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

Authors
  • Schwaeble, Wilhelm J
  • Lynch, Nicholas J
  • Clark, James E
  • Marber, Michael
  • Samani, Nilesh J
  • Ali, Youssif Mohammed
  • Dudler, Thomas
  • Parent, Brian
  • Lhotta, Karl
  • Wallis, Russell
  • Farrar, Conrad A
  • Sacks, Steven
  • Lee, Haekyung
  • Zhang, Ming
  • Iwaki, Daisuke
  • Takahashi, Minoru
  • Fujita, Teizo
  • Tedford, Clark E
  • Stover, Cordula M
Type
Published Article
Journal
Proceedings of the National Academy of Sciences
Publisher
Proceedings of the National Academy of Sciences
Publication Date
May 03, 2011
Volume
108
Issue
18
Pages
7523–7528
Identifiers
DOI: 10.1073/pnas.1101748108
PMID: 21502512
Source
Medline
License
Unknown

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.

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