Abstract

Myocardial ischemia-reperfusion (MI/R) is a common clinical problem in the settings of vascular surgery and myocardial infarction. Complement activation plays an important role in local, and likely remote, tissue injury associated with MI/R. Recent evidence from our laboratory shows that blockade of mannose binding lectin (MBL) in vivo prevents deposition and activation of complement resulting in significantly reduced injury and attenuated inflammatory gene expression following MI/R. Using mice deficient in either C1q or MBL, or effector proteins downstream of both, we propose to identify the events leading to tissue destruction following xperimental MI/R. In this proposal, we will investigate the role of MBL vs C1q (i.e. lectin vs. classical pathway) following MI/R. We hypothesize that irreversible cardiac damage following MI/R is dependent on MBL and lectin complement pathway activation.
The specific aims are as follows: 1) Characterize MBL-dependent complement activation in the initiation of MI/R injury, and additionally evaluate the role of C1q in IMI/R; 2) Determine the mechanism of MBL-dependent injury following MI/R.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
5F32HL079758-02
Application #
7018465
Study Section
Special Emphasis Panel (ZRG1-F10 (20))
Program Officer
Meadows, Tawanna
Project Start
2005-01-01
Project End
2006-10-20
Budget Start
2006-01-01
Budget End
2006-10-20
Support Year
2
Fiscal Year
2006
Total Cost
$41,867
Indirect Cost

  Institution

Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115

  Publications

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:
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
Busche, M N; Walsh, M C; McMullen, M E et al. (2008) Mannose-binding lectin plays a critical role in myocardial ischaemia and reperfusion injury in a mouse model of diabetes. Diabetologia 51:1544-51
Walsh, Mary C; Shaffer, Lisa A; Guikema, Benjamin J et al. (2007) Fluorochrome-linked immunoassay for functional analysis of the mannose binding lectin complement pathway to the level of C3 cleavage. J Immunol Methods 323:147-59
Ganter, Michael T; Brohi, Karim; Cohen, Mitchell J et al. (2007) Role of the alternative pathway in the early complement activation following major trauma. Shock 28:29-34
McMullen, Meghan E; Hart, Melanie L; Walsh, Mary C et al. (2006) Mannose-binding lectin binds IgM to activate the lectin complement pathway in vitro and in vivo. Immunobiology 211:759-66