A1-adenosine receptor antagonists block endotoxin-induced lung injury

Endotoxin produces a variety of biological effects on different cell types, such as priming of neutrophils and macrophages, which then release a number of important mediators of endotoxin-induced lung injury. However, the specific mechanism by which endotoxin initiates its cascade of pathophysiological events in the lung has not been described. Both A1 adenosine receptor activation and endotoxin induce the release of thromboxane A2 from the lung and inhibit adenylate cyclase. By acting on A1 adenosine receptors, adenosine promotes neutrophil chemotaxis and adherence to endothelial cells. We hypothesized that A1 adenosine receptor activation is essential to endotoxin-induced lung injury, and we used the highly selective A1-adenosine receptor antagonists, 8-cyclopentyl-1,3-dipropylxanthine (DPCPX) and 8-benzyl-7,[2-[ethyl(2-hydroxyethyl)amino]-ethyl] theophylline (bamiphylline), to investigate whether selective blocking of the A1 adenosine receptor would prevent endotoxin-induced acute lung injury. An intralobar arterial infusion of endotoxin (15 mg/kg) into the left lower lobe of the lung in intact-chest, spontaneously breathing cats produced lung injury characterized by the presence of neutrophils, macrophages, and red blood cells (RBCs) in alveoli, and alveolar edema and necrosis. Lower doses of endotoxin (5 or 10 mg/kg) produced less severe and dose-dependent lung injury. Endotoxin (15 mg/kg)-induced alveolar injury was blocked in a highly significant manner by A1-adenosine receptor antagonists, DPCPX and bamiphylline. An intravenous bolus of DPCPX 30 min before endotoxin infusion or a continuous intravenous infusion of bamiphylline 30 min before, during, and 30 min after endotoxin reduced the percent injured alveoli (defined as the presence of 2 or more inflammatory cells or RBCs, or edematous fluid) from 57 +/- 31% (endotoxin 15 mg/kg) to 9 +/- 1% (DPCPX) or 21 +/- 14% (bamiphylline), which were not significantly different from control (1-h perfusion only) (4 +/- 1%) (P < 0.05). These data represent the first evidence that A1-adenosine receptor antagonism blocks the capacity of endotoxin to cause lung injury. A1-adenosine receptor antagonists may be useful in preventing adult respiratory distress syndrome associated with septicemia.