CN117385022A - Application of IL-17A as target in preparing medicine for screening treatment or prevention of cardiac arrest - Google Patents
Application of IL-17A as target in preparing medicine for screening treatment or prevention of cardiac arrest Download PDFInfo
- Publication number
- CN117385022A CN117385022A CN202311403663.3A CN202311403663A CN117385022A CN 117385022 A CN117385022 A CN 117385022A CN 202311403663 A CN202311403663 A CN 202311403663A CN 117385022 A CN117385022 A CN 117385022A
- Authority
- CN
- China
- Prior art keywords
- cardiac arrest
- monoclonal antibody
- cardiac
- preparing
- dysfunction
- 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
- 208000010496 Heart Arrest Diseases 0.000 title claims abstract description 100
- 102000013691 Interleukin-17 Human genes 0.000 title claims abstract description 60
- 108050003558 Interleukin-17 Proteins 0.000 title claims abstract description 60
- 239000003814 drug Substances 0.000 title claims abstract description 27
- 238000012216 screening Methods 0.000 title claims abstract description 11
- 230000002265 prevention Effects 0.000 title claims abstract description 7
- 210000005013 brain tissue Anatomy 0.000 claims abstract description 22
- 229940079593 drug Drugs 0.000 claims abstract description 13
- 230000004064 dysfunction Effects 0.000 claims abstract description 13
- 210000002966 serum Anatomy 0.000 claims abstract description 13
- 230000000747 cardiac effect Effects 0.000 claims abstract description 9
- 208000010125 myocardial infarction Diseases 0.000 claims abstract description 9
- 201000002638 post-cardiac arrest syndrome Diseases 0.000 claims abstract description 7
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 3
- 229960004540 secukinumab Drugs 0.000 claims description 5
- 230000000451 tissue damage Effects 0.000 claims description 5
- 231100000827 tissue damage Toxicity 0.000 claims description 5
- 230000009251 neurologic dysfunction Effects 0.000 claims description 4
- 208000015015 neurological dysfunction Diseases 0.000 claims description 4
- 230000003680 myocardial damage Effects 0.000 claims description 3
- 238000002360 preparation method Methods 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims 3
- 230000004083 survival effect Effects 0.000 abstract description 11
- 230000037361 pathway Effects 0.000 abstract description 8
- 238000002474 experimental method Methods 0.000 abstract description 5
- 210000005003 heart tissue Anatomy 0.000 abstract description 5
- 208000037891 myocardial injury Diseases 0.000 abstract description 5
- 230000001105 regulatory effect Effects 0.000 abstract description 5
- 206010052337 Diastolic dysfunction Diseases 0.000 abstract description 4
- 208000029028 brain injury Diseases 0.000 abstract description 4
- 210000005036 nerve Anatomy 0.000 abstract description 4
- 206010071436 Systolic dysfunction Diseases 0.000 abstract description 3
- 208000037816 tissue injury Diseases 0.000 abstract description 3
- 238000002680 cardiopulmonary resuscitation Methods 0.000 description 17
- 230000014509 gene expression Effects 0.000 description 15
- 230000008485 antagonism Effects 0.000 description 11
- 230000002107 myocardial effect Effects 0.000 description 11
- 241000699670 Mus sp. Species 0.000 description 8
- 230000028709 inflammatory response Effects 0.000 description 8
- 238000004393 prognosis Methods 0.000 description 8
- 102000019034 Chemokines Human genes 0.000 description 7
- 108010012236 Chemokines Proteins 0.000 description 7
- 210000001519 tissue Anatomy 0.000 description 7
- 102000039989 IL-17 family Human genes 0.000 description 6
- 108091069193 IL-17 family Proteins 0.000 description 6
- 241000699666 Mus <mouse, genus> Species 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 210000004731 jugular vein Anatomy 0.000 description 6
- 108090000623 proteins and genes Proteins 0.000 description 6
- 230000002269 spontaneous effect Effects 0.000 description 6
- 206010061218 Inflammation Diseases 0.000 description 5
- 210000004369 blood Anatomy 0.000 description 5
- 239000008280 blood Substances 0.000 description 5
- 230000006870 function Effects 0.000 description 5
- 230000004054 inflammatory process Effects 0.000 description 5
- 206010049418 Sudden Cardiac Death Diseases 0.000 description 4
- 230000004087 circulation Effects 0.000 description 4
- 230000003472 neutralizing effect Effects 0.000 description 4
- 230000019491 signal transduction Effects 0.000 description 4
- 208000014221 sudden cardiac arrest Diseases 0.000 description 4
- 206010002091 Anaesthesia Diseases 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- 206010063837 Reperfusion injury Diseases 0.000 description 3
- 230000037005 anaesthesia Effects 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 230000003205 diastolic effect Effects 0.000 description 3
- 230000002757 inflammatory effect Effects 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 230000002980 postoperative effect Effects 0.000 description 3
- 230000009885 systemic effect Effects 0.000 description 3
- UCTWMZQNUQWSLP-VIFPVBQESA-N (R)-adrenaline Chemical compound CNC[C@H](O)C1=CC=C(O)C(O)=C1 UCTWMZQNUQWSLP-VIFPVBQESA-N 0.000 description 2
- 102000004127 Cytokines Human genes 0.000 description 2
- 108090000695 Cytokines Proteins 0.000 description 2
- 102000004889 Interleukin-6 Human genes 0.000 description 2
- 108090001005 Interleukin-6 Proteins 0.000 description 2
- PIWKPBJCKXDKJR-UHFFFAOYSA-N Isoflurane Chemical compound FC(F)OC(Cl)C(F)(F)F PIWKPBJCKXDKJR-UHFFFAOYSA-N 0.000 description 2
- 201000004681 Psoriasis Diseases 0.000 description 2
- 230000033228 biological regulation Effects 0.000 description 2
- 239000000090 biomarker Substances 0.000 description 2
- 230000017531 blood circulation Effects 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 230000006835 compression Effects 0.000 description 2
- 238000007906 compression Methods 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 238000010201 enrichment analysis Methods 0.000 description 2
- 230000003960 inflammatory cascade Effects 0.000 description 2
- 208000028867 ischemia Diseases 0.000 description 2
- 230000000302 ischemic effect Effects 0.000 description 2
- 229960002725 isoflurane Drugs 0.000 description 2
- 210000005240 left ventricle Anatomy 0.000 description 2
- 238000005399 mechanical ventilation Methods 0.000 description 2
- 230000007658 neurological function Effects 0.000 description 2
- 210000000056 organ Anatomy 0.000 description 2
- 238000000513 principal component analysis Methods 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- 238000004904 shortening Methods 0.000 description 2
- 210000003437 trachea Anatomy 0.000 description 2
- 229930182837 (R)-adrenaline Natural products 0.000 description 1
- 208000023275 Autoimmune disease Diseases 0.000 description 1
- 206010008190 Cerebrovascular accident 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
- 206010019280 Heart failures Diseases 0.000 description 1
- 208000013875 Heart injury Diseases 0.000 description 1
- 101000998146 Homo sapiens Interleukin-17A Proteins 0.000 description 1
- 108060003951 Immunoglobulin Proteins 0.000 description 1
- 229940123725 Interleukin 17A antagonist Drugs 0.000 description 1
- 102100033096 Interleukin-17D Human genes 0.000 description 1
- 108010066979 Interleukin-27 Proteins 0.000 description 1
- 102000010781 Interleukin-6 Receptors Human genes 0.000 description 1
- 108010038501 Interleukin-6 Receptors Proteins 0.000 description 1
- 208000009525 Myocarditis Diseases 0.000 description 1
- 206010040047 Sepsis Diseases 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 208000006011 Stroke Diseases 0.000 description 1
- 208000007536 Thrombosis Diseases 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- 210000000683 abdominal cavity Anatomy 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 238000001949 anaesthesia Methods 0.000 description 1
- 230000003042 antagnostic effect Effects 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 230000004872 arterial blood pressure Effects 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 210000004413 cardiac myocyte Anatomy 0.000 description 1
- 238000010523 cascade reaction Methods 0.000 description 1
- 230000002490 cerebral effect Effects 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 210000002808 connective tissue Anatomy 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 230000007123 defense Effects 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 239000003792 electrolyte Substances 0.000 description 1
- 206010014599 encephalitis Diseases 0.000 description 1
- 229960005139 epinephrine Drugs 0.000 description 1
- 229960003072 epinephrine hydrochloride Drugs 0.000 description 1
- 238000011010 flushing procedure Methods 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 230000010247 heart contraction Effects 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 230000000004 hemodynamic effect Effects 0.000 description 1
- 230000013632 homeostatic process Effects 0.000 description 1
- 102000053162 human IL17A Human genes 0.000 description 1
- 230000036737 immune function Effects 0.000 description 1
- 102000018358 immunoglobulin Human genes 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000007925 in vitro drug release testing Methods 0.000 description 1
- 239000000411 inducer Substances 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 230000008595 infiltration Effects 0.000 description 1
- 238000001764 infiltration Methods 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000008383 multiple organ dysfunction Effects 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 208000031225 myocardial ischemia Diseases 0.000 description 1
- 210000000822 natural killer cell Anatomy 0.000 description 1
- 230000000926 neurological effect Effects 0.000 description 1
- 210000000440 neutrophil Anatomy 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 238000010837 poor prognosis Methods 0.000 description 1
- 230000000770 proinflammatory effect Effects 0.000 description 1
- 229940044551 receptor antagonist Drugs 0.000 description 1
- 239000002464 receptor antagonist Substances 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 230000010410 reperfusion Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000000241 respiratory effect Effects 0.000 description 1
- 230000036387 respiratory rate Effects 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 238000010257 thawing Methods 0.000 description 1
- 229940126585 therapeutic drug Drugs 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 229960003989 tocilizumab Drugs 0.000 description 1
- 238000012285 ultrasound imaging Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- 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
- C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
- C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
-
- 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
- A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
- A61K39/3955—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against proteinaceous materials, e.g. enzymes, hormones, lymphokines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- 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
-
- 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
-
- 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
- C12Q2600/00—Oligonucleotides characterized by their use
- C12Q2600/136—Screening for pharmacological compounds
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Cardiology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Heart & Thoracic Surgery (AREA)
- Zoology (AREA)
- Wood Science & Technology (AREA)
- Microbiology (AREA)
- Immunology (AREA)
- Analytical Chemistry (AREA)
- Genetics & Genomics (AREA)
- Biotechnology (AREA)
- Epidemiology (AREA)
- Mycology (AREA)
- Endocrinology (AREA)
- General Engineering & Computer Science (AREA)
- Biochemistry (AREA)
- Hospice & Palliative Care (AREA)
- Molecular Biology (AREA)
- Biophysics (AREA)
- Physics & Mathematics (AREA)
- Pathology (AREA)
- Urology & Nephrology (AREA)
- Vascular Medicine (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
Abstract
The invention provides an application of IL-17A serving as a target spot in preparing a medicine for screening treatment or prevention of cardiac arrest. The invention also provides application of IL-17A as a target spot in preparing a monoclonal antibody medicament for screening treatment or prevention of cardiac arrest. The invention also provides application of the anti-IL-17A monoclonal antibody in preparing medicines for improving post-cardiac arrest syndrome. The invention provides application of an anti-IL-17A monoclonal antibody in preparing a medicament for early intervention of cardiac arrest. The invention also provides application of the anti-IL-17A monoclonal antibody in preparing medicines for improving myocardial injury, cardiac dysfunction, brain injury or nerve dysfunction caused by cardiac arrest. The invention also provides application of the reagent for detecting the IL-17A level in serum in preparing a kit for detecting patients suffering from myocardial infarction and cardiac arrest. Experiments prove that the IL-17 related pathway of heart and brain tissues is obviously activated after cardiac arrest, IL-17A in serum is obviously up-regulated, and IL-17A monoclonal antibody is utilized to antagonize IL-17A in early stage after resuscitation, so that myocardial injury, cardiac dysfunction (systolic and diastolic dysfunction), brain tissue injury or nerve dysfunction after cardiac arrest can be improved, and survival rate after cardiac arrest can be improved.
Description
Technical Field
The invention belongs to the field of biological medicines, relates to a therapeutic target and a cardiovascular medicine, and particularly relates to application of IL-17A serving as a target in preparing medicines for screening treatment or preventing cardiac arrest and application of an anti-IL-17A monoclonal antibody in preparing medicines for improving cardiac arrest prognosis.
Background
It is counted that 55 tens of thousands of people experience sudden Cardiac Arrest (CA) each year in china on average, the first of the most numerous countries. Although cardiopulmonary resuscitation (Cardiopulmonary Resuscitation, CPR) and automated external defibrillators (Automated External Defibrillator, AED) are now widely practiced to some extent to rescue patients with cardiac arrest, their survival rates are still less than 10%. These data indicate that our knowledge of the disease is still extremely deficient, and thus, it is urgent to actively find new research break.
Post-cardiac arrest syndrome (PCAS) is a key factor leading to early mortality in patients, and includes 4 interacting components: sustained inducers of systemic ischemia/reperfusion responses, brain injury, myocardial dysfunction and cardiac arrest. During cardiac arrest, the patient is in a systemic ischemic state, while after spontaneous circulation is restored, reperfusion injury occurs in the body. Both early ischemia and reperfusion injury trigger inflammatory cascades, leading to systemic inflammatory waterfall-like reactions or sepsis-like syndromes, and to subsequent multiple organ dysfunction. Therefore, early intervention in the inflammatory response following cardiac arrest thereby breaks the interaction of PCAS has important clinical implications for the prognosis of cardiac arrest. However, until now, intervention means for cardiac arrest mainly include targeted temperature management, maintenance of hemodynamic homeostasis, etc., and no specific drug treatment for early inflammatory waterfall phases after cardiac arrest has been available.
Interleukin 17A (IL-17A) is produced by helper T17 (Th 17) cells, γδT cells, natural Killer T (NKT) cells, and the like, and has been shown to play a key role in host defense, allergic diseases, and autoimmune diseases. IL-17A, a pro-inflammatory cytokine, induces chemokine expression and promotes infiltration of neutrophil target organs. In recent years, there has been evidence that IL-17A can directly mediate myocardial apoptosis in cardiac ischemia/reperfusion injury and exacerbate ischemic brain injury. The IL-17A monoclonal antibody can be used for improving the prognosis of cerebral apoplexy. However, the role of IL-17A in CA and intervention of IL-17A in prognosis is not completely understood whether or not cardiac arrest can be affected.
Several inflammatory cytokines such as IL-6, IL-23, etc. in serum have been shown to be important biological indicators for assessing the prognosis of cardiac arrest, with early elevated IL-6 and IL-23 being significantly associated with a poor prognosis of cardiac arrest. However, a single-site clinical cohort study with extra-hospital cardiac arrest patients showed that infusion of the IL-6 receptor antagonist Tocilizumab improved cardiac injury following cardiac arrest without significant impact on brain injury or survival following cardiac arrest [15] . Moreover, there is currently no evidence for antagonizing the effects of IL-23 on cardiac arrest prognosis. These results indicate that early inflammation waterfall biological indicators after cardiac arrest found at the present stage are difficult to be an intervention target, or have tissue tendency and poor universality, and are not suitable for treating PCAS.
Secukinumab (Secukinumab) is a recombinant, high-affinity, fully humanized anti-IL-17A monoclonal immunoglobulin G1K antibody, approved by the european union and us FDA for the treatment of moderate to severe plaque psoriasis, following month 1 in 2015. The medicine can be selectively combined with IL-17A, so that inflammatory cascade reaction of psoriasis patients is blocked to a great extent, and the influence on other organism immune functions is small.
Disclosure of Invention
Aiming at the technical problems in the prior art, the invention provides application of IL-17A serving as a target point in preparing a drug for screening treatment or preventing cardiac arrest, and the application of the IL-17A serving as the target point in preparing the drug for screening treatment or preventing cardiac arrest aims to solve the technical problem that the drug in the prior art has poor treatment effect on early inflammation waterfall stage after cardiac arrest.
The invention provides an application of IL-17A serving as a target spot in preparing a medicine for screening treatment or prevention of cardiac arrest.
The invention also provides application of IL-17A as a target spot in preparing a monoclonal antibody medicament for screening treatment or prevention of cardiac arrest.
The invention also provides application of the anti-IL-17A monoclonal antibody in preparing medicines for improving post-cardiac arrest syndrome.
The invention also provides application of the anti-IL-17A monoclonal antibody in preparing medicines for early intervention of cardiac arrest.
The invention also provides the use of an anti-IL-17A monoclonal antibody in the preparation of a medicament for ameliorating myocardial damage, cardiac dysfunction (systolic and diastolic dysfunction), brain tissue damage or neurological dysfunction caused by cardiac arrest.
Further, the anti-IL-17A monoclonal antibody is Stuzumab.
The invention also provides application of the reagent for detecting the IL-17A level in serum in preparing a kit for detecting patients suffering from myocardial infarction and cardiac arrest.
Experiments prove that the IL-17 related pathway of heart and brain tissues is obviously activated after cardiac arrest, IL-17A in serum is obviously up-regulated, and IL-17A monoclonal antibody is utilized to antagonize IL-17A in early stage after resuscitation, so that myocardial injury, cardiac dysfunction (systolic and diastolic dysfunction), brain tissue injury or nerve dysfunction after cardiac arrest can be improved, and survival rate after cardiac arrest can be improved.
The invention provides a novel application of IL-17A as a core target of early multi-organ inflammation waterfall reaction after cardiac arrest resuscitation in treating or preventing cardiac arrest. The feasibility of preparing the early intervention therapeutic drug for the clinical critical disease of the sudden cardiac arrest of IL-17A is clarified by animal experiment exploration and clinical specimen observation experiment evidence.
Compared with the prior art, the invention has the technical effects of being positive and obvious. According to the invention, animal and clinical data prove the core effect of IL-17A in influencing the prognosis and the prognosis of cardiac arrest for the first time, and the monoclonal neutralizing antibody is utilized to antagonize IL-17A in early stage, so that the inflammation and dysfunction of a multi-organ system after cardiac arrest and resuscitation can be obviously improved, the method has positive guiding significance for the drug intervention after clinical cardiac arrest, and a new strategy is provided for preventing and treating cardiac arrest clinically.
Drawings
FIG. 1 shows that cardiac tissue transcriptomics reveals that cardiac arrest induces a myocardial inflammatory response.
FIG. 2 shows that brain tissue transcriptomics reveals that cardiac arrest induces a encephalitis response.
FIG. 3 shows the changes in the expression of the IL-17 family in serum after cardiac arrest.
FIG. 4 shows that early antagonism of IL-17A improves myocardial inflammatory response and cardiac dysfunction following cardiac arrest.
FIG. 5 shows that early antagonism of IL-17A improves brain tissue inflammatory response, neurological dysfunction and survival after cardiac arrest.
Detailed Description
The following description of the preferred embodiments of the present invention is provided in conjunction with the accompanying drawings, which are intended to illustrate and explain, rather than limit, the invention.
The experimental methods for which specific conditions are not specified in the examples are generally in accordance with conventional conditions, such as those described in textbooks and experimental guidelines, or in accordance with recommended conditions provided by the manufacturer.
Example 1 transcriptomic detection of myocardial tissue following cardiac arrest.
1. Establishing a mouse cardiac arrest model:
(1) anesthesia: c57BL/6 mice (purchased from Jiangsu Jiugang Biotech Co., ltd.) were fasted overnight and induced for anesthesia with isoflurane.
(2) Tracheal cannula: the anesthetized mouse is fixed in supine position and connected to the electrocardio remote measuring system. The neck skin is cleaned and disinfected, and after being cut off by scissors, the surrounding muscle and connective tissue of the trachea are rapidly separated so as to fully expose the trachea. A properly sized tracheal cannula was inserted through the mouth of the mouse and fed anteriorly into the airway, after which the cannula was fixed, connected to the ventilator of the small animal (tidal volume: 200 μl, respiratory rate: 150 beats/min) and isoflurane anaesthesia was maintained.
(3) Jugular vein catheterization: the right jugular vein of the free mouse was left, the distal end was ligated with silk thread, and the proximal end was lifted with silk thread to block blood flow. A small opening is cut in the middle section of a blood vessel by utilizing micro-shears, a venous indwelling tube is inserted through a notch and fixed by a silk thread, and a small amount of normal saline is pushed into a flushing pipeline to flush blood flowing back to prevent thrombosis.
2. Cardiac arrest induction and cardiopulmonary resuscitation
(1) Sudden cardiac arrest: a high concentration KCl solution (0.08 mg/g) was rapidly catheterized through the jugular vein into the jugular vein and the electrocardiographic changes were observed in real time until the heart lost electrical activity for a period of 9 minutes.
(2) Cardiopulmonary resuscitation: after a cardiac arrest of 9min, cardiopulmonary resuscitation is started, achieved by mechanical ventilation in combination with mechanical chest compressions. Mechanical ventilation parameters as above, the mechanical compression frequency was about 350 times/min. Epinephrine hydrochloride was injected three times (resuscitation initiation, 1min, 2 min) via jugular vein during resuscitation to stimulate the heart to resume spontaneous heart rate. Cardiopulmonary resuscitation is stopped when the mice resume spontaneous circulation or cardiopulmonary resuscitation duration reaches 5min, and the presence of any of the following indications may be considered a resumption of spontaneous circulation: 1) Electrocardiogram shows recovery of spontaneous heart beat with frequency > 200 times/min; 2) Mean arterial pressure > 40mmHg.
3. Postoperative management
After the mice recovered from the spontaneous circulation, the arteriovenous catheterization was removed and the neck skin was sutured. Continuously observing the electrocardiographic change and respiratory condition of the mice, transferring to a constant temperature heating table at 32 ℃ after 30min, and injecting glucose physiological saline into the abdominal cavity to supplement lost electrolyte and water.
The cardiac tissue from the cardiac arrest group (CA/CPR) and Sham surgery group (Sham) was collected 3h post-operatively, total RNA was extracted and transcriptome sequenced, showing that cardiac arrest could significantly induce myocardial inflammatory responses, with the IL-17 signaling pathway changes most pronounced (first rank, FIGS. 1A-C), where chemokine-related genes were significantly up-regulated after cardiac arrest (FIG. 1D).
Drawing A: PCA analysis revealed that the gene expression of myocardial tissue of the CA/CPR group and the Sham group differed significantly at the transcriptome level.
B, drawing: volcanic images reveal differential gene up-down regulation of myocardial tissue in the CA/CPR group and the Sham group.
C, drawing: KEGG pathway enrichment analysis for myocardial tissue differential genes showed that differential pathways before and after cardiac arrest were primarily associated with inflammatory responses, with IL-17 signaling pathway changes most pronounced.
D, drawing: the heat map shows changes in IL-17 pathway gene expression levels before and after cardiac arrest.
Example 2
Transcriptomic detection of brain tissue following cardiac arrest.
Mice were modeled for cardiac arrest following the protocol in example 1, brain tissue from the cardiac arrest group (CA/CPR) and the Sham group (Sham) were collected 3h post-operatively, total RNA was extracted and transcriptome sequenced, and the results showed that cardiac arrest could significantly induce brain tissue inflammatory responses, with IL-17 signaling pathway alterations ranking second (fig. 2A-C), where chemokine-related genes were significantly up-regulated after cardiac arrest (fig. 2D).
Drawing A: PCA analysis revealed that the gene expression of brain tissue of CA/CPR group and Sham group differed significantly at the transcriptome level.
B, drawing: volcanic images reveal differential gene up-down regulation of brain tissue in the CA/CPR group and the Sham group.
C, drawing: KEGG pathway enrichment analysis for brain tissue differential genes showed that differential pathways before and after cardiac arrest are primarily associated with inflammatory responses, with IL-17 signaling pathway altering ranking secondary.
D, drawing: the heat map shows changes in IL-17 pathway gene expression levels before and after cardiac arrest.
Example 3
Detection of IL-17 family expression levels in serum after cardiac arrest.
A mouse cardiac arrest model was established following the protocol in example 1, and blood samples from the cardiac arrest group (CA/CPR) and Sham group (Sham) were collected 3h post-operatively. In addition, blood samples of clinical patients with myocardial infarction complicated with CA and blood samples of patients with myocardial infarction without CA were collected simultaneously. The blood samples collected above were left at room temperature for 1h to fully coagulate, centrifuged at 3000rpm at 4℃for 10min, serum was collected and split into 1.5mL EP tubes to prevent repeated freeze thawing for subsequent IL-17 family serum levels. By examining the changes in expression of all IL-17 family members (IL-17A, IL-17B, IL-17C, IL-17D, IL-17E and IL-17F) in mouse serum after cardiac arrest, we found that IL-17A was the most significant member of the changes (FIG. 3A). In addition, in serum of clinical patients with CA concurrent with myocardial infarction, we detected higher IL-17A expression levels than those of patients with myocardial infarction without CA (fig. 3B). These results suggest that the altered expression of the IL-17 family, and in particular IL-17A, early after CA/CPR, may be a key node in regulating multiple organ functions.
Drawing A: mice were serologically altered in the CA/CPR and Sham (Sham) early (3 h) IL-17 family.
B, drawing: myocardial infarction combined with cardiac arrest patients (CA) and myocardial infarction not combined with cardiac arrest patients (Non-CA) showed altered expression of IL-17A in serum.
Example 4
Early use of the anti-IL-17A monoclonal neutralizing antibody, secukinumab (Secukinumab), a human interleukin-17A antagonist, purchased from North America, switzerland pharmaceutical company, improved myocardial damage and cardiac dysfunction following cardiac arrest.
After the cardiac arrest model was established by the method of example 1, anti-IL-17A monoclonal neutralizing antibody, the securikinumab and its isotype control antibody isotype (isotype control of human IgG1 kappa antibody, purchased from selleck) were administered via jugular vein, in combination with epinephrine, at an antibody dose of 10mg/kg at the beginning of resuscitation (i.e., early intervention) to achieve early antagonism of IL-17A.
Myocardial injury was assessed by extracting total RNA from heart tissue 3h after resuscitation to detect changes in myocardial inflammation levels in the securumab and isotype groups following cardiac arrest. Systolic and diastolic functional changes in the securinumab and isotype groups after cardiac arrest were detected using a Vevo2100 ultrasound imaging system. The method comprises the following steps: collecting images of a long axis and a short axis of the heart, measuring the numerical value of ejection fraction (Ejection Fraction, EF) and shortening fraction (Fractional Shortening, FS) of the heart in an M mode, and analyzing the systole function; and acquiring a four-chamber heart picture of the heart, measuring blood flow parameters in a PW (pulse width) doppler mode, and analyzing the diastolic function. Each measurement index value is an average of 5 cardiac cycles.
The results show that early antagonism of IL-17A significantly reduced expression of chemokines in myocardial tissue and decreased cardiomyocyte injury compared to the isotype group (fig. 4A); significantly improving systolic (fig. 4B) and diastolic dysfunction (fig. 4C) caused by sudden cardiac arrest.
Drawing A: early antagonism of IL-17A significantly reduced expression of chemokines in myocardial tissue, demonstrating a significant reduction in myocardial injury.
B, drawing: the result of the heart failure shows that the early antagonism IL-17A obviously improves the EF and FS values of the left ventricle, and proves that the heart contraction function is obviously improved.
C, drawing: the results of the cardiac superconduction show that the early antagonism IL-17A significantly increases the E/A ratio of the left ventricle and reduces the isovolumetric relaxation time (Isovolumic Relaxation Time, IVRT), which proves that the diastolic function is significantly improved.
Example 5
Early application of anti-IL-17A monoclonal neutralizing antibody, the improvement effect of the monoclonal antibody on brain tissue injury and nerve dysfunction and survival rate after cardiac arrest.
Total RNA of brain tissue was extracted 3h after resuscitation to detect changes in brain tissue inflammation levels in the securumab and isotype groups after cardiac arrest by modeling and IL-17A intervention protocols described in example 4, and brain tissue damage was assessed. Two groups of mice were assessed for neurological function 24h after resuscitation. Statistics of post-operative survival rate were cut off to 72 hours post-operative, during which two groups of mice were observed for survival every 3 hours, and survival curves for each group were plotted.
The results show that early antagonism of IL-17A significantly reduced chemokine expression in brain tissue and reduced brain tissue damage compared to the isotype group (fig. 5A); significantly improved neurological dysfunction due to cardiac arrest (fig. 5B) and increased survival after resuscitation (fig. 5C).
Drawing A: early antagonism of IL-17A significantly reduced expression of chemokines in brain tissue, demonstrating a significant reduction in brain tissue damage.
B, drawing: early antagonism of IL-17A significantly improved neurological score 24h post-resuscitation, demonstrating improved neurological function.
C, drawing: early antagonism of IL-17A significantly improved survival rate 72h after cardiac arrest.
Claims (7)
- The application of IL-17A as a target in preparing medicines for screening and treating or preventing cardiac arrest.
- The use of il-17A as a target in the preparation of a monoclonal antibody medicament for screening treatment or prevention of cardiac arrest.
- 3. Use of an anti-IL-17A monoclonal antibody in the manufacture of a medicament for ameliorating post-cardiac arrest syndrome.
- 4. Use of an anti-IL-17A monoclonal antibody in the manufacture of a medicament for early intervention in cardiac arrest.
- 5. Use of an anti-IL-17A monoclonal antibody in the manufacture of a medicament for ameliorating myocardial damage, cardiac dysfunction, brain tissue damage or neurological dysfunction caused by cardiac arrest.
- 6. The use according to any one of claims 3 to 5, wherein the anti-IL-17A monoclonal antibody is secukinumab.
- 7. Use of a reagent for detecting IL-17A levels in serum for the preparation of a kit for detecting patients suffering from myocardial infarction with cardiac arrest.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202311403663.3A CN117385022A (en) | 2023-10-26 | 2023-10-26 | Application of IL-17A as target in preparing medicine for screening treatment or prevention of cardiac arrest |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202311403663.3A CN117385022A (en) | 2023-10-26 | 2023-10-26 | Application of IL-17A as target in preparing medicine for screening treatment or prevention of cardiac arrest |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN117385022A true CN117385022A (en) | 2024-01-12 |
Family
ID=89469888
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202311403663.3A Pending CN117385022A (en) | 2023-10-26 | 2023-10-26 | Application of IL-17A as target in preparing medicine for screening treatment or prevention of cardiac arrest |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN117385022A (en) |
-
2023
- 2023-10-26 CN CN202311403663.3A patent/CN117385022A/en active Pending
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Blakemore et al. | Electrothermic coagulation of aortic aneurysms | |
| Westin et al. | Neonatal asphyxia pallida treated with hypothermia alone or with hypothermia and transfusion of oxygenated blood | |
| Edgeworth | A report of progress on the use of ephedrine in a case of myasthenia gravis | |
| Banting | The history of insulin | |
| Shnider et al. | Vasopressors in obstetrics: I. Correction of fetal acidosis with ephedrine during spinal hypotension | |
| JP3731071B2 (en) | Hemodynamic measurement method | |
| CN113730388B (en) | Application of sodium octoate in preparation of medicine for improving cardiopulmonary resuscitation effect and multi-organ dysfunction after cardiopulmonary resuscitation | |
| Angelo-Khattar et al. | Motility of the human ureter, with special reference to the effect of indomethacin | |
| Cushny | On the interpretation of pulse-tracings | |
| Cohn et al. | The Beneficial Effects of Barium Chlorid on Adams-Stokes Disease: Report of Three Cases | |
| Ashman et al. | Right atrial myxoma: Diagnosis during life; Successful surgical removal | |
| CN117385022A (en) | Application of IL-17A as target in preparing medicine for screening treatment or prevention of cardiac arrest | |
| Gilboe et al. | Isolation and mechanical maintenance of the dog brain | |
| Rajs et al. | Unexpected death in patients suffering from eating disorders: A medico‐legal study | |
| Aida et al. | Use of sevoflurane for anesthetic management of horses during thoracotomy | |
| Jensen et al. | Studies on the functional cardiac diseases and the essential cardiac hypertrophy, in normal pregnant women | |
| Thorn et al. | Gordon Wilson Lecture. Studies on the Adrenal Cortical Response to Stress in Man | |
| AU612428B2 (en) | Cgrp for cerebral blood supply improvement | |
| CN117257803B (en) | Application of lurasidone in preparation of drugs for treating or preventing ischemia/reperfusion injury and cytoprotective drugs | |
| CN116983294A (en) | Application of treprostinil and analogue thereof in treating sepsis shock | |
| Jean et al. | Respiratory and metabolic effects of massive administration of isotonic saline solution in heaves‐affected and control horses | |
| CN102657658B (en) | Medicine composition for treating myocardial infarction, vascular circulatory disturbance and thrombosis | |
| RU2467333C1 (en) | Diagnostic technique for aggravation of non-specific ulcerative colitis in children | |
| ROBINSON | Paroxysmal auricular fibrillation | |
| Yusupov et al. | COMBINED LOW-FLOW INHALATION ANESTHESIA FOR NEUROSURGERY OF CHILDREN |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination |