Coagulation blockade prevents sepsis-induced respiratory and renal failure in baboons.
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.
Welty-Wolf
K E
KE
Division of Pulmonary and Critical Care Medicine, Department of Medicine, Duke University and Durham VA Medical Centers, Durham, North Carolina 27710, USA. welty001@mc.duke.edu
Carraway
M S
MS
Miller
D L
DL
Ortel
T L
TL
Ezban
M
M
Ghio
A J
AJ
Idell
S
S
Piantadosi
C A
CA
D058186:Acute Kidney Injury / Q000382:microbiology* / Q000517:prevention & control*; D000818:Animals; D016470:Bacteremia / Q000097:blood / Q000150:complications* / Q000276:immunology / Q000473:pathology / Q000503:physiopathology; D001777:Blood Coagulation / Q000187:drug effects* / Q000502:physiology; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D004927:Escherichia coli Infections / Q000097:blood / Q000150:complications* / Q000276:immunology / Q000503:physiopathology; D015944:Factor VIIIa / Q000502:physiology* / Q000627:therapeutic use*; D005340:Fibrinogen / Q000032:analysis / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects; D007249:Inflammation; D015850:Interleukin-6 / Q000097:blood; D007677:Kidney Function Tests; D008170:Lung Compliance / Q000187:drug effects; D008297:Male; D010215:Papio; D011654:Pulmonary Edema / Q000382:microbiology / Q000517:prevention & control; D011659:Pulmonary Gas Exchange / Q000187:drug effects; D011897:Random Allocation; D012128:Respiratory Distress Syndrome / Q000382:microbiology* / Q000517:prevention & control*; D013925:Thromboplastin / Q000037:antagonists & inhibitors* / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha; D015944:Factor VIIIa; D005340:Fibrinogen; D013925:Thromboplastin