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

Abstract

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.

• Authors: Debra L Miller, Karen Welty-Wolf, Martha Sue Carraway, Mirella Ezban, Andrew Ghio, Hagir Suliman, Claude A Piantadosi
• Journal: American journal of respiratory cell and molecular biology (Am J Respir Cell Mol Biol) Vol. 26 Issue 6 Pg. 650-8 (Jun 2002) ISSN: 1044-1549 [Print] United States
• PMID: 12034563 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

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

Topics

• 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, enzymology, 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