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Am. J. Respir. Cell Mol. Biol., Volume 26, Number 6, June, 2002 650-658

Extrinsic Coagulation Blockade Attenuates Lung Injury and Proinflammatory Cytokine Release after Intratracheal Lipopolysaccharide

Debra L. Miller, Karen Welty-Wolf, Martha Sue Carraway, Mirella Ezban, Andrew Ghio, Hagir Suliman, and Claude A. Piantadosi

Department of Medicine, Divisions of Infectious Diseases and Pulmonary and Critical Care Medicine, Duke University Medical Center, Durham, North Carolina; and Novo Nordisk Corporation Copenhagen, Denmark

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)-kappa B. 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.

Abbreviations: acute lung injury, ALI; bronchoalveolar lavage, BAL; bovine serum albumin, BSA; enzyme-linked immunosorbent assay, ELISA; electrophoretic mobility shift assay, EMSA; site-inactivated FVIIa, FFR-FVIIa; TF-factor VIIa, FVIIa; glyceraldehyde phosphate dehydrogenase, GAPDH; immunohistochemistry, IHC; interleukin, IL; lactate dehydrogenase, LDH; lipopolysaccharide, LPS; mitogen-activated protein kinase, MAPK; nuclear factor-kappa B, NF-kappa B; phosphate-buffered saline, PBS; procoagulant activity, PCA; reverse transcription-polymerase chain reaction, RT-PCR; tissue factor, TF; tumor necrosis factor, TNF.




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