Crosstalk between thrombosis and inflammation in lung reperfusion injury.
BACKGROUND
Activation of extravascular coagulation has been reported in acute lung injury models of sepsis and acute respiratory distress syndrome. Thrombin, the main effector protease of extravascular coagulation, activates proinflammatory cell types, including macrophages, endothelial cells, and neutrophils, each of which participates in lung ischemia-reperfusion injury. We used hirudin, a potent, specific direct thrombin inhibitor, to define the role of thrombin in lung ischemia-reperfusion injury.


METHODS
Rats were pretreated with hirudin 30 minutes before warm, in situ left lung ischemia and reperfusion. Multiple in vivo assessments of lung injury were determined, and mechanistic studies assessed transcriptional regulation early in reperfusion and proinflammatory protein secretion late in reperfusion. Immunohistochemistry localized thrombin activation.


RESULTS
Thrombin localized to macrophages and endothelial and epithelial cells early in reperfusion. Hirudin significantly limited lung ischemia-reperfusion injury-induced derangements in vascular permeability and intraalveolar inflammatory cell sequestration, resulting in improved arterial oxygenation after ischemia and 4 hours of reperfusion. The protection was transcriptionally mediated by attenuated activator protein-1 and early growth response-1 transactivation, but not nuclear factor kappa B transactivation. This was associated with reduced chemokine, but not tumor necrosis factor alpha, secretion late in reperfusion.


CONCLUSIONS
Thrombin promotes lung ischemia-reperfusion injury, as hirudin protected against experimental acute lung injury. Hirudin conferred protection through a mechanism independent of nuclear factor kappa B and tumor necrosis factor alpha, suggesting that its effects may be mediated by a parallel, synergistic inflammatory pathway through activator protein-1 and early growth response-1.
Division of Cardiothoracic Surgery, University of Washington Medical Center, Seattle, Washington 98195, USA. afarivar@u.washington.edu
Alexander S
AS
Farivar
Mauricio F
MF
Delgado
Anton S
AS
McCourtie
Andrew D
AD
Barnes
Edward D
ED
Verrier
Michael S
MS
Mulligan
D000818:Animals; D002199:Capillary Permeability; D004195:Disease Models, Animal; D006801:Humans; D007249:Inflammation / Q000503:physiopathology*; D007511:Ischemia / Q000503:physiopathology; D009195:Peroxidase / Q000032:analysis; D011652:Pulmonary Circulation; D051381:Rats; D020318:Rats, Long-Evans; D015424:Reperfusion; D015427:Reperfusion Injury / Q000503:physiopathology*; D012129:Respiratory Function Tests; D013927:Thrombosis / Q000503:physiopathology*
D009195:Peroxidase