Ubiquitin enhances the Th2 cytokine response and attenuates ischemia-reperfusion injury in the lung

OBJECTIVE: To determine whether ubiquitin treatment modulates the lung cytokine response and attenuates lung ischemia-reperfusion injury. DESIGN AND SETTING: Randomized and blinded treatment of unilateral lung ischemia-reperfusion injury in a research laboratory. SUBJECTS: Twenty anesthetized and mechanically ventilated Brown Norway rats. INTERVENTIONS: Unilateral clamping of the left lung for 90 mins followed by 60 mins of reperfusion. Intravenous administration of 1.5 mg/kg of ubiquitin (n = 10) or albumin (n = 10) 5 mins before reperfusion. MEASUREMENTS AND MAIN RESULTS: Blood pressure was measured by the tail-cuff method. Oxygenation via the ischemic lung was assessed by PaO2 measurements after right lung exclusion. Wet-to-dry weight ratios of the ischemic lungs were determined gravimetrically. Tissue homogenates (n = 5/group) were prepared from ischemic lungs at the end of reperfusion and assayed for malondialdehyde in combination with 4-hydroxyalkenals to assess lipid peroxidation, and for a panel of 22 cytokines/chemokines using a multiplex assay. Ubiquitin serum levels were determined by enzyme-linked immunosorbent assay.All animals were hemodynamically stable during the experimental procedure. Ubiquitin serum levels (mean +/- SD) were 650 +/- 40 ng/mL in controls and 1206 +/- 181 ng/mL in the ubiquitin treatment group at the end of the experiment. PaO2 after right lung exclusion was 45 (32-72) mm Hg with albumin and 61 (range, 36-132) mm Hg with ubiquitin (p = .0185). Wet-to-dry weight ratios of the injured lungs were 8.7 (range, 5.5-19.1) and 7.8 (range, 5.7-8.3) in the albumin and ubiquitin groups, respectively (p = .035). Malondialdehyde/4-hydroxyalkenals concentrations (mean +/- SD, nmol/mg protein) were 2.5 +/- 0.4 with ubiquitin and 3.0 +/- 0.3 with albumin (p > .05). Concentrations of the interleukins 4, 10, and 13 were significantly increased in lung homogenates after ubiquitin treatment (p < .05). CONCLUSION: Ubiquitin treatment enhances the Th2 cytokine response in postischemic lungs during reperfusion, reduces lung edema formation, and improves pulmonary function during lung ischemia-reperfusion injury. This study further defines ubiquitin's anti-inflammatory properties, and suggests that it could be used therapeutically to improve function of postischemic lungs.