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Edited* by Douglas T. Fearon, University of Cambridge School of Clinical Medicine, Cambridge, United Kingdom, and approved March 16, 2011 (received for review February 1, 2011)
Abstract
Complement research experienced a renaissance with the discovery of a third activation route, the lectin pathway. We developed a unique model of total lectin pathway deficiency, a mouse strain lacking mannan-binding lectin-associated serine protease-2 (MASP-2), and analyzed the role of MASP-2 in two models of postischemic reperfusion injury (IRI). In a model of transient myocardial IRI, MASP-2–deficient mice had significantly smaller infarct volumes than their wild-type littermates. Mice deficient in the downstream complement component C4 were not protected, suggesting the existence of a previously undescribed lectin pathway-dependent C4-bypass. Lectin pathway-mediated activation of C3 in the absence of C4 was demonstrated in vitro and shown to require MASP-2, C2, and MASP-1/3. MASP-2 deficiency also protects mice from gastrointestinal IRI, as do mAb-based inhibitors of MASP-2. The therapeutic effects of MASP-2 inhibition in this experimental model suggest the utility of anti–MASP-2 antibody therapy in reperfusion injury and other lectin pathway-mediated disorders.
Footnotes
- ↵1To whom correspondence should be addressed. E-mail: ws5{at}le.ac.uk.
Author contributions: W.J.S., N.J.L., J.E.C., M.M., S.S., C.E.T., and C.M.S. designed research; N.J.L., J.E.C., Y.M.A., T.D., B.P., H.L., M.Z., D.I., M.T., T.F., and C.M.S. performed research; T.D., B.P., K.L., R.W., C.A.F., D.I., M.T., T.F., C.E.T., and C.M.S. contributed new reagents/analytic tools; W.J.S., N.J.L., J.E.C., M.M., N.J.S., S.S., and M.Z. analyzed data; and W.J.S., N.J.L., J.E.C., and N.J.S. wrote the paper.
Conflict of interest statement: C.E.T., B.P., and T.D. hold shares in Omeros Inc., Seattle, WA, which aims to market recombinant anti–MASP-2 mAb for therapeutic purposes.
↵*This Direct Submission article had a prearranged editor.
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1101748108/-/DCSupplemental.
Targeting of mannan-binding lectin-associated serine protease-2 (Masp2) confers a significant degree of protection from myocardial and gastrointestinal ischemia/reperfusion injury
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