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Am. J. Respir. Crit. Care Med., Volume 164, Number 10, November 2001, 1988-1996

Coagulation Blockade Prevents Sepsis-induced Respiratory and Renal Failure in Baboons

KAREN E. WELTY-WOLF, MARTHA S. CARRAWAY, DEBRA L. MILLER, THOMAS L. ORTEL, MIRELLA EZBAN, ANDREW J. GHIO, STEVEN IDELL, and CLAUDE A. PIANTADOSI

Divisions of Pulmonary and Critical Care Medicine and Hematology, Department of Medicine, Duke University and Durham VA Medical Centers, Durham, North Carolina; Novo Nordisk, Copenhagen, Denmark; and Department of Specialty Care Services, University of Texas, Tyler, Texas

Sepsis-induced tissue factor (TF) expression activates coagulation in the lung and leads to a procoagulant environment, which results in fibrin deposition and potentiates inflammation. We hypothesized that preventing initiation of coagulation at TF-Factor VIIa (FVIIa) complex would block fibrin deposition and control inflammation in sepsis, thereby limiting acute lung injury (ALI) and other organ damage in baboons. A model of ALI was used in which adult baboons were primed with killed Escherichia coli (1 × 109 CFU/kg), and bacteremic sepsis was induced 12 h later by infusion of live E. coli at 1 × 1010 CFU/kg. Animals in the treatment group were given a competitive inhibitor of TF, site-inactivated FVIIa (FVIIai), intravenously at the time of the infusion of live bacteria and monitored physiologically for another 36 h. FVIIai dramatically protected gas exchange and lung compliance, prevented lung edema and pulmonary hypertension, and preserved renal function relative to vehicle (all p < 0.05). Treatment attenuated sepsis-induced fibrinogen depletion (p < 0.01) and decreased systemic proinflammatory cytokine responses, for example, interleukin 6 (p < 0.01). The protective effects of TF blockade in sepsis-induced ALI were confirmed by using tissue factor pathway inhibitor. The results show that TF-FVIIa complex contributes to organ injury in septic primates in part through selective stimulation of proinflammatory cytokine release and fibrin deposition.




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