Extrinsic coagulation blockade attenuates lung injury and proinflammatory cytokine release after intratracheal lipopolysaccharide

Am J Respir Cell Mol Biol. 2002 Jun;26(6):650-8. doi: 10.1165/ajrcmb.26.6.4688.


Initiation of coagulation by tissue factor (TF) is a potentially powerful regulator of local inflammatory responses. We hypothesized that blockade of TF-factor VIIa (FVIIa) complex would decrease lung inflammation and proinflammatory cytokine release after tracheal instillation of Escherichia coli lipopolysaccharide (LPS 0111:B4). At the time of injury, rats received one dose of site-inactivated FVIIa (FFR-FVIIa) or saline intravenously. At 0, 6,12, 24, and 48 h after injury, lungs were examined for histologic changes and bronchoalveolar lavage (BAL) was performed to assess protein, lactate dehydrogenase (LDH) activity, cell counts, and cytokine levels. LPS-injured rats treated with FFR-FVIIa showed decreased intra-alveolar inflammation and fibrin deposition by light microscopy compared with untreated rats. This was accompanied by decreased protein leakage (P < 0.0001), LDH activity (P < 0.0001), and local elaboration of interleukin (IL)-1beta, IL-6, and IL-10 (all P < 0.0001), but not tumor necrosis factor (TNF)-alpha. Protection was associated with reduction of TF mRNA expression in whole lung, but not with changes in nuclear translocation of nuclear factor (NF)-kappaB. FFR-FVIIa given 6 h after LPS afforded equivalent lung protection. Therefore, blockade of TF-FVIIa complex protects the lung from injury by LPS in part by reducing local expression of proinflammatory cytokines and may offer promise for therapy of acute lung injury.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Base Sequence
  • Blood Coagulation*
  • Cell Nucleus / metabolism
  • Cytokines / metabolism*
  • DNA Primers
  • Electrophoretic Mobility Shift Assay
  • Inflammation Mediators / metabolism*
  • L-Lactate Dehydrogenase / metabolism
  • Lipopolysaccharides / pharmacology*
  • Lung / drug effects*
  • Lung / enzymology
  • Lung / metabolism
  • Lung Injury
  • Male
  • NF-kappa B / metabolism
  • Protein Transport
  • Prothrombin / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Reverse Transcriptase Polymerase Chain Reaction
  • Thrombin / antagonists & inhibitors
  • Thromboplastin / metabolism
  • Trachea


  • Cytokines
  • DNA Primers
  • Inflammation Mediators
  • Lipopolysaccharides
  • NF-kappa B
  • Prothrombin
  • Factor IIa
  • Thromboplastin
  • L-Lactate Dehydrogenase
  • Thrombin