title: Tissue factor in experimental acute lung injury.
abstract: Acute lung injury (ALI) is characterized by fibrin deposition in the tissue and vascular spaces. Coagulation is activated after exposure to endotoxin or bacteria, and a procoagulant environment rapidly develops in the vascular, interstitial, and alveolar spaces of the lung. These changes are tissue factor (TF)-dependent and associated with increases in inflammatory cytokines. Procoagulant changes also occur in the lungs of patients with the acute respiratory distress syndrome (ARDS), suggesting that epithelial inflammation activates the extrinsic pathway. Many inflammatory mediators have specific effects on coagulation; however, the role of TF in regulation of pulmonary inflammatory responses is less clear. Here we report initial data on blockade of TF-initiated coagulation in baboons with Escherichia coli sepsis-induced ALI, using active site-inactivated FVIIa (FVIIai ASIS). Treatment with FVIIai prevented plasma fibrinogen depletion and attenuated fibrin deposition in the tissues. The drug also decreased systemic cytokine responses and inflammatory changes in the lung, including neutrophil infiltration, and decreased edema. Coagulation blockade with FVIIai improved lung function by preserving gas exchange and compliance, decreased pulmonary hypertension, and enhanced renal function. These results show that TF-FVIIa complex is an important regulatory site for the pathologic response of the lung to sepsis.
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Medicine, Duke University and Durham Veterans Affairs Medical Centers, Durham, NC 27710, USA.
authors.forename: K E
authors.initials: KE
authors.lastname: Welty-Wolf
authors.forename: M S
authors.initials: MS
authors.lastname: Carraway
authors.forename: S
authors.initials: S
authors.lastname: Idell
authors.forename: T L
authors.initials: TL
authors.lastname: Ortel
authors.forename: M
authors.initials: M
authors.lastname: Ezban
authors.forename: C A
authors.initials: CA
authors.lastname: Piantadosi
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D006801:Humans; D010215:Papio; D012128:Respiratory Distress Syndrome / Q000378:metabolism* / Q000382:microbiology / Q000503:physiopathology; D013925:Thromboplastin / Q000378:metabolism* / Q000502:physiology
chemical_list: D013925:Thromboplastin