WO2007060278A1 - Empleo de neumocitos tipo ii en el tratamiento de enfermedades pulmonares que cursan con fibrosis pulmonar - Google Patents
Empleo de neumocitos tipo ii en el tratamiento de enfermedades pulmonares que cursan con fibrosis pulmonar Download PDFInfo
- Publication number
- WO2007060278A1 WO2007060278A1 PCT/ES2006/070182 ES2006070182W WO2007060278A1 WO 2007060278 A1 WO2007060278 A1 WO 2007060278A1 ES 2006070182 W ES2006070182 W ES 2006070182W WO 2007060278 A1 WO2007060278 A1 WO 2007060278A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- pneumocytes
- type
- pharmaceutical composition
- lung
- use according
- Prior art date
Links
- 210000002588 alveolar type II cell Anatomy 0.000 title claims abstract description 66
- 208000005069 pulmonary fibrosis Diseases 0.000 title claims abstract description 37
- 238000011282 treatment Methods 0.000 title claims abstract description 33
- 208000019693 Lung disease Diseases 0.000 title claims abstract description 28
- 210000002950 fibroblast Anatomy 0.000 claims abstract description 18
- 239000003814 drug Substances 0.000 claims abstract description 14
- 230000035755 proliferation Effects 0.000 claims abstract description 9
- 230000002401 inhibitory effect Effects 0.000 claims abstract description 6
- 210000004072 lung Anatomy 0.000 claims description 65
- 239000008194 pharmaceutical composition Substances 0.000 claims description 54
- 210000001519 tissue Anatomy 0.000 claims description 43
- 241001465754 Metazoa Species 0.000 claims description 34
- 201000009794 Idiopathic Pulmonary Fibrosis Diseases 0.000 claims description 15
- 208000036971 interstitial lung disease 2 Diseases 0.000 claims description 15
- 229940079593 drug Drugs 0.000 claims description 13
- 238000000034 method Methods 0.000 claims description 13
- 230000002685 pulmonary effect Effects 0.000 claims description 13
- 201000010099 disease Diseases 0.000 claims description 11
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 11
- 239000000843 powder Substances 0.000 claims description 11
- 230000000241 respiratory effect Effects 0.000 claims description 10
- 208000029523 Interstitial Lung disease Diseases 0.000 claims description 8
- 238000002360 preparation method Methods 0.000 claims description 8
- 201000001155 extrinsic allergic alveolitis Diseases 0.000 claims description 7
- 208000022098 hypersensitivity pneumonitis Diseases 0.000 claims description 7
- 238000000338 in vitro Methods 0.000 claims description 7
- 201000003838 Idiopathic interstitial pneumonia Diseases 0.000 claims description 6
- 206010006451 bronchitis Diseases 0.000 claims description 6
- 230000000694 effects Effects 0.000 claims description 6
- 208000035939 Alveolitis allergic Diseases 0.000 claims description 5
- 208000027932 Collagen disease Diseases 0.000 claims description 5
- 206010039710 Scleroderma Diseases 0.000 claims description 5
- 239000000203 mixture Substances 0.000 claims description 5
- 206010035653 pneumoconiosis Diseases 0.000 claims description 4
- 238000001959 radiotherapy Methods 0.000 claims description 4
- 201000000306 sarcoidosis Diseases 0.000 claims description 4
- 206010001881 Alveolar proteinosis Diseases 0.000 claims description 3
- 208000031071 Hamman-Rich Syndrome Diseases 0.000 claims description 3
- 208000026350 Inborn Genetic disease Diseases 0.000 claims description 3
- 201000005099 Langerhans cell histiocytosis Diseases 0.000 claims description 3
- 208000024556 Mendelian disease Diseases 0.000 claims description 3
- 208000037011 Microlithiasis Diseases 0.000 claims description 3
- 201000004073 acute interstitial pneumonia Diseases 0.000 claims description 3
- 230000004075 alteration Effects 0.000 claims description 3
- 206010002022 amyloidosis Diseases 0.000 claims description 3
- 208000023367 bronchiolitis obliterans with obstructive pulmonary disease Diseases 0.000 claims description 3
- 210000000987 immune system Anatomy 0.000 claims description 3
- 210000001821 langerhans cell Anatomy 0.000 claims description 3
- 201000004071 non-specific interstitial pneumonia Diseases 0.000 claims description 3
- 208000005987 polymyositis Diseases 0.000 claims description 3
- 201000009732 pulmonary eosinophilia Diseases 0.000 claims description 3
- 206010039073 rheumatoid arthritis Diseases 0.000 claims description 3
- 201000000596 systemic lupus erythematosus Diseases 0.000 claims description 3
- 201000009803 desquamative interstitial pneumonia Diseases 0.000 claims description 2
- 238000007912 intraperitoneal administration Methods 0.000 claims description 2
- 208000005158 lymphoid interstitial pneumonia Diseases 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 abstract description 7
- 238000004519 manufacturing process Methods 0.000 abstract description 3
- 210000004027 cell Anatomy 0.000 description 28
- 108010006654 Bleomycin Proteins 0.000 description 14
- 229960001561 bleomycin Drugs 0.000 description 14
- 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 description 13
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 12
- 238000007796 conventional method Methods 0.000 description 9
- 210000002919 epithelial cell Anatomy 0.000 description 9
- 210000004043 pneumocyte Anatomy 0.000 description 9
- 206010016654 Fibrosis Diseases 0.000 description 8
- 230000004761 fibrosis Effects 0.000 description 8
- 238000002054 transplantation Methods 0.000 description 8
- 241000700159 Rattus Species 0.000 description 7
- 230000037396 body weight Effects 0.000 description 6
- 230000008569 process Effects 0.000 description 6
- 239000011780 sodium chloride Substances 0.000 description 6
- 102000008186 Collagen Human genes 0.000 description 5
- 108010035532 Collagen Proteins 0.000 description 5
- 210000002383 alveolar type I cell Anatomy 0.000 description 5
- 230000003510 anti-fibrotic effect Effects 0.000 description 5
- 229920001436 collagen Polymers 0.000 description 5
- 230000007423 decrease Effects 0.000 description 5
- PMMYEEVYMWASQN-UHFFFAOYSA-N dl-hydroxyproline Natural products OC1C[NH2+]C(C([O-])=O)C1 PMMYEEVYMWASQN-UHFFFAOYSA-N 0.000 description 5
- 239000003937 drug carrier Substances 0.000 description 5
- -1 for example Substances 0.000 description 5
- 230000006698 induction Effects 0.000 description 5
- 230000002757 inflammatory effect Effects 0.000 description 5
- 239000003112 inhibitor Substances 0.000 description 5
- 230000007170 pathology Effects 0.000 description 5
- 230000009467 reduction Effects 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- 230000001225 therapeutic effect Effects 0.000 description 5
- PMMYEEVYMWASQN-DMTCNVIQSA-N Hydroxyproline Chemical compound O[C@H]1CN[C@H](C(O)=O)C1 PMMYEEVYMWASQN-DMTCNVIQSA-N 0.000 description 4
- 208000004852 Lung Injury Diseases 0.000 description 4
- 206010069363 Traumatic lung injury Diseases 0.000 description 4
- RWSXRVCMGQZWBV-WDSKDSINSA-N glutathione Chemical compound OC(=O)[C@@H](N)CCC(=O)N[C@@H](CS)C(=O)NCC(O)=O RWSXRVCMGQZWBV-WDSKDSINSA-N 0.000 description 4
- 239000003102 growth factor Substances 0.000 description 4
- 229960002591 hydroxyproline Drugs 0.000 description 4
- 238000001727 in vivo Methods 0.000 description 4
- 210000004969 inflammatory cell Anatomy 0.000 description 4
- 231100000515 lung injury Toxicity 0.000 description 4
- 230000004048 modification Effects 0.000 description 4
- 238000012986 modification Methods 0.000 description 4
- XOAAWQZATWQOTB-UHFFFAOYSA-N taurine Chemical compound NCCS(O)(=O)=O XOAAWQZATWQOTB-UHFFFAOYSA-N 0.000 description 4
- FGMPLJWBKKVCDB-UHFFFAOYSA-N trans-L-hydroxy-proline Natural products ON1CCCC1C(O)=O FGMPLJWBKKVCDB-UHFFFAOYSA-N 0.000 description 4
- 238000010171 animal model Methods 0.000 description 3
- 239000003963 antioxidant agent Substances 0.000 description 3
- 210000000981 epithelium Anatomy 0.000 description 3
- 230000003176 fibrotic effect Effects 0.000 description 3
- 239000007789 gas Substances 0.000 description 3
- BCQZXOMGPXTTIC-UHFFFAOYSA-N halothane Chemical compound FC(F)(F)C(Cl)Br BCQZXOMGPXTTIC-UHFFFAOYSA-N 0.000 description 3
- 229960003132 halothane Drugs 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 230000030248 negative regulation of fibroblast proliferation Effects 0.000 description 3
- 108090000765 processed proteins & peptides Proteins 0.000 description 3
- 235000018102 proteins Nutrition 0.000 description 3
- 108090000623 proteins and genes Proteins 0.000 description 3
- 102000004169 proteins and genes Human genes 0.000 description 3
- 210000004879 pulmonary tissue Anatomy 0.000 description 3
- 230000008439 repair process Effects 0.000 description 3
- 230000004044 response Effects 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 238000009331 sowing Methods 0.000 description 3
- 239000004094 surface-active agent Substances 0.000 description 3
- 238000002560 therapeutic procedure Methods 0.000 description 3
- 230000035899 viability Effects 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- 206010001889 Alveolitis Diseases 0.000 description 2
- 206010002091 Anaesthesia Diseases 0.000 description 2
- 241001631457 Cannula Species 0.000 description 2
- 208000032544 Cicatrix Diseases 0.000 description 2
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 description 2
- 102000004127 Cytokines Human genes 0.000 description 2
- 108090000695 Cytokines Proteins 0.000 description 2
- 102400000686 Endothelin-1 Human genes 0.000 description 2
- 101800004490 Endothelin-1 Proteins 0.000 description 2
- 102000010834 Extracellular Matrix Proteins Human genes 0.000 description 2
- 108010037362 Extracellular Matrix Proteins Proteins 0.000 description 2
- 102000003972 Fibroblast growth factor 7 Human genes 0.000 description 2
- 108090000385 Fibroblast growth factor 7 Proteins 0.000 description 2
- 108010024636 Glutathione Proteins 0.000 description 2
- 206010061218 Inflammation Diseases 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- RAHZWNYVWXNFOC-UHFFFAOYSA-N Sulphur dioxide Chemical compound O=S=O RAHZWNYVWXNFOC-UHFFFAOYSA-N 0.000 description 2
- 102000004887 Transforming Growth Factor beta Human genes 0.000 description 2
- 108090001012 Transforming Growth Factor beta Proteins 0.000 description 2
- 230000002159 abnormal effect Effects 0.000 description 2
- 230000016571 aggressive behavior Effects 0.000 description 2
- 210000001132 alveolar macrophage Anatomy 0.000 description 2
- 230000037005 anaesthesia Effects 0.000 description 2
- 238000000540 analysis of variance Methods 0.000 description 2
- 230000003078 antioxidant effect Effects 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 238000001574 biopsy Methods 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000006285 cell suspension Substances 0.000 description 2
- 238000005119 centrifugation Methods 0.000 description 2
- 238000002648 combination therapy Methods 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 229960004397 cyclophosphamide Drugs 0.000 description 2
- 210000000805 cytoplasm Anatomy 0.000 description 2
- 230000034994 death Effects 0.000 description 2
- 230000008021 deposition Effects 0.000 description 2
- 231100000676 disease causative agent Toxicity 0.000 description 2
- 210000002744 extracellular matrix Anatomy 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 229960003180 glutathione Drugs 0.000 description 2
- 230000012010 growth Effects 0.000 description 2
- 230000036541 health Effects 0.000 description 2
- 229960003444 immunosuppressant agent Drugs 0.000 description 2
- 239000003018 immunosuppressive agent Substances 0.000 description 2
- 230000001965 increasing effect Effects 0.000 description 2
- 208000015181 infectious disease Diseases 0.000 description 2
- 230000004054 inflammatory process Effects 0.000 description 2
- 230000003993 interaction Effects 0.000 description 2
- 210000000265 leukocyte Anatomy 0.000 description 2
- 238000011694 lewis rat Methods 0.000 description 2
- 239000003580 lung surfactant Substances 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- 230000002297 mitogenic effect Effects 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 229960001639 penicillamine Drugs 0.000 description 2
- 229960001412 pentobarbital Drugs 0.000 description 2
- WEXRUCMBJFQVBZ-UHFFFAOYSA-N pentobarbital Chemical compound CCCC(C)C1(CC)C(=O)NC(=O)NC1=O WEXRUCMBJFQVBZ-UHFFFAOYSA-N 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 239000002953 phosphate buffered saline Substances 0.000 description 2
- 230000002265 prevention Effects 0.000 description 2
- 238000004393 prognosis Methods 0.000 description 2
- 230000000750 progressive effect Effects 0.000 description 2
- 210000001147 pulmonary artery Anatomy 0.000 description 2
- 231100000241 scar Toxicity 0.000 description 2
- 230000037390 scarring Effects 0.000 description 2
- 230000037387 scars Effects 0.000 description 2
- BNRNXUUZRGQAQC-UHFFFAOYSA-N sildenafil Chemical compound CCCC1=NN(C)C(C(N2)=O)=C1N=C2C(C(=CC=1)OCC)=CC=1S(=O)(=O)N1CCN(C)CC1 BNRNXUUZRGQAQC-UHFFFAOYSA-N 0.000 description 2
- 230000001629 suppression Effects 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 229960003080 taurine Drugs 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 230000002227 vasoactive effect Effects 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- HRANPRDGABOKNQ-ORGXEYTDSA-N (1r,3r,3as,3br,7ar,8as,8bs,8cs,10as)-1-acetyl-5-chloro-3-hydroxy-8b,10a-dimethyl-7-oxo-1,2,3,3a,3b,7,7a,8,8a,8b,8c,9,10,10a-tetradecahydrocyclopenta[a]cyclopropa[g]phenanthren-1-yl acetate Chemical compound C1=C(Cl)C2=CC(=O)[C@@H]3C[C@@H]3[C@]2(C)[C@@H]2[C@@H]1[C@@H]1[C@H](O)C[C@@](C(C)=O)(OC(=O)C)[C@@]1(C)CC2 HRANPRDGABOKNQ-ORGXEYTDSA-N 0.000 description 1
- BJBUEDPLEOHJGE-UHFFFAOYSA-N (2R,3S)-3-Hydroxy-2-pyrolidinecarboxylic acid Natural products OC1CCNC1C(O)=O BJBUEDPLEOHJGE-UHFFFAOYSA-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
- CUKWUWBLQQDQAC-VEQWQPCFSA-N (3s)-3-amino-4-[[(2s)-1-[[(2s)-1-[[(2s)-1-[[(2s,3s)-1-[[(2s)-1-[(2s)-2-[[(1s)-1-carboxyethyl]carbamoyl]pyrrolidin-1-yl]-3-(1h-imidazol-5-yl)-1-oxopropan-2-yl]amino]-3-methyl-1-oxopentan-2-yl]amino]-3-(4-hydroxyphenyl)-1-oxopropan-2-yl]amino]-3-methyl-1-ox Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](C)C(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@@H](N)CC(O)=O)C(C)C)C1=CC=C(O)C=C1 CUKWUWBLQQDQAC-VEQWQPCFSA-N 0.000 description 1
- 206010001488 Aggression Diseases 0.000 description 1
- 102000005862 Angiotensin II Human genes 0.000 description 1
- 101800000733 Angiotensin-2 Proteins 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- 239000002083 C09CA01 - Losartan Substances 0.000 description 1
- 208000005623 Carcinogenesis Diseases 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 206010011224 Cough Diseases 0.000 description 1
- VVNCNSJFMMFHPL-VKHMYHEASA-N D-penicillamine Chemical compound CC(C)(S)[C@@H](N)C(O)=O VVNCNSJFMMFHPL-VKHMYHEASA-N 0.000 description 1
- 206010013453 Disseminated tuberculosis Diseases 0.000 description 1
- 208000000059 Dyspnea Diseases 0.000 description 1
- 206010013975 Dyspnoeas Diseases 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 102000018233 Fibroblast Growth Factor Human genes 0.000 description 1
- 108050007372 Fibroblast Growth Factor Proteins 0.000 description 1
- CEAZRRDELHUEMR-URQXQFDESA-N Gentamicin Chemical compound O1[C@H](C(C)NC)CC[C@@H](N)[C@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](NC)[C@@](C)(O)CO2)O)[C@H](N)C[C@@H]1N CEAZRRDELHUEMR-URQXQFDESA-N 0.000 description 1
- 229930182566 Gentamicin Natural products 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- 208000028782 Hereditary disease Diseases 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 206010058490 Hyperoxia Diseases 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
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- 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 description 1
- 206010049459 Lymphangioleiomyomatosis Diseases 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 201000006836 Miliary Tuberculosis Diseases 0.000 description 1
- 241001430197 Mollicutes Species 0.000 description 1
- 241001529936 Murinae Species 0.000 description 1
- 241000244206 Nematoda Species 0.000 description 1
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 1
- 208000037273 Pathologic Processes Diseases 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- 102000035195 Peptidases Human genes 0.000 description 1
- 108091005804 Peptidases Proteins 0.000 description 1
- 206010035664 Pneumonia Diseases 0.000 description 1
- 241000288906 Primates Species 0.000 description 1
- 208000035977 Rare disease Diseases 0.000 description 1
- 108090000103 Relaxin Proteins 0.000 description 1
- 102000003743 Relaxin Human genes 0.000 description 1
- 208000004756 Respiratory Insufficiency Diseases 0.000 description 1
- 102000004142 Trypsin Human genes 0.000 description 1
- 108090000631 Trypsin Proteins 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 210000004712 air sac Anatomy 0.000 description 1
- 210000002821 alveolar epithelial cell Anatomy 0.000 description 1
- 235000001014 amino acid Nutrition 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- IYIKLHRQXLHMJQ-UHFFFAOYSA-N amiodarone Chemical compound CCCCC=1OC2=CC=CC=C2C=1C(=O)C1=CC(I)=C(OCCN(CC)CC)C(I)=C1 IYIKLHRQXLHMJQ-UHFFFAOYSA-N 0.000 description 1
- 229960005260 amiodarone Drugs 0.000 description 1
- 239000002333 angiotensin II receptor antagonist Substances 0.000 description 1
- 229950006323 angiotensin ii Drugs 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 238000011861 anti-inflammatory therapy Methods 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 210000000702 aorta abdominal Anatomy 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000007900 aqueous suspension Substances 0.000 description 1
- 239000010425 asbestos Substances 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- 238000002555 auscultation Methods 0.000 description 1
- 229960002170 azathioprine Drugs 0.000 description 1
- LMEKQMALGUDUQG-UHFFFAOYSA-N azathioprine Chemical compound CN1C=NC([N+]([O-])=O)=C1SC1=NC=NC2=C1NC=N2 LMEKQMALGUDUQG-UHFFFAOYSA-N 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000003123 bronchiole Anatomy 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 230000036952 cancer formation Effects 0.000 description 1
- 231100000504 carcinogenesis Toxicity 0.000 description 1
- 230000030833 cell death Effects 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 239000002738 chelating agent Substances 0.000 description 1
- GLNADSQYFUSGOU-UHFFFAOYSA-J chembl1640 Chemical compound [Na+].[Na+].[Na+].[Na+].C1=C(S([O-])(=O)=O)C=C2C=C(S([O-])(=O)=O)C(N=NC3=CC=C(C=C3C)C=3C=C(C(=CC=3)N=NC=3C(=CC4=CC(=CC(N)=C4C=3O)S([O-])(=O)=O)S([O-])(=O)=O)C)=C(O)C2=C1N GLNADSQYFUSGOU-UHFFFAOYSA-J 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 208000037976 chronic inflammation Diseases 0.000 description 1
- 230000006020 chronic inflammation Effects 0.000 description 1
- 239000003245 coal Substances 0.000 description 1
- 210000002808 connective tissue Anatomy 0.000 description 1
- 239000003246 corticosteroid Substances 0.000 description 1
- 229960001334 corticosteroids Drugs 0.000 description 1
- 229940127089 cytotoxic agent Drugs 0.000 description 1
- 231100000599 cytotoxic agent Toxicity 0.000 description 1
- 239000002254 cytotoxic agent Substances 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- 235000001434 dietary modification Nutrition 0.000 description 1
- 230000029087 digestion Effects 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
- 229940042399 direct acting antivirals protease inhibitors Drugs 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 208000017574 dry cough Diseases 0.000 description 1
- 210000003038 endothelium Anatomy 0.000 description 1
- 210000003989 endothelium vascular Anatomy 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 230000009841 epithelial lesion Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000012091 fetal bovine serum Substances 0.000 description 1
- 239000000835 fiber Substances 0.000 description 1
- 230000003328 fibroblastic effect Effects 0.000 description 1
- 230000000893 fibroproliferative effect Effects 0.000 description 1
- 230000009795 fibrotic process Effects 0.000 description 1
- 230000037406 food intake Effects 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 230000008014 freezing Effects 0.000 description 1
- 238000007710 freezing Methods 0.000 description 1
- 239000003517 fume Substances 0.000 description 1
- 230000014509 gene expression Effects 0.000 description 1
- 238000012239 gene modification Methods 0.000 description 1
- 238000001415 gene therapy Methods 0.000 description 1
- 230000005017 genetic modification Effects 0.000 description 1
- 235000013617 genetically modified food Nutrition 0.000 description 1
- 229960002518 gentamicin Drugs 0.000 description 1
- 239000003862 glucocorticoid Substances 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 1
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 1
- 239000010931 gold Substances 0.000 description 1
- 229910052737 gold Inorganic materials 0.000 description 1
- 229940076085 gold Drugs 0.000 description 1
- 208000035474 group of disease Diseases 0.000 description 1
- 244000144993 groups of animals Species 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 230000000222 hyperoxic effect Effects 0.000 description 1
- 208000026278 immune system disease Diseases 0.000 description 1
- 229940124622 immune-modulator drug Drugs 0.000 description 1
- 238000002650 immunosuppressive therapy Methods 0.000 description 1
- 239000007943 implant Substances 0.000 description 1
- 238000002513 implantation Methods 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 230000028709 inflammatory response Effects 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 102000006495 integrins Human genes 0.000 description 1
- 108010044426 integrins Proteins 0.000 description 1
- 239000007928 intraperitoneal injection Substances 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 210000001503 joint Anatomy 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 231100000518 lethal Toxicity 0.000 description 1
- 230000001665 lethal effect Effects 0.000 description 1
- 210000003041 ligament Anatomy 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 239000002502 liposome Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- KJJZZJSZUJXYEA-UHFFFAOYSA-N losartan Chemical compound CCCCC1=NC(Cl)=C(CO)N1CC1=CC=C(C=2C(=CC=CC=2)C=2[N]N=NN=2)C=C1 KJJZZJSZUJXYEA-UHFFFAOYSA-N 0.000 description 1
- 229960004773 losartan Drugs 0.000 description 1
- 210000005265 lung cell Anatomy 0.000 description 1
- 230000000527 lymphocytic effect Effects 0.000 description 1
- 239000003550 marker Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 229960000485 methotrexate Drugs 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 239000003226 mitogen Substances 0.000 description 1
- 235000001968 nicotinic acid Nutrition 0.000 description 1
- 229960003512 nicotinic acid Drugs 0.000 description 1
- 239000011664 nicotinic acid Substances 0.000 description 1
- 238000000399 optical microscopy Methods 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- FIKAKWIAUPDISJ-UHFFFAOYSA-L paraquat dichloride Chemical compound [Cl-].[Cl-].C1=C[N+](C)=CC=C1C1=CC=[N+](C)C=C1 FIKAKWIAUPDISJ-UHFFFAOYSA-L 0.000 description 1
- 210000004738 parenchymal cell Anatomy 0.000 description 1
- 230000008506 pathogenesis Effects 0.000 description 1
- 230000001717 pathogenic effect Effects 0.000 description 1
- 230000009543 pathological alteration Effects 0.000 description 1
- 230000009054 pathological process Effects 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 1
- 238000011422 pharmacological therapy Methods 0.000 description 1
- 231100000614 poison Toxicity 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 229960004618 prednisone Drugs 0.000 description 1
- 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 1
- 230000035935 pregnancy Effects 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002206 pro-fibrotic effect Effects 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 235000019833 protease Nutrition 0.000 description 1
- 201000003651 pulmonary sarcoidosis Diseases 0.000 description 1
- 230000008704 pulmonary vasodilation Effects 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 239000002516 radical scavenger Substances 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 230000007115 recruitment Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 201000004193 respiratory failure Diseases 0.000 description 1
- 230000029058 respiratory gaseous exchange Effects 0.000 description 1
- 210000001533 respiratory mucosa Anatomy 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 229910052895 riebeckite Inorganic materials 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 239000003352 sequestering agent Substances 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 229960003310 sildenafil Drugs 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 210000003491 skin Anatomy 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 238000010186 staining Methods 0.000 description 1
- 238000007619 statistical method Methods 0.000 description 1
- 210000000130 stem cell Anatomy 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 229940124530 sulfonamide Drugs 0.000 description 1
- 150000003456 sulfonamides Chemical class 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 229940037128 systemic glucocorticoids Drugs 0.000 description 1
- ZRKFYGHZFMAOKI-QMGMOQQFSA-N tgfbeta Chemical compound C([C@H](NC(=O)[C@H](C(C)C)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CC(C)C)NC(=O)CNC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CCSC)C(C)C)[C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O)C1=CC=C(O)C=C1 ZRKFYGHZFMAOKI-QMGMOQQFSA-N 0.000 description 1
- 230000008719 thickening Effects 0.000 description 1
- 210000000115 thoracic cavity Anatomy 0.000 description 1
- 230000017423 tissue regeneration Effects 0.000 description 1
- 239000003440 toxic substance Substances 0.000 description 1
- 231100000027 toxicology Toxicity 0.000 description 1
- 210000003437 trachea Anatomy 0.000 description 1
- BJBUEDPLEOHJGE-IMJSIDKUSA-N trans-3-hydroxy-L-proline Chemical compound O[C@H]1CC[NH2+][C@@H]1C([O-])=O BJBUEDPLEOHJGE-IMJSIDKUSA-N 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 239000012588 trypsin Substances 0.000 description 1
- 210000001835 viscera Anatomy 0.000 description 1
- 230000004580 weight loss Effects 0.000 description 1
Classifications
-
- 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
- C12N5/06—Animal cells or tissues; Human cells or tissues
- C12N5/0602—Vertebrate cells
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
- A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
- A61K35/42—Respiratory system, e.g. lungs, bronchi or lung cells
-
- 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
- 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
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
-
- 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
- A61P35/00—Antineoplastic agents
-
- 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
-
- 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
- A61P37/08—Antiallergic agents
-
- 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
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/10—Antioedematous agents; Diuretics
Definitions
- the invention relates, in general, to the treatment of lung diseases that present with pulmonary fibrosis; and, in particular, with the use of type II pneumocytes in the treatment of said diseases.
- EID diffuse interstitial lung diseases
- the main pathological alterations affect the alveolo-interstitial structures .
- they also affect the small airways, as well as the pulmonary vessels.
- This group of lung diseases is characterized by inflammation and scarring of the alveoli and their supporting structures (the interstitium), which leads to the loss of the alveolar functional units and a reduction in the transfer of oxygen from the air to the blood.
- EPID The etiology of EPID is very varied. Currently, more than 150 different causes are known, although it is only possible to identify their causative agent in approximately 35% of them. Its classification has recently been modified following the consensus drawn up by the American Thoracic Society (ATS) and the European Respiratory Society (ERS) (see Table 1). Several groups of EPID are distinguished. The first group corresponds to idiopathic interstitial pneumonias although granulomatous lung diseases, such as sarcoidosis, are also included in this group.
- the second group includes EPIDs of known cause or associated with other well-defined clinical entities; This group includes pulmonary manifestations of collagen diseases, which often have an indistinguishable histology of idiopathic interstitial pneumonias, as well as EPIDs caused by drugs, organic powders (extrinsic allergic alveolitis), powders inorganic (pneumoconiosis) and those associated with hereditary diseases.
- the third group consists of a group of diseases that, although idiopathic, have a well-defined clinical and histology.
- EPID diffuse interstitial lung diseases
- Pulmonary eosinophilias Histiocytosis X granulomatosis of Langerhans cells
- Amyloidosis The most frequent EPIDs are idiopathic pulmonary fibrosis and sarcoidosis, followed by extrinsic allergic alveolitis and those associated with collagen diseases.
- Idiopathic pulmonary fibrosis is the most frequent of the EPIDs and refers to pathologies that present a form of chronic interstitial fibrosing pneumopathy, limited to the lung and associated with a histopathological pattern of usual interstitial pneumonia (classic pattern associated with the biopsy of the IPF).
- the estimated prevalence of IPF is 20 cases per 100,000 (20 / 100,000) inhabitants in men and 13 / 100,000 in women. This disease can occur at any age although it is more common between 40 and 70 years. Once the disease is diagnosed, mortality is 50% at 5 years. The incidence, prevalence and mortality rate increases with age.
- inflammatory cells are considered to act directly on fibroblasts, through a wide variety of inflammatory mediators, cytokines and growth factors, although the interactions of these inflammatory modulators with lung parenchyma cells also play an important role.
- cytokines cytokines
- growth factors cytokines
- interactions between inflammatory cells with the epithelium and pulmonary endothelium are also important.
- the interstitium of the alveoli is very thin and the number of fibroblasts is limited. Most of the fibroblasts and collagen fibers are distributed along the vessels and ducts of the airways. It seems that the balance between fibrotic and antifibrotic factors results in the suppression of fibroblast proliferation and extracellular matrix.
- the IPF is currently considered to be the end result of an unknown aggression that causes chronic inflammation associated with lung tissue disruption and fibrosis formation as a result of abnormal lesion repair. All this would lead to a progressive accumulation of extracellular matrix, a decrease between the fibroblast-myofibroblast balance, the continued death of epithelial cells and, finally, an abnormal re-epithelialization.
- the main objectives of the treatment for EPIDs are, in general, to avoid exposure to the causative agent, suppress the inflammatory component of the disease (alveolitis) and treat complications.
- the first objective can only be achieved in diseases of known etiology.
- the suppression of alveolitis is the only therapeutic means in EPIDs of unknown cause, since antifibrotic drugs with proven efficacy are currently unavailable.
- the drugs used are glucocorticoids and immunosuppressants. Indications and duration of treatment vary according to the type of EPID. A recent study has shown that sildenafil causes pulmonary vasodilation and improvement of gas exchange. However, there is no recommended strategy.
- corticosteroids prednisone
- immunosuppressants / cytotoxic agents
- antifibrotic agents colxicine or D-penicillamine
- Pulmonary transplantation is the last therapeutic option for EPIDs that progress to fibrosis and cause respiratory failure. There are more than 120 causes of EPID that evolve to fibrosis and, therefore, it is very difficult to identify the transplant window (ideal time for transplantation in each patient, without being too early or too late to compromise the viability of the transplant).
- the new therapies could include: inhibitors of oxidizing agents, cytokine inhibitors, protease inhibitors, inhibitors of fibroblasts or growth factors, antifibrotic agents, dietary modifications, better efficiency of the drugs administered intrapulmonary route, such as the use of liposomes, antioxidants, leukocyte integrin inhibitors, and, finally, gene therapy.
- Relaxin a peptide that is used in the last stages of pregnancy and helps to reshape pubic ligaments, decreases the production of collagen in fibroblast cultures and disrupts the balance between proteinases and anti-proteinases, in favor of the breakage of the matrix .
- Sumarin a synthetic compound that has been used for many years to treat infections caused by nematodes, inhibits the effects of numerous profibrotic growth factors.
- Endothelin-1 a mitogenic and vasoactive peptide that is synthesized and secreted in the vascular endothelium and in the epithelium of the airways, has been found associated with the fibroblastic focus of biopsies and can be obtained in broncho-alveolar washes; In animal models, inhibition of endothelin-1 prevents scars after causing lung injury.
- Angiotensin II is another vasoactive peptide with mitogenic effects on fibroblasts.
- antioxidant strategies might be beneficial. Possible strategies would include the administration of antioxidant enzymes or promoting an increase in their gene expression. Glutathione a natural scavenger agent of the RLO suppresses the proliferation of pulmonary fibroblasts in response to mitogens. Taurine and niacin inhibit the development of fibrosis in animal models.
- the use of high doses of N-acetyl-L-cysteine has been suggested, as a precursor to glutathione, taurine and RLO sequestering agents, as a therapeutic combination in immunosuppressive therapies for IPF.
- Adhesion molecules play a very important role in this process. Antibodies against these adhesion molecules have shown a prevention of collagen deposition in animal models of lung injury. Immunomodulatory drugs have also been studied in both in vitro studies and research animals. These works suggest that the modification of the inflammatory response in tissue repair can modulate the degree of final fibrosis after lung injury. An effective therapy should try to prevent or inhibit the fibroproliferative response and be aimed at improving the repair of alveolar re-epithelialization. In this way, the impact of the disease would be reduced by improving the health of the patients.
- the inventors have observed that through the transplantation of said cells a correct re-epithelialization of the damaged lung is achieved. Therefore, the transplantation of type II pneumocytes intratracheally produces a synergistic effect in the transplanted animals since, on the one hand, it slows the growth of fibroblasts, and, on the other hand, produces a correct re-epithelialization of the damaged lung, thus stopping the progression of the disease.
- Treatment with said type II pneumocytes can be combined, if desired, with other therapies useful in the treatment of lung diseases that present with pulmonary fibrosis. Therefore, the present invention relates to the use of type II pneumocytes in the preparation of a pharmaceutical composition for the treatment of lung diseases that present with pulmonary fibrosis.
- said lung diseases are selected from EPID, among which is the IPF, and some alterations of the immune system, among which is the scleroderma.
- Figure 1 is a graph that represents the evolution of the body weight of the animals; on zero day (0) the animals are treated with bleomycin (BLM) that results in weight loss, the arrows show the days of cell transplants (3, 7 and 15 days).
- the graph shows that the administration of type II pneumocytes makes body weight recover more quickly in all transplanted animals. Data represent the mean ⁇ SEM of a total of 8 animals per group.
- Figure 2 is a bar chart that represents the weight of the lungs in control animals and to which they have been induced pulmonary fibrosis (BLM) and the different times in which the cell transplants have been performed (3, 7 and 15 days - BLM T3, BLM T7 and BLM Tl 5, respectively). The graph shows that the administration of type II pneumocytes results in a significant decrease in lung weight in transplanted animals at 7 days and at 15 days. Data represent the mean ⁇ SEM of a total of 8 animals per group.
- BLM induced pulmonary fibrosis
- Figure 3 is a bar chart showing hydroxyproline levels in the lung.
- the graph shows that the levels of hydroxyproline in lungs that had been transplanted type II pneumocytes are reduced at all times (days 3, 7 and 15) with respect to non-transplanted animals. This decrease in collagen levels is really evident in transplanted animals at 7 and 15 days, where it is observed that hydroxyproline levels match the control animals.
- Data represent the mean ⁇ SEM of a total of 8 animals per group.
- Figure 4 shows some optical microscopy photographs of lung preparations. The photographs show a reduction in the foci of induced pulmonary fibrosis in those animals that have been transplanted with type II pneumocytes at different times (days 3, 7 and 15). DETAILED DESCRIPTION OF THE INVENTION
- the present invention relates to the use of type II pneumocytes in the preparation of a pharmaceutical composition for the treatment of lung diseases that occur with pulmonary fibrosis.
- type II pneumocytes refers to pulmonary epithelial cells with a cuboidal appearance, whose apical surface is covered by microbilis and its cytoplasm is filled with bodies of laminar inclusions composed of lipids and proteins that constitute the surfactant.
- An important function of type II pneumocytes (or type II epithelial cells) is the synthesis, storage and secretion of pulmonary surfactant, which acts by reducing surface tension and preventing collapse of the alveoli.
- Type II epithelial cells comprise 14% of the total alveolar epithelial cells, these cells can be separated from other lung cells using conventional techniques [Richards RJ et al, 1987. Isolation, biochemical characterization, and culture of lung type II cells of the rat Lung 165: 143-158].
- Type II pneumocytes are the progenitors of type I pneumocytes [Johnson NF et al., 1990. Epithelial progenitor cells in the rat respiratory traxt. In: Byology, toxicology, and carcinogenesis of respiratory epithelium. Thomassen, DG and Nettesheim, P (E.d). Hemipere publish Corporation, New York: 1990; 1-308].
- type I pneumocytes refers to pulmonary epithelial cells specialized in gas exchange. Type I cells are very thin and flattened and cover 95% of the alveolar surface [Crapo et al, 1982. CeIl numbers and cell characteristics of the normal lung. Am. Rev. Respir.Dis. 126: 332-337].
- type II pneumocytes Under normal conditions, approximately 1% of type II pneumocytes are responsible for alveolar surface renewal differentiating from type I pneumocytes. This fact is important since type I pneumocytes are especially vulnerable to lung injury due to their surface and simplicity of its cytoplasm. Under these circumstances, type II pneumocytes proliferate and repopulate the surface of the alveoli, providing the integrity of the epithelium. Thus, said type II pneumocytes become type I pneumocytes, completely restructuring the alveolar surface.
- type II pneumocytes can be "wild type” type II pneumocytes, that is, they have not been genetically engineered.
- said type II pneumocytes they can be genetically modified to increase, enhance or favor the fibrogenesis inhibitory activity of said "wt" type II pneumocytes and / or to increase, enhance or favor the re-epithelial activity of said "wt" type II pneumocytes, giving rise to called “genetically modified type II pneumocytes" in this description.
- modifications that may be introduced include modifications aimed at overexpressing proteins related to the production of pulmonary surfactant, for example, surfactant proteins A and D, etc., as well as modifications aimed at increasing the proliferation of type pneumocytes. II, for example, the keratinocyte growth factor, etc., among others. Genetic modifications to be made in type II pneumocytes can be made by conventional methods known to those skilled in the art. Therefore, as used herein, the term "type II pneumocytes" includes (i) type II "wt" pneumocytes, (ii) genetically modified type II pneumocytes, and (iii) combinations of type "wt" pneumocytes and pneumocytes Type II genetically modified. Type II pneumocytes can be of autologous or heterologous origin, preferably type II pneumocytes are of autologous origin.
- subject refers to any member of an animal species of mammals and includes, but is not limited to, domestic animals, primates and humans;
- the subject is preferably a male or female human being of any age or race.
- lung diseases that occur with pulmonary fibrosis refers to lung diseases characterized by the presence of scars in the lungs so that, gradually, the air sacs (alveoli) are replaced by fibrotic tissue.
- Illustrative, non-limiting examples of such lung diseases that present with pulmonary fibrosis include diffuse interstitial lung diseases (EPID), as well as some immune system disorders (eg, rheumatoid arthritis, scleroderma, polymyositis, and, in rare cases, systemic lupus erythematosus ).
- EPID diffuse interstitial lung diseases
- immune system disorders eg, rheumatoid arthritis, scleroderma, polymyositis, and, in rare cases, systemic lupus erythematosus ).
- pulmonary fibrosis include (by way of illustration not limitation): infections caused by viruses, rickettsiae, mycoplasmas and disseminated tuberculosis; the inhalation of organic or inorganic powders, for example, mineral powders such as silica, coal, etc., metal powders and asbestos, etc .; the inhalation of gases, fumes and vapors (eg, chlorine, sulfur dioxide, etc.); radiotherapy for antitumor treatments and industrial radiation; and the ingestion of some drugs and toxic substances such as bleomycin, methotrexate, bususlfan, cyclophosphamide, gold, penicillamine, nitrofurantiine, sulfonamides, amiodarone, paraquat, etc .; In general, these agents produce, in principle, diffuse diseases of the lung parenchyma.
- EPID refers to those lung diseases characterized by inflammation and scarring (fibrosis) of the alveoli and their supporting structures (the interstitium).
- Illustrative, non-limiting examples of such EPIDs include idiopathic interstitial pneumonia, granulomatous lung diseases, and EPID of known cause or associated with other well-defined clinical entities.
- said pulmonary pathology is selected from idiopathic pulmonary fibrosis (IPF), acute interstitial pneumonia, non-specific interstitial pneumonia, respiratory bronchitis with interstitial lung disease (respiratory bronchitis / EPID), desquamative interstitial pneumonia, crypto-genetic organized pneumonia, lymphocytic interstitial pneumonia, sarcoidosis, EPID associated with collagen diseases, caused by inorganic powders (pneumoconiosis), induced by drugs and radiotherapy, caused by organic powders (extrinsic allergic alveolitis), associated with hereditary diseases, alveolar proteinosis, alveolar microlithiasis, lymphangioleiasis myomatosis, pulmonary eosinophilias, histiocytosis X (granulomatosis of Langerhans cells), amyloidosis.
- said EPID is FPI.
- said pulmonary disease with pulmonary fibrosis is an alteration of the immune system, for example, rheumatoid arthritis, scleroderma, polymyositis, and, in rare cases, systemic lupus erythematosus.
- the term "scleroderma”, as used herein, refers to a rare disease of the connective tissue that can cause thickening and hardening of skin tissues, joints and internal organs such as the lungs. This form is more serious and can be fatal.
- type II pneumocytes For administration in the treatment of a pulmonary pathology with pulmonary fibrosis, type II pneumocytes will be formulated in an appropriate pharmaceutical composition, hereinafter referred to as the "pharmaceutical composition of the invention", in a therapeutically effective amount, together with one or more pharmaceutically acceptable carriers, adjuvants or excipients.
- the term "type II pneumocytes” includes “wt” type II pneumocytes, genetically modified type II pneumocytes, and combinations of "wt” type II pneumocytes and genetically modified type II pneumocytes. Therefore, in a particular embodiment, the pharmaceutical composition of the invention comprises "wt" type II pneumocytes. In another particular embodiment, the pharmaceutical composition of the invention comprises genetically modified type II pneumocytes.
- the pharmaceutical composition of the invention comprises a mixture or combination of "wt" type II pneumocytes and genetically modified type II pneumocytes.
- therapeutically effective amount refers to the amount of type II ("wt" and / or genetically modified) pneumocytes contained in the pharmaceutical composition of the invention calculated to produce the desired effect and, in general, it will be determined, among other causes, by the characteristics of said type II pneumocytes and the effect of inhibition of fibroblast proliferation and re-epithelialization of the alveolar surface to be achieved.
- the therapeutically effective amount of type II pneumocytes to be administered will depend, among other factors, on the subject to be treated, on the pathology he suffers, on his severity, on the form of administration chosen, etc. For this reason, the doses mentioned in this invention should be considered only as guidelines for the person skilled in the art, and he must adjust the doses according to the variables mentioned above.
- the pharmaceutical composition of the invention can be administered in a single dose containing between about IxIO 6 cells and about 25xlO 6 cells, advantageously, between about 2.5x10 6 cells and about 2OxIO 6 cells, preferably, between about 5xlO 6 cells and approximately 1OxIO 6 cells, depending on the factors mentioned previously.
- the dose of type II pneumocytes can be repeated, depending on the patient's condition and evolution, at intervals of time (days, weeks or months) that will have to be established in each case by the specialist.
- the pharmaceutical composition of the invention will be prepared, in general, in a pharmaceutical form of administration suitable to facilitate contact between type II ("wt" and / or genetically modified) pneumocytes and the affected lung tissue in order for it to occur.
- the desired effect that is, an inhibition of fibroblast proliferation and, advantageously, a correct re-epithelialization of the affected tissue; therefore, said pharmaceutical composition of the invention will be formulated in a pharmaceutical form suitable to the route of administration chosen.
- Said pharmaceutical composition of the invention can be administered in vivo directly on the lung tissue of the subject in need of treatment, or it can be administered in vitro on the affected lung tissue previously removed and subsequently re-implanted in the subject in need of treatment afterwards. of the administration of the pharmaceutical composition of the invention.
- the pharmaceutical composition of the invention may be administered by any appropriate route, for example, by pulmonary, intratracheal, nasal, parenteral, intraperitoneal, etc., preferably, pulmonary route. , intratracheal, nasal or parenteral, for which the pharmaceutical composition of the invention will incorporate the appropriate pharmaceutically acceptable carriers, excipients and auxiliary substances depending on the pharmaceutical form of administration selected.
- Said dosage forms of administration can be prepared by conventional methods. A review of the different pharmaceutical pharmaceutical administration forms and their preparation can be found in the book "Treaty of Galician Pharmacy", by C. Faul ⁇ i Trillo, 10 Edition, 1993, Luzán 5, S.A. of Editions.
- the pharmaceutical composition of the invention can be administered using the appropriate equipment, apparatus and devices, which are known to those skilled in the art, for example, catheters, cannulas, etc.
- the in vitro administration of the pharmaceutical composition of the invention can be carried out as indicated below.
- the damaged or affected fibrosis lung tissue is removed (eg, a lung lobe).
- the lung tissue is contacted with the pharmaceutical composition of the invention under conditions that allow contact and adhesion of type II pneumocytes to the lung tissue so that said cells can exert their inhibitory action on fibroblast proliferation and, advantageously, epithelializing the affected tissue.
- the treated lung tissue is implanted in the subject. Both the removal of lung tissue and its implantation in the subject once subjected to treatment with the pharmaceutical composition of the invention can be carried out by conventional methods, typically by surgical methods. Conventionals known to those skilled in the art.
- the pharmaceutical composition of the invention can be contacted with the lung tissue by conventional methods, for example, by injection of the pharmaceutical composition of the invention into the lung tissue, or by washing the lung tissue with the pharmaceutical composition of the invention, or either by immersing the lung tissue in a bath containing the pharmaceutical composition of the invention, or by "sowing" type II pneumocytes directly on the lung tissue in order to establish a cell population, etc.
- Pulmonary tissue removed from the subject may be re-implanted in the subject, once treated with type II pneumocytes, after a variable period of time, typically between 6 and 24 hours after removal in order not to compromise the viability of lung tissue.
- composition of the invention will be administered using the appropriate equipment, apparatus and devices, which are known to those skilled in the art, for example, catheters, cannulas, etc. .
- the pharmaceutical composition of the invention is prepared in the form of an aqueous solution or suspension, in a pharmaceutically acceptable carrier, such as a saline solution, a phosphate buffered saline solution (PBS), or any other pharmaceutically acceptable carrier.
- a pharmaceutically acceptable carrier such as a saline solution, a phosphate buffered saline solution (PBS), or any other pharmaceutically acceptable carrier.
- pharmaceutically acceptable carriers for the administration of type II pneumocytes include, for example, a sterile saline solution (eg, 0.9% NaCl).
- the pharmaceutical composition of the invention may also contain, if necessary, other auxiliary substances or pharmaceutically acceptable compounds, such as co-solvents, additives for stabilizing the suspension, eg pharmaceutically acceptable preservatives, pharmaceutically acceptable acids, bases or buffers for adjust pH, surfactants, etc.
- the stability of the cells present in the liquid medium of the pharmaceutical composition of the invention can be increased by the addition of additional substances, for example, amino acids such as aspartic acid, glutamic acid, etc.
- additional substances for example, amino acids such as aspartic acid, glutamic acid, etc.
- These pharmaceutically acceptable substances that can be used in the pharmaceutical composition of the invention are generally known to those skilled in the art and are commonly used in the preparation of formulations for cellular compositions. Additional information on these substances can be found in the Galenic or animal health treaties, for example, in the book “Treaty of Galenic Pharmacy", by C. Faul ⁇ i Trillo, 10 Edition, 1993, Luzán 5, SA de Ediations.
- the pharmaceutical composition of the invention can be preserved until used by conventional methods known to those skilled in the art; In a particular embodiment, the pharmaceutical composition of the invention can be preserved until used by freezing.
- the pharmaceutical composition of the invention can be used together with other additional drugs useful in the prevention and / or treatment of said pulmonary pathologies that are actively involved with pulmonary fibrosis to provide a combination therapy.
- additional drugs may be part of the same pharmaceutical composition provided by this invention or, alternatively, they may be provided in the form of a separate composition for simultaneous or sequential administration to that of the pharmaceutical composition of the invention.
- anti-inflammatory, anti-fibrotic, type II pneumocyte growth factors such as keratinocyte growth factor, etc .
- inhibitors of fibroblast growth factors such as antagonists of the transforming growth factor ⁇ (TGF ⁇ ), etc .
- angiotensin II inhibitors such as pans, e.g., losartan, etc.
- the pharmaceutical composition of the invention can be administered in vitro, that is, on damaged or affected fibrosis lung tissue previously removed from the subject in need of treatment in order to inhibit fibroblast proliferation and, advantageously, re-epithelize the affected lung tissue. Therefore, in another aspect, the invention relates to a method for inhibiting in vitro fibroblast proliferation or for re-epithelizing lung tissue comprising contacting lung tissue with a pharmaceutical composition of the invention.
- said lung tissue is damaged lung tissue, that is, affected by pulmonary fibrosis, and has been previously removed from a subject suffering from a lung disease that is suffering from pulmonary fibrosis.
- lung tissue extraction can be carried out by conventional, typically surgical, methods known to those skilled in the art.
- the pharmaceutical composition of the invention can be contacted with the lung tissue by conventional methods, for example, by injection of the pharmaceutical composition of the invention into the lung tissue, or by washing the lung tissue with the pharmaceutical composition of the invention, or either by immersing the lung tissue in a bath containing the pharmaceutical composition of the invention, or by "sowing" type II pneumocytes directly on the lung tissue in order to establish a cell population, etc.
- Pulmonary tissue removed from the subject and subjected to treatment with type II pneumocytes can be re-implanted in the subject, after a variable period of time, typically between 6 and 24 hours after removal.
- the invention in another aspect, relates to a method for the treatment of a lung disease that is associated with pulmonary fibrosis in a subject in need of treatment comprising administering to said subject a pharmaceutical composition comprising type II pneumocytes.
- the administration of the pharmaceutical composition of the invention can be carried out by conventional methods as previously mentioned in connection with the in vivo administration of said pharmaceutical composition of the invention to a subject in need of treatment.
- the invention in another aspect, relates to a method for the treatment of a pulmonary disease that is associated with pulmonary fibrosis in a subject in need of treatment comprising extracting lung tissue from said subject, bringing it into contact with a pharmaceutical composition comprising type pneumocytes. II, and re-implant it in said subject.
- said lung tissue is damaged lung tissue, that is, affected by pulmonary fibrosis, and has been previously removed from a subject suffering from a lung disease that is suffering from pulmonary fibrosis.
- the pharmaceutical composition of the invention can be contacted with the extracted lung tissue by conventional methods as previously mentioned, for example, by injection of the pharmaceutical composition of the invention into the lung tissue, or by washing the lung tissue with the pharmaceutical composition of the invention, either by immersing the lung tissue in a bath containing the pharmaceutical composition of the invention, or by "sowing" type II pneumocytes directly on the lung tissue in order to establish a cell population , etc.
- Pulmonary tissue removed from the subject can be re-implanted in the subject, once treated with type II pneumocytes, after a period of time variable, typically between 6 and 24 hours after extraction.
- Type II ncumocyte transplantation in rats in which pulmonary fibrosis has been induced I. Materials and Methods
- the animals were housed in constant environmental conditions of temperature 22-24 ° C, relative humidity 60-65% and with light / dark cycles of 12 hours. They were supplied with a standard AO4 feed diet (Panlab, Barcelona) and water from the Barcelona ad libitum network. All studies were conducted in accordance with European Union regulatory standards for animal experimentation models (Directive 86/609 / EEC).
- Pulmonary fibrosis was caused by an intratracheal instillation of a single dose of 0.25 U of bleomycin per 100 grams of animal weight, dissolved in a volume of 0.25 ml of saline (0.9% NaCl). Control animals received the same volume of saline instead of bleomycin. Intratracheal instillation was performed with animals anesthetized with halothane by inhalation.
- Type II pneumocyte transplants were performed in female Lewis rats at 3, 7, and 15 days after induction of pulmonary fibrosis. Said transplants were performed by intratracheal instillation of the cells (2.5x10 6 cells per animal, suspended in 0.5 ml of saline) under inhalation anesthesia with halothane. Control animals were transplanted by intratracheal instillation of the cells (2.5x10 6 cells per animal / suspended in 0.5 ml of saline) under inhalation anesthesia with halothane, 3 days after instillation of solution saline. All animals were sacrificed 21 days after induction of pulmonary fibrosis.
- the animals were slaughtered by means of a lethal intraperitoneal injection of sodium pentobarbital (100 mg / kg) and later exanguination of the animal by the abdominal aorta; finally, the lungs attached to the trachea were removed.
- Type II epithelial cells were isolated from male Lewis rats. First, the animals were anesthetized with sodium pentobarbital (100 mg / kg). The lungs were permeated with saline solution by cannulation of the pulmonary artery. The lungs were removed and a bronchoalveolar lavage (4 x 10 ml) was performed to remove the alveolar macrophages. After digestion with trypsin (Sigma) in a 37 ° C water bath, the lungs were chopped into small fragments and 5 ml of fetal bovine serum and DNAse (Roche Diagnostics) were added until the solution was brought to a final volume of 20 mi.
- trypsin Sigma
- the cell suspension was filtered first by a gauze tissue, a 150 ⁇ m filter and finally by a 30 ⁇ m filter.
- the cells were separated by a gradient of percol (Amersham biosciences) and centrifugation at 250 g, for 20 minutes at 10 0 C. The band of cells remaining between the two gradients was collected and DNAse was added to a final volume of 40 ml. . It was centrifuged at 250 g for 20 minutes at 10 0 C.
- the cell precipitate was resuspended with 5 ml of DCCMl culture medium (Biological Industries) supplemented with 2 mM glutamine, 100 ⁇ g / ml penicillin and 60 ⁇ g / ml gentamicin.
- type II (T) pneumocyte transplants were performed at several times after the induction of pulmonary fibrosis: day 3 (BLM T3), day 7 (BLM T7) and day 15 (BLM Tl 5).
- Pulmonary fibrosis leads to loss of body weight. However, the results show that such loss is recovered earlier in animals transplanted with type II pneumocytes ( Figure 1).
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Immunology (AREA)
- Biomedical Technology (AREA)
- Cell Biology (AREA)
- Zoology (AREA)
- Biotechnology (AREA)
- Pulmonology (AREA)
- Wood Science & Technology (AREA)
- Genetics & Genomics (AREA)
- Virology (AREA)
- Developmental Biology & Embryology (AREA)
- Physiology (AREA)
- Epidemiology (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Physical Education & Sports Medicine (AREA)
- Rheumatology (AREA)
- Microbiology (AREA)
- Biochemistry (AREA)
- General Engineering & Computer Science (AREA)
- Neurology (AREA)
- Pain & Pain Management (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
Claims
Priority Applications (9)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
ES06841789T ES2384564T3 (es) | 2005-11-28 | 2006-11-27 | Uso de neumocitos de tipo II en el tratamiento de enfermedades pulmonares asociadas con fibrosis pulmonar |
CA2631172A CA2631172C (en) | 2005-11-28 | 2006-11-27 | Use of type ii pneumocytes in the treatment of pulmonary diseases associated with pulmonary fibrosis |
JP2008541769A JP5702521B2 (ja) | 2005-11-28 | 2006-11-27 | 肺線維症に関連した肺疾患の治療におけるii型肺胞細胞の使用 |
BRPI0619353-6A BRPI0619353A2 (pt) | 2005-11-28 | 2006-11-27 | emprego de pneumócitos de tipo ii no tratamento de doenças pulmonares que evoluem para fibrose pulmonar |
DK06841789.8T DK1961423T3 (da) | 2005-11-28 | 2006-11-27 | Anvendelse af pneumocytter af type II ved behandling af lungesygdomme i forbindelse med lungefibrose |
US12/095,028 US9610305B2 (en) | 2005-11-28 | 2006-11-27 | Method for using type II pneumocytes in pulmonary fibrosis |
AT06841789T ATE550027T1 (de) | 2005-11-28 | 2006-11-27 | Verwendung von pneumozyten des typs ii bei der behandlung von mit pulmonaler fibrose assoziierten lungenkrankheiten |
PL06841789T PL1961423T3 (pl) | 2005-11-28 | 2006-11-27 | Zastosowanie pneumocytów typu II w leczeniu chorób płuc związanych z zwłóknieniem płuc |
EP06841789A EP1961423B1 (en) | 2005-11-28 | 2006-11-27 | Use of type ii pneumocytes in the treatment of pulmonary diseases associated with pulmonary fibrosis |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
ESP200502939 | 2005-11-28 | ||
ES200502939A ES2308877B1 (es) | 2005-11-28 | 2005-11-28 | Empleo de nuemocitos tipo ii en el tratamiento de enfermedades pulmonares que cursan con fibrosis pulmonar. |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2007060278A1 true WO2007060278A1 (es) | 2007-05-31 |
Family
ID=38066937
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/ES2006/070182 WO2007060278A1 (es) | 2005-11-28 | 2006-11-27 | Empleo de neumocitos tipo ii en el tratamiento de enfermedades pulmonares que cursan con fibrosis pulmonar |
Country Status (11)
Country | Link |
---|---|
US (1) | US9610305B2 (es) |
EP (1) | EP1961423B1 (es) |
JP (1) | JP5702521B2 (es) |
AT (1) | ATE550027T1 (es) |
BR (1) | BRPI0619353A2 (es) |
CA (1) | CA2631172C (es) |
DK (1) | DK1961423T3 (es) |
ES (2) | ES2308877B1 (es) |
PL (1) | PL1961423T3 (es) |
PT (1) | PT1961423E (es) |
WO (1) | WO2007060278A1 (es) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20180264047A1 (en) * | 2014-12-24 | 2018-09-20 | Ube Industries, Ltd. | Cell culture supernatant fluid derived from lung tissue |
Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2001042425A2 (en) | 1999-12-07 | 2001-06-14 | Childrens Hospital Los Angeles Research Institute | Lung stem cells and lung regeneration |
US20020182732A1 (en) | 2001-04-09 | 2002-12-05 | University Of Southern California | Lentivirus vectors for gene transfer to alveolar epithelial cells |
WO2004015091A2 (en) | 2002-08-07 | 2004-02-19 | Novathera Limited | Preparation of type ii pneumocytes from stem cells |
WO2005017164A1 (en) * | 2003-08-11 | 2005-02-24 | University Of South Florida | Vigilant cells |
WO2005040391A1 (en) * | 2003-10-27 | 2005-05-06 | Murdoch Childrens Research Institute | Compositions and methods for differentiating stem cells |
WO2005052141A1 (en) * | 2003-11-11 | 2005-06-09 | Deltacell B.V. | Inhibition of stem cell differentiation, enhancement of proliferation and selective induction of apoptosis by wnt factors |
WO2005113748A2 (en) | 2004-04-21 | 2005-12-01 | Regents Of The University Of Minnesota | Mapc generation of lung tissue |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8609412B2 (en) * | 1999-08-05 | 2013-12-17 | Regents Of The University Of Minnesota | Mapc generation of lung tissue |
-
2005
- 2005-11-28 ES ES200502939A patent/ES2308877B1/es not_active Expired - Fee Related
-
2006
- 2006-11-27 CA CA2631172A patent/CA2631172C/en not_active Expired - Fee Related
- 2006-11-27 WO PCT/ES2006/070182 patent/WO2007060278A1/es active Application Filing
- 2006-11-27 US US12/095,028 patent/US9610305B2/en not_active Expired - Fee Related
- 2006-11-27 PT PT06841789T patent/PT1961423E/pt unknown
- 2006-11-27 EP EP06841789A patent/EP1961423B1/en not_active Not-in-force
- 2006-11-27 BR BRPI0619353-6A patent/BRPI0619353A2/pt not_active Application Discontinuation
- 2006-11-27 DK DK06841789.8T patent/DK1961423T3/da active
- 2006-11-27 ES ES06841789T patent/ES2384564T3/es active Active
- 2006-11-27 PL PL06841789T patent/PL1961423T3/pl unknown
- 2006-11-27 JP JP2008541769A patent/JP5702521B2/ja not_active Expired - Fee Related
- 2006-11-27 AT AT06841789T patent/ATE550027T1/de active
Patent Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2001042425A2 (en) | 1999-12-07 | 2001-06-14 | Childrens Hospital Los Angeles Research Institute | Lung stem cells and lung regeneration |
US20020182732A1 (en) | 2001-04-09 | 2002-12-05 | University Of Southern California | Lentivirus vectors for gene transfer to alveolar epithelial cells |
WO2004015091A2 (en) | 2002-08-07 | 2004-02-19 | Novathera Limited | Preparation of type ii pneumocytes from stem cells |
WO2005017164A1 (en) * | 2003-08-11 | 2005-02-24 | University Of South Florida | Vigilant cells |
WO2005040391A1 (en) * | 2003-10-27 | 2005-05-06 | Murdoch Childrens Research Institute | Compositions and methods for differentiating stem cells |
WO2005052141A1 (en) * | 2003-11-11 | 2005-06-09 | Deltacell B.V. | Inhibition of stem cell differentiation, enhancement of proliferation and selective induction of apoptosis by wnt factors |
WO2005113748A2 (en) | 2004-04-21 | 2005-12-01 | Regents Of The University Of Minnesota | Mapc generation of lung tissue |
Non-Patent Citations (6)
Title |
---|
C. FAULI I TRILLO: "Tratado de Farmacia Ga enca", 1993 |
CRAPO ET AL.: "Cell numbers and cell characteristics of the normal lung", AM. REV. RESPIR.DIS., vol. 126, 1982, pages 332 - 337 |
JOHNSON NF ET AL.: "Biology, toxicology, and carcinogenesis of respiratory epithelium", 1990, HEMIPERE PUBLISH CORPORATION, article "Epithelial progenitor cells in the rat respiratory traxt", pages: 1 - 308 |
PORTNOY ET AL.: "Role of alveolar type II epithelial cells in pulmonary fibrosis lung", BIOLOGY IN HEALTH AND DISEASE, vol. 185, 2004, pages 573 - 608 * |
PORTNOY ET AL.: "Role of alveolar type II epithelial cells in pulmonary fibrosis", LUNG BIOLOGY IN HEALTH AND DISEASE, vol. 185, 2004, pages 573 - 608 |
RICHARDS RJ ET AL.: "Isolation, biochemical characterisation, and culture of lung type II cells of the rat", LUNG, vol. 165, 1987, pages 143 - 158 |
Also Published As
Publication number | Publication date |
---|---|
US9610305B2 (en) | 2017-04-04 |
PL1961423T3 (pl) | 2012-09-28 |
BRPI0619353A2 (pt) | 2011-09-27 |
DK1961423T3 (da) | 2012-06-25 |
ES2384564T3 (es) | 2012-07-09 |
CA2631172A1 (en) | 2007-05-31 |
ATE550027T1 (de) | 2012-04-15 |
EP1961423B1 (en) | 2012-03-21 |
PT1961423E (pt) | 2012-06-28 |
US20090220467A1 (en) | 2009-09-03 |
ES2308877A1 (es) | 2008-12-01 |
CA2631172C (en) | 2014-08-05 |
JP2009517372A (ja) | 2009-04-30 |
ES2308877B1 (es) | 2009-10-26 |
EP1961423A1 (en) | 2008-08-27 |
JP5702521B2 (ja) | 2015-04-15 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US11639368B2 (en) | Method for preventing and treating hyperpermeability | |
ES2259998T3 (es) | Un tetrapeptido que demuestra el efecto gerontoprotector, sustancia farmacologica a base de el metodo de su utilizacion. | |
KR102035716B1 (ko) | 간엽줄기세포 유래 인공나노좀을 포함하는 폐질환 예방 또는 치료용 약학적 조성물 | |
US8748367B2 (en) | Use of antisecretory factor | |
ES2738658T3 (es) | Composición farmacéutica para inhibir la respuesta inmunitaria a través de la inducción de la diferenciación en células T reguladoras y la promoción de la proliferación de células T reguladoras | |
Kruk et al. | Mesenchymal stromal cells to regenerate emphysema: on the horizon? | |
ES2569391T3 (es) | Tritocualina para uso en el tratamiento de la fibrosis quística | |
US20100247491A1 (en) | Potentiation of Stem Cell Homing and Treatment of Organ Dysfunction or Organ Failure | |
WO2007098715A1 (es) | Composición farmacéutica conteniendo ghrp-6 capaz de prevenir y eliminar las fibrosis y otras formas de depósito patológico en los tejidos | |
WO2022242189A1 (zh) | 干细胞来源的外泌体在制备治疗慢性阻塞性肺疾病药物中的应用 | |
JP7045670B2 (ja) | 多能性幹細胞による虚血再灌流肺障害の軽減及び治療 | |
JP2021524864A (ja) | 軽度の認知障害、抑うつ、および精神障害の治療のための治療薬組成物およびその使用方法 | |
ES2569608T3 (es) | Procedimientos de regulación del reordenamiento del citoesqueleto de actina y formación de espacios intercelulares | |
ES2308877B1 (es) | Empleo de nuemocitos tipo ii en el tratamiento de enfermedades pulmonares que cursan con fibrosis pulmonar. | |
ES2316359T3 (es) | Tratamiento con peptidos pequeños para inducir una actividad antifibrotica. | |
MXPA02007683A (es) | Metodo para tratar o inhibir la lesion celular o muerte celular. | |
CN114599379A (zh) | 一种用于预防或治疗脓毒症的药物组合物、试剂盒及其应用和治疗方法 | |
Mutsaers et al. | Future directions in mesothelial transplantation research | |
WO2008123758A1 (es) | Composición farmacéutica que comprende n-sulfoetilnicotinamida utilizable en el tratamiento o prevención de una enfermedad pulmonar y uso de dicha composición para el tratamiento o prevención de dicha enfermedad | |
ES2864853T3 (es) | Pacritinib para su uso en el tratamiento de rechazo de trasplante | |
de Alba | Alpha 1 Antitrypsin Treatment of Donor Lungs: A Translational Pathway to Clinical Application | |
Korpela et al. | Healing of bronchial allografts in pigs | |
Mariscal de Alba | Alpha 1 Antitrypsin Treatment of Donor Lungs: A Translational Pathway to Clinical Application | |
Sharma et al. | DOZ047. 69: Tracking outcomes of tracheoesophageal fistula and esophageal atresia in pediatric population | |
WO2016060158A1 (ja) | 細胞障害抑制剤、前記細胞障害抑制剤を含む低酸素血症によって生じる臓器障害の予防又は治療用医薬組成物、及び前記細胞障害抑制剤を含む虚血性脳血管障害の予防又は治療用医薬組成物 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
121 | Ep: the epo has been informed by wipo that ep was designated in this application | ||
WWE | Wipo information: entry into national phase |
Ref document number: 2008541769 Country of ref document: JP Ref document number: 2006841789 Country of ref document: EP Ref document number: 2631172 Country of ref document: CA |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
WWE | Wipo information: entry into national phase |
Ref document number: 5578/DELNP/2008 Country of ref document: IN |
|
WWP | Wipo information: published in national office |
Ref document number: 2006841789 Country of ref document: EP |
|
WWE | Wipo information: entry into national phase |
Ref document number: 12095028 Country of ref document: US |
|
ENP | Entry into the national phase |
Ref document number: PI0619353 Country of ref document: BR Kind code of ref document: A2 Effective date: 20080528 |