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Platelet shedding of CD 40 L is regulated by matrix metalloproteinase‐9 in abdominal sepsis
Author(s) -
Rahman M.,
Zhang S.,
Chew M.,
Syk I.,
Jeppsson B.,
Thorlacius H.
Publication year - 2013
Publication title -
journal of thrombosis and haemostasis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.947
H-Index - 178
eISSN - 1538-7836
pISSN - 1538-7933
DOI - 10.1111/jth.12273
Subject(s) - platelet , sepsis , myeloperoxidase , immunology , medicine , platelet activation , chemokine , cxcl1 , matrix metalloproteinase , septic shock , infiltration (hvac) , lung , inflammation , physics , thermodynamics
Summary Background and objectives Platelet‐derived CD 40 L is known to regulate neutrophil recruitment and lung damage in sepsis. However, the mechanism regulating shedding of CD 40 L from activated platelets is not known. We hypothesized that matrix metalloproteinase ( MMP )‐9 might cleave surface‐expressed CD 40 L and regulate pulmonary accumulation of neutrophils in sepsis. Methods Abdominal sepsis was induced by cecal ligation and puncture ( CLP ) in wild‐type and MMP ‐9‐deficient mice. Edema formation, CXC chemokine levels, myeloperoxidase levels, neutrophils in the lung and plasma levels of CD 40 L and MMP ‐9 were quantified. Results CLP increased plasma levels of MMP ‐9 but not MMP ‐2. The CLP ‐induced decrease in platelet surface CD 40 L and increase in soluble CD 40 L levels were significantly attenuated in MMP ‐9 gene‐deficient mice. Moreover, pulmonary myeloperoxidase ( MPO ) activity and neutrophil infiltration in the alveolar space, as well as edema formation and lung injury, were markedly decreased in septic mice lacking MMP ‐9. In vitro studies revealed that inhibition of MMP ‐9 decreased platelet shedding of CD 40 L . Moreover, recombinant MMP ‐9 was capable of cleaving surface‐expressed CD 40 L on activated platelets. In human studies, plasma levels of MMP ‐9 were significantly increased in patients with septic shock as compared with healthy controls, although MMP ‐9 levels did not correlate with organ injury score. Conclusions Our novel data propose a role of MMP ‐9 in regulating platelet‐dependent infiltration of neutrophils and tissue damage in septic lung injury by controlling CD 40 L shedding from platelets. We conclude that targeting MMP ‐9 may be a useful strategy to limit acute lung injury in abdominal sepsis.