・インコーポレーテッド | 末梢血線維細胞の分化経路及び創傷部位への遊走 |
Non-Patent Citations (2)
Title |
---|
JPN6012011140; 王谷卓也: '外科学会会員のための企画 外科と免疫 "組織線維化とfibrocyte"' 日本外科学会雑誌 Vol.106,No.6, 20050601, P.401-404, 社団法人 日本外科学会 * |
JPN6012011142; Nagira,M. et al.: 'Molecular cloning of a novel human CC chemokine secondary lymphoid -tissue chemokine that is a poten' J. Biol. Chem. Vol.272,No.31, 19970801, P.19518-19524 * |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2012043533A1 (ja) | 2010-09-28 | 2012-04-05 | 積水化学工業株式会社 | 抗ヒトccr7抗体、ハイブリドーマ、核酸、ベクター、細胞、医薬組成物、並びに、抗体固定化担体 |
KR20130119923A (ko) | 2010-09-28 | 2013-11-01 | 세키스이가가쿠 고교가부시키가이샤 | 항인간 ccr7 항체, 하이브리도마, 핵산, 벡터, 세포, 의약 조성물 및 항체 고정화 담체 |
US8865170B2 (en) | 2010-09-28 | 2014-10-21 | Sekisui Chemical Co., Ltd. | Anti-human CCR7 antibody, hybridoma, nucleic acid, vector, cell, pharmaceutical composition, and antibody-immobilized carrier |
WO2015147335A1 (ja) * | 2014-03-27 | 2015-10-01 | 国立大学法人大阪大学 | 脳マラリアの診断および治療 |
Also Published As
Publication number | Publication date |
---|---|
CA2633641A1 (en) | 2007-07-05 |
NO20082434L (no) | 2008-08-26 |
TNSN08277A1 (en) | 2009-10-30 |
BRPI0619638A2 (pt) | 2011-10-04 |
RU2008130410A (ru) | 2010-01-27 |
WO2007075592A2 (en) | 2007-07-05 |
WO2007075592A9 (en) | 2007-09-13 |
RU2446825C2 (ru) | 2012-04-10 |
NZ568991A (en) | 2012-04-27 |
WO2007075592A3 (en) | 2008-06-12 |
TW200733974A (en) | 2007-09-16 |
CN101351545A (zh) | 2009-01-21 |
MA31060B1 (fr) | 2010-01-04 |
EP1963492A4 (en) | 2010-06-09 |
US20070172856A1 (en) | 2007-07-26 |
US8795668B2 (en) | 2014-08-05 |
EP1963492A2 (en) | 2008-09-03 |
MX2008008238A (es) | 2009-01-07 |
ZA200804294B (en) | 2009-07-29 |
KR20080081069A (ko) | 2008-09-05 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
RU2446825C2 (ru) | Материалы и способы лечения хронических фиброзных заболеваний | |
JP6251234B2 (ja) | Gi症候群及び移植片対宿主病を治療及び予防する方法 | |
JP5576275B2 (ja) | 再灌流障害および組織損傷を処置するためのtlr−2拮抗薬の使用 | |
US20140212412A1 (en) | Use of il-33 antagonists to treat fibrotic disease | |
JP2015524793A (ja) | 炎症阻害用の抗cxcl9、抗cxcl10、抗cxcl11、抗cxcl13、抗cxcr3、及び抗cxcr5作用剤 | |
KR20220152554A (ko) | 코로나바이러스-유도된 급성 호흡 곤란 증후군의 치료 및/또는 예방을 위해 masp-2를 억제하는 방법 | |
JP2022512735A (ja) | 肝疾患を治療するための組成物および方法 | |
KR20150064147A (ko) | Herv-w 외막 단백질의 발현과 관련된 질환에서 마이엘린의 재생 차단을 치료하는 화합물 | |
JP5746038B2 (ja) | Cnsの炎症性疾患の治療のための化合物および方法 | |
JP2010532334A (ja) | 腎疾患を処置するための化合物および方法 | |
EP3366286A1 (en) | Compounds for treating sepsis | |
JP2023526529A (ja) | サイトカイン放出症候群の診断及び処置の方法 | |
JP2022512706A (ja) | 眼科におけるAkt阻害剤の使用 | |
US20230109697A1 (en) | Combined anti-cytokine therapy to reduce metastatic cancer | |
JP5874124B2 (ja) | 緑内障の処置に使用するための薬学的組成物 | |
US20240316011A1 (en) | Anti-fibrosis pharmaceutical composition and application thereof | |
US20210253705A1 (en) | Methods and agents for treating organ injury and transplant rejection | |
US20200062855A1 (en) | Compositions and methods of promoting wound healing | |
EP4282424A1 (en) | Anti-fibrosis pharmaceutical composition and application thereof | |
US20160304881A1 (en) | Ddr1 antagonist or an inhibitor of ddr1 gene expression for use in the prevention or treatment of crescentic glomerulonephritis | |
JP2021001165A (ja) | オンコスタチンm受容体シグナリング制御による尿路結石の予防と治療 | |
EP4204086A1 (en) | Anti-fibrotic combination | |
Shihan | The regulation of transforming growth factor beta (TGFβ) signaling in posterior capsular opacification | |
WO2018085645A1 (en) | Macrophages redirect phagocytosis by non-professional phagocytes and influence inflammation | |
WO2017046035A1 (en) | Methods and pharmaceutical compositions for the treatment of liver fibrosis |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20091216 |
|
A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20091216 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20101209 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20120301 |
|
A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20120403 |
|
A602 | Written permission of extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A602 Effective date: 20120410 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20120903 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A821 Effective date: 20120903 |
|
A02 | Decision of refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A02 Effective date: 20130529 |