title: Metalloproteinases regulate CD40L shedding from platelets and pulmonary recruitment of neutrophils in abdominal sepsis.
abstract: OBJECTIVE
  Platelets promote sepsis-induced activation of neutrophils via secretion of CD40L. However, the mechanism regulating the release of platelet-derived CD40L is not known. We hypothesized that matrix metalloproteinases (MMPs) might regulate shedding of platelet-expressed CD40L and neutrophil activation in sepsis.
  
  
  METHODS
  Wild-type C57BL/6 mice were subjected to cecal ligation and puncture (CLP). Animals were pretreated with a broad-range MMP inhibitor, GM6001, prior to CLP induction. Edema formation, CXC chemokine and myeloperoxidase (MPO) levels and bronchoalveolar neutrophils in the lung as well as plasma levels of CD40L were quantified. Flow cytometry was used to determine expression of Mac-1 on neutrophils and CD40L on platelets. Intravital fluorescence microscopy was used to analyze leukocyte-endothelial cell interactions in the pulmonary microcirculation.
  
  
  RESULTS
  The MMP inhibitor reduced sepsis-induced release of CD40L and maintained normal levels of CD40L on platelets. Inhibition of MMP decreased CLP-induced neutrophil expression of Mac-1, formation of CXC chemokines and edema as well as neutrophil infiltration in the lung. Intravital fluorescence microscopy revealed that the MMP inhibitor attenuated leukocyte adhesion in venules whereas capillary trapping of leukocytes was not affected by MMP inhibition.
  
  
  CONCLUSIONS
  We describe a novel role of metalloproteinases in regulating platelet-dependent activation and infiltration of neutrophils in septic lung injury which might be related to controlling CD40L shedding from platelets. We conclude that targeting metalloproteinases may be a useful strategy for limiting acute lung injury in abdominal sepsis.
authors.affiliation: Department of Clinical Sciences, Malmo, Section of Surgery, Skåne University Hospital, Lund University, 205 02, Malmö, Sweden.
authors.forename: Milladur
authors.initials: M
authors.lastname: Rahman
authors.forename: Jonas
authors.initials: J
authors.lastname: Roller
authors.forename: Su
authors.initials: S
authors.lastname: Zhang
authors.forename: Ingvar
authors.initials: I
authors.lastname: Syk
authors.forename: Michael D
authors.initials: MD
authors.lastname: Menger
authors.forename: Bengt
authors.initials: B
authors.lastname: Jeppsson
authors.forename: Henrik
authors.initials: H
authors.lastname: Thorlacius
mesh_terms: D000005:Abdomen; D000818:Animals; D001792:Blood Platelets / Q000276:immunology*; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology; D023201:CD40 Ligand / Q000097:blood / Q000276:immunology*; D004151:Dipeptides / Q000494:pharmacology; D004195:Disease Models, Animal; D007958:Leukocyte Count; D016177:Macrophage-1 Antigen / Q000276:immunology; D008297:Male; D061965:Matrix Metalloproteinase Inhibitors; D020782:Matrix Metalloproteinases / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D020556:Neutrophil Infiltration; D009504:Neutrophils / Q000276:immunology*; D009195:Peroxidase / Q000276:immunology; D010976:Platelet Count; D011480:Protease Inhibitors / Q000494:pharmacology; D011654:Pulmonary Edema / Q000097:blood / Q000276:immunology; D018805:Sepsis / Q000097:blood / Q000276:immunology*
chemical_list: D004151:Dipeptides; D016177:Macrophage-1 Antigen; D061965:Matrix Metalloproteinase Inhibitors; C078131:N-(2(R)-2-(hydroxamidocarbonylmethyl)-4-methylpentanoyl)-L-tryptophan methylamide; D011480:Protease Inhibitors; D023201:CD40 Ligand; D009195:Peroxidase; D020782:Matrix Metalloproteinases