Article

Coagulation blockade prevents sepsis-induced respiratory and renal failure in baboons.

Division of Pulmonary and Critical Care Medicine, Department of Medicine, Duke University and Durham VA Medical Centers, Durham, North Carolina 27710, USA.
American Journal of Respiratory and Critical Care Medicine (impact factor: 11.08). 11/2001; 164(10 Pt 1):1988-96. pp.1988-96
Source: PubMed

ABSTRACT 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 x 10(9) CFU/kg), and bacteremic sepsis was induced 12 h later by infusion of live E. coli at 1 x 10(10) 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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Keywords

acute lung injury
 
adult baboons
 
bacteremic sepsis
 
control inflammation
 
fibrin deposition
 
lung compliance
 
lung edema
 
organ damage
 
organ injury
 
potentiates inflammation
 
proinflammatory cytokine release
 
pulmonary hypertension
 
renal function
 
sepsis-induced ALI
 
Sepsis-induced tissue factor
 
site-inactivated FVIIa
 
systemic proinflammatory cytokine responses
 
TF blockade
 
TF-FVIIa complex contributes
 
tissue factor pathway inhibitor
 

K E Welty-Wolf