title: Inhibition of mannose-binding lectin reduces postischemic myocardial reperfusion injury.
abstract: BACKGROUND
  Complement consists of a complex cascade of proteins involved in innate and adaptive immunity. The cascade can be activated through 3 distinct mechanisms, designated the classical, alternative, and lectin pathways. Although complement is widely accepted as participating in the pathophysiology of ischemia-reperfusion injury, the specific role of the lectin pathway has not been addressed.
  
  
  RESULTS
  Monoclonal antibodies (mAbs; P7E4 and 14C3.74, IgG1kappa isotypes) were raised against rat mannose-binding lectin (rMBL). Both mAbs recognized rMBL-A by Western analysis or surface plasmon resonance. P7E4, but not 14C3.74, exhibited a concentration-dependent inhibition of the lectin pathway, with maximal effect at 10 microg/mL. In vivo, rats were subjected to 30 minutes of left coronary artery occlusion and 4 hours of reperfusion. Complement C3 deposition was greatly attenuated in hearts pretreated with P7E4 compared with 14C3.74-treated hearts. Pretreatment with P7E4 (1 mg/kg) significantly reduced myocardial creatine kinase loss (48%), infarct size (39%), and neutrophil infiltration (47%) compared with 14C3.74-treated animals. In addition, P7E4 pretreatment significantly attenuated the expression of proinflammatory genes (intercellular adhesion molecule-1, vascular cell adhesion molecule-1, and interleukin-6) after ischemia-reperfusion.
  
  
  CONCLUSIONS
  The lectin complement pathway is activated after myocardial ischemia-reperfusion and leads to tissue injury. Blockade of the lectin pathway with inhibitory mAbs protects the heart from ischemia-reperfusion by reducing neutrophil infiltration and attenuating proinflammatory gene expression.
authors.affiliation: Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: J E
authors.initials: JE
authors.lastname: Jordan
authors.forename: M C
authors.initials: MC
authors.lastname: Montalto
authors.forename: G L
authors.initials: GL
authors.lastname: Stahl
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000378:metabolism / Q000494:pharmacology; D000918:Antibody Specificity; D002352:Carrier Proteins / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D015815:Cell Adhesion Molecules / Q000096:biosynthesis / Q000235:genetics; D037222:Collectins; D003167:Complement Activation / Q000187:drug effects; D003176:Complement C3 / Q000378:metabolism; D003402:Creatine Kinase / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D007378:Interleukins / Q000096:biosynthesis / Q000235:genetics; D008297:Male; D008358:Mannose / Q000494:pharmacology; D015846:Monokines / Q000096:biosynthesis / Q000235:genetics; D017202:Myocardial Ischemia / Q000150:complications / Q000378:metabolism / Q000473:pathology; D015428:Myocardial Reperfusion Injury / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D009195:Peroxidase / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects; D020349:Surface Plasmon Resonance
chemical_list: D000911:Antibodies, Monoclonal; D002352:Carrier Proteins; D015815:Cell Adhesion Molecules; D037222:Collectins; D003176:Complement C3; D007378:Interleukins; D015846:Monokines; D012333:RNA, Messenger; D009195:Peroxidase; D003402:Creatine Kinase; D008358:Mannose