Priming for enhanced alveolar fibrin deposition after hemorrhagic shock - Role of tumor necrosis factor

Hemorrhagic shock due to major trauma predisposes to the development of acu te respiratory distress syndrome. Because lung fibrin deposition is one of the hallmarks of this syndrome, we hypothesized that resuscitated shock mig ht predispose to the development of a net procoagulant state in the lung. A rodent model of shock/resuscitation followed by low-dose intratracheal lip opolysaccharide (LPS), a clinically relevant "two-hit" model, was used to t est this hypothesis. Resuscitated shock primed the lungs for an increased t issue factor and plasminogen activator (PA) inhibitor-1 gene expression in reponse to LPS, while the fibrinolytic PA was reduced, These alterations we re recapitulated in isolated alveolar macrophages, suggesting their role in the process. LPS-induced tumor necrosis factor (TNF) was also augmented in animals after antecedent shock/resuscitation, and studies using anti-TNF a ntibodies revealed that TNF expression was critical to the induction of the procoagulant molecules and the reduction in PA. By contrast, TNF did not a ppear to play an important role in neutrophil sequestration in this model, inasmuch as anti-TNF had no effect on lung neutrophil accumulation or chemo kine expression, However, treatment prevented albumin leak by preventing al veolar neutrophil activation. The inclusion of the antioxidant N-acetyl-cys teine in the resuscitation fluid resulted in prevention of both the develop ment of the net procoagulant state and lung neutrophil sequestration, sugge sting a role for upstream oxidant effects in the priming process. These stu dies provide a cellular and molecular basis for lung fibrin deposition afte r resuscitated shock and demonstrate a divergence of pathways responsible f or fibrin generation and neutrophil accumulation.