期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 108, 期 18, 页码 7523-7528出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1101748108
关键词
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资金
- Wellcome Trust [060574]
- Medical Research Council [G0700859]
- National Institutes of Health [R43 HL082004-1]
- British Heart Foundation
- MRC [G0700859, G0600892, G1000191] Funding Source: UKRI
- Medical Research Council [G0600698B, G0700859, G0600892, G1000191] Funding Source: researchfish
- Grants-in-Aid for Scientific Research [21390086, 23590342] Funding Source: KAKEN
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.
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