Ischemia in adult male C57BL/6 mice was induced by fastening the superior mesenteric artery with 4-0 suture. At 45 min later, the vascular suture was released to allow reperfusion. cRGD (5 mg/kg BW) or normal saline (vehicle) was administered by intra-peritoneal injection 1 h prior to ischemia. Blood, gut, and lung tissues were collected at 4 h after reperfusion for various measurements.Intestinal I/R caused severe widespread injury to the gut and lungs. Treatment with cRGD improved the integrity of microscopic structures in the gut and lungs, as judged by histological examination. Intestinal I/R induced the expression of 1, 2 and 3 integrins, ICAM-1, and fibronectin. cRGD significantly inhibited myeloperoxidase activity in the gut and lungs, as well as neutrophils and macrophages infiltrating the lungs. cRGD reduced the levels of TNF- and IL-6 in serum, in addition to IL-6 and MIP-2 in the gut and lungs. Furthermore, the number of TUNEL-staining cells and levels of cleaved caspase-3 in the lungs were significantly lowered in the cRGD-treated mice in comparison to the vehicle mice.Treatment with cRGD effectively protected ALI and gut injury, lowered neutrophil infiltration, suppressed inflammation, and inhibited lung apoptosis after intestinal I/R. Thus, there is a potential of developing cRGD as a treatment for patients suffering from ALI caused by intestinal I/R.