To determine the possible mechanisms underlying beneficial effect of recombinant bactericidal/permeability-increasing protein (rBPI) on acute lung injury response to blood loss, we used reverse transcription polymerase chain reaction to measure pulmonary tumor necrosis factor (TNF), interleukin 6 (IL-6) mRNA expression in a rat model of prolonged hemorrhagic shock (4.00 kPa, 180 min) followed by adequate resuscitation. The results showed that systemic plasma endotoxin concentrations elevated rapidly after a 180-min hemorrhagic insult (P < 0.05), and TNF, IL-6 mRNA expression in the lung were significantly increased at 2, 8 hours after resuscitation respectively. However, treatment with rBPI resulted in almost neutralization of plasma endotoxin values, remarkable reduction of TNF, IL-6 mRNA levels following hemorrhage/resuscitation. Also, it was found that rBPI administration markedly blunted the increase in pulmonary Evans blue dye extravasation, concomitant with a significant decrease in lung myeloperoxidase activity compared with the control group (P < 0.05-0.01). These data suggest that local proinflammatory cytokine mRNA expression associated with gut origin endotoxemia may be an important mechanism contributing to the development of hemorrhage-induced lung injury. Treatment with rBPI is effective in inhibiting marked TNF, IL-6 mRNA expression and ameliorating acute lung injury secondary to severe hemorrhagic shock.