title: Targeting of mannan-binding lectin-associated serine protease-2 confers protection from myocardial and gastrointestinal ischemia/reperfusion injury.
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.
authors.affiliation: Department of Infection, University of Leicester, Leicester LE1 9HN, United Kingdom. ws5@le.ac.uk
authors.forename: Wilhelm J
authors.initials: WJ
authors.lastname: Schwaeble
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Lynch
authors.forename: James E
authors.initials: JE
authors.lastname: Clark
authors.forename: Michael
authors.initials: M
authors.lastname: Marber
authors.forename: Nilesh J
authors.initials: NJ
authors.lastname: Samani
authors.forename: Youssif Mohammed
authors.initials: YM
authors.lastname: Ali
authors.forename: Thomas
authors.initials: T
authors.lastname: Dudler
authors.forename: Brian
authors.initials: B
authors.lastname: Parent
authors.forename: Karl
authors.initials: K
authors.lastname: Lhotta
authors.forename: Russell
authors.initials: R
authors.lastname: Wallis
authors.forename: Conrad A
authors.initials: CA
authors.lastname: Farrar
authors.forename: Steven
authors.initials: S
authors.lastname: Sacks
authors.forename: Haekyung
authors.initials: H
authors.lastname: Lee
authors.forename: Ming
authors.initials: M
authors.lastname: Zhang
authors.forename: Daisuke
authors.initials: D
authors.lastname: Iwaki
authors.forename: Minoru
authors.initials: M
authors.lastname: Takahashi
authors.forename: Teizo
authors.initials: T
authors.lastname: Fujita
authors.forename: Clark E
authors.initials: CE
authors.lastname: Tedford
authors.forename: Cordula M
authors.initials: CM
authors.lastname: Stover
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology / Q000627:therapeutic use; D003181:Complement C4 / Q000172:deficiency; D005260:Female; D041981:Gastrointestinal Tract / Q000473:pathology*; D050606:Mannose-Binding Protein-Associated Serine Proteases / Q000172:deficiency / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D008853:Microscopy; D009206:Myocardium / Q000473:pathology*; D015427:Reperfusion Injury / Q000276:immunology / Q000517:prevention & control*
chemical_list: D000911:Antibodies, Monoclonal; D003181:Complement C4; C491340:MASP-2 protein, mouse; D050606:Mannose-Binding Protein-Associated Serine Proteases