Extrinsic coagulation blockade attenuates lung injury and proinflammatory cytokine release after intratracheal lipopolysaccharide.
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.
Miller
Debra L
DL
Department of Medicine, Division of Infectious Diseases, Duke University Medical Center, Durham, North Carolina 27710, USA. mille093@mc.duke.edu
Welty-Wolf
Karen
K
Carraway
Martha Sue
MS
Ezban
Mirella
M
Ghio
Andrew
A
Suliman
Hagir
H
Piantadosi
Claude A
CA
D000818:Animals; D001483:Base Sequence; D001777:Blood Coagulation; D002467:Cell Nucleus / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism*; D017931:DNA Primers; D024202:Electrophoretic Mobility Shift Assay; D018836:Inflammation Mediators / Q000378:metabolism*; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008168:Lung / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D055370:Lung Injury; D008297:Male; D016328:NF-kappa B / Q000378:metabolism; D021381:Protein Transport; D011516:Prothrombin / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013917:Thrombin / Q000037:antagonists & inhibitors; D013925:Thromboplastin / Q000378:metabolism; D014132:Trachea
D016207:Cytokines; D017931:DNA Primers; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D016328:NF-kappa B; D011516:Prothrombin; C025337:Factor IIa; D013925:Thromboplastin; D007770:L-Lactate Dehydrogenase; D013917:Thrombin