Mannitol Dose-Dependently Attenuates Lung Reperfusion Injury Following Liver Ischemia Reperfusion: A Dose-Response Study in an Isolated Perfused Double-Organ Model

Abstract

We had previously studied different modes of prevention of liver ischemia-reperfusion (IR)-induced remote organ reperfusion injury, a challenge that remains partly unmet. We have now studied the capability of mannitol at different doses in abrogating liver IR-induced lung reperfusion injury in an isolated double-organ model. Rat livers (n = 8/group) were perfused with Krebs-Henseleit solution (control) or made globally ischemic (IR) for 2 h, after which they were paired with normal lungs and “reperfused” together for 15 min. The lungs were then perfused alone with the accumulated Krebs for an additional 45 min. Another 4 control and 4 IR pairs were reperfused with Krebs containing mannitol at .22 mmol, .55 mmol, .77 mmol, or 1.1 mmol. Mannitol .22 mmol and 1.1 mmol failed to attenuate IR-lung injury as indicated by 50–95% increases in inspiratory and perfusion pressures and compliance reduction, a 70% increase in weight gain, and a 2–50-fold increase in bronchoalveolar lavage volume and content. Mannitol .55 mmol prevented all these abnormalities, and .77 mmol attenuated only changes in ventilatory parameters. The latter two treatments were also associated with a 50% reduction in xanthine oxidase activity and a 35–45% increase in the reduced glutathione tissue content compared with the nontreated IR-paired lungs. It is concluded that mannitol in a narrow therapeutic dose range can reduce oxidalive stress-induced lung damage that is related to liver IR.