Document Detail


Inhibition of the tissue factor-thrombin pathway limits infarct size after myocardial ischemia-reperfusion injury by reducing inflammation.
MedLine Citation:
PMID:  11106558     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Functional inhibition of tissue factor (TF) has been shown to improve coronary blood flow after myocardial ischemia/reperfusion (I/R) injury. TF initiates the coagulation protease cascade, resulting in the generation of the serine protease thrombin and fibrin deposition. Thrombin can also contribute to an inflammatory response by activating various cell types, including vascular endothelial cells. We used a rabbit coronary ligation model to investigate the role of TF in acute myocardial I/R injury. At-risk areas of myocardium showed increased TF expression in the sarcolemma of cardiomyocytes, which was associated with a low level of extravascular fibrin deposition. Functional inhibition of TF activity with an anti-rabbit TF monoclonal antibody administered either 15 minutes before or 30 minutes after coronary ligation reduced infarct size by 61% (P = 0.004) and 44% (P = 0.014), respectively. Similarly, we found that inhibition of thrombin with hirudin reduced infarct size by 59% (P = 0.014). In contrast, defibrinogenating the rabbits with ancrod had no effect on infarct size, suggesting that fibrin deposition does not significantly contribute to infarct size. Functional inhibition of thrombin reduced chemokine expression and inhibition of either TF or thrombin reduced leukocyte infiltration. We propose that cardiomyocyte TF initiates extravascular thrombin generation, which enhances inflammation and injury during myocardial I/R.
Authors:
J H Erlich; E M Boyle; J Labriola; J C Kovacich; R A Santucci; C Fearns; E N Morgan; W Yun; T Luther; O Kojikawa; T R Martin; T H Pohlman; E D Verrier; N Mackman
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  The American journal of pathology     Volume:  157     ISSN:  0002-9440     ISO Abbreviation:  Am. J. Pathol.     Publication Date:  2000 Dec 
Date Detail:
Created Date:  2000-12-18     Completed Date:  2001-01-04     Revised Date:  2013-06-11    
Medline Journal Info:
Nlm Unique ID:  0370502     Medline TA:  Am J Pathol     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  1849-62     Citation Subset:  AIM; IM    
Affiliation:
Scripps Research Institute, La Jolla, California. Seattle, Washington. Dresden, Germany.
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MeSH Terms
Descriptor/Qualifier:
Animals
Antibodies, Monoclonal / pharmacology
Antithrombins / pharmacology
Cell Movement / physiology
Chemokines / antagonists & inhibitors
Fibrin / metabolism
Fibrinogen / metabolism
Hirudins / pharmacology
Microscopy, Electron
Myocardial Infarction / etiology*,  pathology*
Myocardial Ischemia / complications*,  metabolism,  pathology
Myocardial Reperfusion Injury / complications*,  metabolism,  pathology
Myocarditis / etiology*,  prevention & control
Myocardium / pathology
Neutrophils / physiology
Rabbits
Thrombin / antagonists & inhibitors,  physiology*
Thromboplastin / antagonists & inhibitors,  immunology,  physiology*
Grant Support
ID/Acronym/Agency:
GM07037/GM/NIGMS NIH HHS; GM46662/GM/NIGMS NIH HHS; HL16411/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
0/Antibodies, Monoclonal; 0/Antithrombins; 0/Chemokines; 0/Hirudins; 9001-31-4/Fibrin; 9001-32-5/Fibrinogen; 9035-58-9/Thromboplastin; EC 3.4.21.5/Thrombin
Comments/Corrections

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