Journal Article

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

Dudler, Thomas, Tedford, Clark E, Iwaki, Daisuke, Takahashi, Minoru, Marber, Michael, Samani, Nilesh J, Ali, Youssif Mohammed, Wallis, Russell, Lynch, Nicholas J, Parent, Brian, Lhotta, Karl, Schwaeble, Wilhelm J, Clark, James E, Farrar, Conrad A, Sacks, Steven, Fujita, Teizo, Stover, Cordula M, Lee, Haekyung, Zhang, Ming

2011

Overview

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.

• Publisher: National Academy of Sciences,National Acad Sciences
• Subject: Animal models / Animals / Antibodies / Antibodies, Monoclonal - pharmacology / Antibodies, Monoclonal - therapeutic use / Binding sites / Biological Sciences / complement / Complement activation / Complement C4 - deficiency / Complement component C3 / complement component C4 / Female / Gastrointestinal diseases / gastrointestinal system / Gastrointestinal Tract - pathology / Heart / Immunotherapy / infarction / Injuries / Ischemia / Lectins / Mannans / Mannose-Binding Protein-Associated Serine Proteases - deficiency / Mannose-Binding Protein-Associated Serine Proteases - immunology / Mannose-Binding Protein-Associated Serine Proteases - metabolism / MASP-1 protein / MASP-2 protein / Mice / Mice, Knockout / Mice, Mutant Strains / Microscopy / Myocardium - pathology / Pathology / Physical trauma / Proteases / Proteins / Reperfusion / Reperfusion injury / Reperfusion Injury - immunology / Reperfusion Injury - prevention & control / Rodents / Serine / Signal transduction / therapeutics