Mac-1 (CD11b/CD18) links inflammation and thrombosis after glomerular injury

Junichi Hirahashi, Keiichi Hishikawa, Shinya Kaname, Naotake Tsuboi, Yunmei Wang, Daniel I. Simon, George Stavrakis, Tatsuo Shimosawa, Ling Xiao, Yutaka Nagahama, Kazuo Suzuki, Toshiro Fujita, Tanya N. Mayadas

研究成果: Article査読

62 被引用数 (Scopus)

抄録

BACKGROUND-: Inflammation and thrombosis coexist in several disorders. Although it is recognized that leukocytes may induce a procoagulant state at sites of inflammation, the critical molecular determinants of this process remain largely unknown. METHODS AND RESULTS-: To examine mechanisms of inflammation-induced thrombosis, we developed a murine model of thrombotic glomerulonephritis (TGN), a known cause of acute renal failure in patients. This model, induced by lipopolysaccharide and antibody to the glomerular basement membrane, led to rapid glomerular neutrophil recruitment, thrombotic glomerular lesions with endothelial cell injury, and renal dysfunction. In mice immunodepleted of neutrophils or lacking the leukocyte-specific integrin Mac-1, neutrophil recruitment, endothelial injury, glomerular thrombosis, and acute renal failure were markedly attenuated despite the robust generation of renal cytokines. Neutrophil elastase is a likely effector of Mac-1 because its activity was reduced in Mac-1-deficient mice and the phenotype in mice deficient in Mac-1 or neutrophil elastase was similar. Platelets accumulated in glomerular capillaries within 4 hours of TGN before evidence of thrombosis. Platelet immunodepletion before TGN markedly exacerbated hematuria (hemorrhage), inflammation, and injury, whereas thrombocytopenic Mac-1-deficient mice remained resistant to disease, indicating that initial glomerular platelet deposition protects the vessel wall from neutrophil-mediated sequelae. The subsequent thrombosis relied on the interaction of Mac-1 on recruited neutrophils with glycoprotein Ibα on platelets as antibody-mediated disruption of this interaction attenuated TGN without affecting renal neutrophil accumulation. CONCLUSIONS-: These observations establish Mac-1 on neutrophils as a critical molecular link between inflammation and thrombosis and suggest it as an attractive target for antithrombotic therapy.

本文言語English
ページ(範囲)1255-1265
ページ数11
ジャーナルCirculation
120
13
DOI
出版ステータスPublished - 2009 9月
外部発表はい

ASJC Scopus subject areas

  • 循環器および心血管医学
  • 生理学(医学)

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