Abstract
Pulmonary complications frequently occur after liver transplantation and are often life-threatening. Thus, we investigated whether hepatic ischemic preconditioning (IP) attenuates acute lung injury (ALI) after small-for-size liver transplantation. Rat livers were explanted after 9-min ischemia plus 5-min reperfusion, reduced to 50% of original size ex vivo, and implanted into recipients with approximately twice the donor body weight, resulting in quarter-size liver grafts (QSG). After QSG transplantation, hepatic Toll-like receptor 4 (TLR4) and tumor necrosis factor-α (TNFα ) expression increased markedly and high mobility group box-1 (HMGB1), an endogenous damage-associated molecular pattern molecule (DAMP), was released from QSG into the blood. IP blunted TLR4 and TNFα expression and HMGB1 release from QSG. In the lungs of QSG recipients without IP treatment, nuclear factor-κB (NF-κB) activation and intercellular adhesion molecule (ICAM)-1 expression increased; alveolar septal walls thickened with increased cellularity as neutrophils, monocytes/macrophage and T lymphocytes infiltrated into alveolar septa and alveolar spaces; and pulmonary cleaved caspase-8 and -3 and TUNEL-positive cells increased. In contrast, in the lungs of recipients of ischemic-preconditioned QSG, NF-κB activation and ICAM-1 expression were blunted; leukocyte infiltration was decreased; and alveolar septal wall thickening, caspase activation, and cell apoptosis were attenuated. IP did not increase heat-shock proteins in the lungs of QSG recipients. In conclusion, toxic cytokine and HMGB1 released from failing small-for-size grafts leads to pulmonary adhesion molecule expression, leukocyte infiltration and injury. IP prevents DAMP release and toxic cytokine formation in small-for-size grafts, thereby attenuating ALI.