Targeting of mannan-binding lectin-associated serine protease-2 confers protection from myocardial and gastrointestinal ischemia/reperfusion injury

WJ Schwaeble, NJ Lynch, JE Clark… - Proceedings of the …, 2011 - National Acad Sciences
WJ Schwaeble, NJ Lynch, JE Clark, M Marber, NJ Samani, YM Ali, T Dudler, B Parent…
Proceedings of the National Academy of Sciences, 2011National Acad Sciences
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 …
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.
National Acad Sciences