LIVER ISCHEMIA-REPERFUSION INCREASES PULMONARY PERMEABILITY IN RAT - ROLE OF CIRCULATING XANTHINE-OXIDASE

Reactive oxygen species play an important role in pathogenesis of a variety of pathological processes, e.g., ischemia-reperfusion, acute viral infections, thermal injury, hepatic diseases, and acute lung injury. Xanthine oxidase (XO) may be a significant source of these cytotoxic oxygen species. We tested the hypothesis that hepatic ischemia-reperfusion releases xanthine dehydrogenase + XO (XDH + XO) into the circulation and that circulating XO damages isolated perfused lung. Isolated Liver + lung preparation was perfused with Krebs-Henseleit buffer to minimize confounding effects of circulating neutrophils. In one group, livers were rendered globally ischemic for 2 h and then reperfused (I/R). In another group, livers were pretreated with allopurinol and perfused with buffer containing additional allopurinol (I/R + Allo). After 2 h of ischemia, an isolated lung was connected to liver, and liver + lung preparation was reperfused in series for 15 min. Liver reperfusion was terminated, and lung was recirculated with liver effluent for 45 min. Capillary filtration coefficient (ml . min(-1). cmH(2)O(-1). 100 g lung dry wt(-1)) was 2.0 +/- 0.3 and 1.9 +/- 0.4 in control and I/R + Allo lungs, respectively, and 9.0 +/- 1.2 in I/R lungs (P < 0.001). Lung wet-to-dry weight ratio in control and I/R + Allo lungs was 8.6 +/- 0.3 and 9.1 +/- 0.5, respectively, and 14.9 +/- 1.1 in I/R lungs (P < 0.01). Control and I/R + Allo bronchoalveolar lavage protein content was <1.0 mg/ml compared with 32.6 +/- 8.4 mg/ml in I/R group. XDH + XO activity in control and I/R + Allo liver effluent was 0.5-10 mu U/ml throughout the experiments, whereas in I/R it increased to 2,303 +/- 688 mu/ml upon reperfusion. XDH + XO activity in lung tissue was 28 +/- 2 mU/g in control and increased 14-fold after perfusion with ischemic liver effluent. We conclude that ischemic-reperfused Liver releases large amounts of XDH + XO into the circulation and that this circulating XDH + XO alters alveolar-capillary membrane integrity in the absence of circulating neutrophils.