While the exact mechanisms of ischemia/reperfusion injury remain to be elucidated, inhibition of complement activation (e.g., sCR1 or C 1 esterase inhibitor), depletion of complement components (e.g., cobra venom factor) and complement component (e.g., C3 and C4) knockout mice have revealed an important role of complement in ischemia/reperfusion injury. During the previous two funding cycles we have shown that the complement component C5 plays an important role in the pathogenesis of reperfusion injury and in the production of vasoactive eicosanoids. These preclinical findings have led to two 1000 patient Phase II clinical trials in acute myocardial infarction. Further, we have shown that mannose binding lectin (MBL) may play an important role in the initiation of complement activation following ischemia/reperfusion (I/R). However, the specific pathways involved, the order of pathway activation, and the specific contribution of C5a versus C5b-9 in the setting of I/R is not well characterized. Reports in the literature suggest that the classical pathway is the initiating complement pathway involved in I/R injury by way of natural antibody deposition. Our preliminary data suggest that the lectin pathway is involved and may be the initiating pathway. This application will investigate the several """"""""holes"""""""" present in our knowledge about complement and its role in mediating tissue injury and inflammation associated with myocardial (M) I/R. Novel anti-complement reagents and knockout mice have been developed and will be developed for characterizing the role of specific complement components in MI/R. Specifically we will identify the importance of each specific complement pathway (e.g., lectin, classical and alternative) in M I/R. Previous reports by our group and others have demonstrated that complement activation influences gene expression and we will identify novel pro- and anti-inflammatory genes that are regulated by C5a and/or C5b-9. The approach for this competitive renewal is to identify the specific role of C5a, C5b-9, C1q, MBL and factor D in MI/R. We will identify/characterize C5a or C5b-9 induced gene expression in vitro using isolated myocytes from rats and humans. Novel and potential therapeutically useful reagents will be made and used in vivo to establish and validate the genes expressed in vitro, anti-inflammatory effects and resolution of inflammation in vivo.
Our aims are to: 1) Characterize complement pathways involved in complement activation on anoxic/reoxygenated myocytes; 2) Develop novel reagents against """"""""key"""""""" complement components to investigate fully the role of complement in MI/R and 3) Characterize the role of specific complement pathways in MI/R in vivo.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL052886-12
Application #
7091441
Study Section
Special Emphasis Panel (ZRG1-SSS-W (01))
Program Officer
Massicot-Fisher, Judith
Project Start
1995-08-01
Project End
2008-07-31
Budget Start
2006-08-01
Budget End
2007-07-31
Support Year
12
Fiscal Year
2006
Total Cost
$468,152
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
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Pavlov, Vasile I; La Bonte, Laura R; Baldwin, William M et al. (2012) Absence of mannose-binding lectin prevents hyperglycemic cardiovascular complications. Am J Pathol 180:104-12
Burk, Anne-Maud; Martin, Myriam; Flierl, Michael A et al. (2012) Early complementopathy after multiple injuries in humans. Shock 37:348-54
Li, Qian; Li, Yong Xing; Stahl, Gregory L et al. (2011) Essential role of factor B of the alternative complement pathway in complement activation and opsonophagocytosis during acute pneumococcal otitis media in mice. Infect Immun 79:2578-85
Takahashi, Kazue; Chang, Wei-Chuan; Takahashi, Minoru et al. (2011) Mannose-binding lectin and its associated proteases (MASPs) mediate coagulation and its deficiency is a risk factor in developing complications from infection, including disseminated intravascular coagulation. Immunobiology 216:96-102
Busche, Marc N; Stahl, Gregory L (2010) Role of the complement components C5 and C3a in a mouse model of myocardial ischemia and reperfusion injury. Ger Med Sci 8:
Tong, Hua Hua; Li, Yong Xing; Stahl, Gregory L et al. (2010) Enhanced susceptibility to acute pneumococcal otitis media in mice deficient in complement C1qa, factor B, and factor B/C2. Infect Immun 78:976-83
Michelow, Ian C; Dong, Mingdong; Mungall, Bruce A et al. (2010) A novel L-ficolin/mannose-binding lectin chimeric molecule with enhanced activity against Ebola virus. J Biol Chem 285:24729-39
Busche, Marc N; Pavlov, Vasile; Takahashi, Kazue et al. (2009) Myocardial ischemia and reperfusion injury is dependent on both IgM and mannose-binding lectin. Am J Physiol Heart Circ Physiol 297:H1853-9
Gorsuch, W Brian; Guikema, Benjamin J; Fritzinger, David C et al. (2009) Humanized cobra venom factor decreases myocardial ischemia-reperfusion injury. Mol Immunol 47:506-10

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