Bactericidal/permeability-increasing protein attenuates systemic inflammation and acute lung injury in porcine lower limb ischemia-reperfusion injury

Objective To investigate the role of recombinant bactericidal/permeabillty-increasing protein (rBPI(21)) in the attenuation of the sepsis syndrome and acute lun g injury associated with lower limb ischemia-reperfusion (I/R) injury. Summary Background Data Gut-derived endotoxin has been implicated in the conversion of the sterile inflammatory response to a lethal sepsis syndrome after lower torso I/R inj ury. rBPI(21) is a novel antiendotoxin therapy with proven benefit in sepsi s. Methods Anesthetized ventilated swine underwent midline laparotomy and bilateral ex ternal iliac artery occlusion for 2 hours followed by 2.5 hours of reperfus ion. Two groups (n = 6 per group) were randomized to receive, by intravenou s infusion over 30 minutes, at the start of reperfusion, either thaumatin, a control-protein preparation, at 2 mg/kg body weight, or rBPI(21) at 2 mg/ kg body weight. A control group (n = 6) underwent laparotomy without furthe r treatment and was administered thaumatin at 2 mg/kg body weight after 2 h ours of anesthesia. Blood from a carotid artery cannula was taken every hal f-hour for arterial blood gas analysis. Plasma was separated and stored at -70 degreesC for later determination of plasma tumor necrosis factor (TNF)- alpha, interleukin (IL)-6 by bioassay, and IL-8 by enzyme-linked immunosorb ent assay (ELISA), as a markers of systemic inflammation, Plasma endotoxin concentration was measured using ELISA. Lung tissue wet-to-dry weight ratio and myeloperoxidase concentration were used as markers of edema and neutro phil sequestration, respectively. Bronchoalveolar lavage protein concentrat ion was measured by the bicinclinoic acid method as a measure of capillary- alveolar protein leak. The alveolar-arterial gradient was measured; a large gradient indicated impaired oxygen transport and hence lung injury. Results Bilateral hind limb I/R injury increased significantly intestinal mucosal a cidosis, intestinal permeability, portal endotoxemia, plasma IL-6 concentra tions, circulating phagocytic cell priming and pulmonary leukosequestration , edema, capillary-alveolar protein leak, and impaired gas exchange. Conver sely, pigs treated with rBPI(21) 2 mg/kg at the onset of reperfusion had si gnificantly reduced intestinal mucosal acidosis, portal endotoxin concentra tions, and circulating phagocytic cell priming and had significantly less p ulmonary edema, leukosequestration, and respiratory failure. Conclusions Endotoxin transmigration across a hyperpermeable gut barrier, p hagocytic cell priming, and cytokinemia are key events of I/R injury, sepsi s, and pulmonary dysfunction. This study shows that rBPI(21) ameliorates th ese adverse effects and may provide a novel therapeutic approach for preven tion of I/R-associated sepsis syndrome.