Recombinant tissue factor pathway inhibitor reduces lipopolysaccharide-induced pulmonary vascular injury by inhibiting leukocyte activation

Perenlei Enkhbaatar, Kenji Okajima, Kazunori Murakami, Mitsuhiro Uchiba, Hiroaki Okabe, Kazutoshi Okabe, Yasuo Yamaguchi

Research output: Contribution to journalArticle

73 Scopus citations

Abstract

Tissue factor pathway inhibitor (TFPI) is an important physiologic inhibitor of the extrinsic pathway of the coagulation system. We investigated whether recombinant TFPI (rTFPI) could reduce pulmonary vascular injury by inhibiting leukocyte activation in rats given lipopolysaccharide (LPS). Pre- or posttreatment of animals with rTFPI significantly inhibited LPS-induced pulmonary vascular injury, as well as coagulation abnormalities. rTFPI significantly inhibited increases in lung tissue levels of tumor necrosis factor (TNF)-α, cytokine-induced neutrophil chemoattractant, and myeloperoxidase. Expression of TNF-α messenger RNA in the lung after LPS administration was significantly reduced by rTFPI administration. However, neither DX-9065a, a selective inhibitor of Factor Xa, nor recombinant Factor VIIa treated with dansyl-glutamylglycylarginyl-chloromethyl ketone, a selective inhibitor of Factor VIIa, had any effects on LPS-induced pulmonary vascular injury despite their potent anticoagulant effects. rTFPI significantly inhibited TNF-α production by LPS-stimulated monocytes in vitro. rTFPI also significantly inhibited several formyl-Met-Leu-Phe-induced neutrophil functions, as well as increases in the expression of CD11b and CD18 on the neutrophil cell surface in vitro. Additionally, rTFPI inhibited increases in levels of intracellular calcium, a second messenger of neutrophil activation, in formyl-Met-Leu-Phe-stimulated neutrophils in vitro. These results strongly suggested that rTFPI reduces pulmonary vascular injury by inhibiting leukocyte activation, as well as coagulation abnormalities in rats given LPS.

Original languageEnglish (US)
Pages (from-to)1752-1759
Number of pages8
JournalAmerican Journal of Respiratory and Critical Care Medicine
Volume162
Issue number5
DOIs
StatePublished - Jan 1 2000
Externally publishedYes

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine
  • Critical Care and Intensive Care Medicine

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