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Background: Successful drug treatment for ischemia--reperfusion-induced lung injury remains a major clinical problem. Melatonin (MT) is a hormone that is principally synthesized in the pineal gland. It has been shown to exhibit a variety of functions including anti-inflammatory and antioxidant effects. Previous reports on N-myc downstream-regulated gene (NDRG)2 have suggested that it is involved in cellular differentiation, development, antiapoptosis, anti-inflammatory cytokine, and antioxidant. The objective of this study was to test whether MT, a novel NDRG2 activator, can protect against intestinal ischemia-reperfusion-induced lung injury (IIRI)., Materials and Methods: IIRI was induced in rats by occlusion of the superior mesenteric artery for 60 min, and the occlusion was then released for reperfusion. Rats were randomly divided into six groups as follows: control group; MT group; IIRI group; IIRI+5 mg/kg MT group; IIRI+15 mg/kg MT group; and IIRI+25 mg/kg MT group. The effects of MT on intestinal ischemia-reperfusion-induced lung pathologic changes, inflammatory cytokines release, myeloperoxidase and superoxide dismutase activities, and malondialdehyde level were examined. In addition, the NDRG2 activation in lung tissues was detected by Western blot analysis., Results: MT pretreatment attenuated edema and the pathologic changes in the lung. MT also decreased the levels of tumor necrosis factor-α, interleukin-1β, and interleukin-8 in bronchoalveolar lavage fluid. In addition, MT markedly prevented IIRI-induced elevation of malondialdehyde and myeloperoxidase levels, as well as reduction of superoxide dismutase activity. Furthermore, the expression of NDRG2 was activated by MT pretreatment in lung tissues., Conclusions: The present study demonstrates that MT exerted protection against IIRI-induced oxidative stress. The potential mechanism of this action may attribute partly to the activation of NDRG2 expression., (Copyright © 2015 Elsevier Inc. All rights reserved.)