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Intestinal ischemia-reperfusion can occur in shock and mesenteric occlusive diseases, causing significant morbidity and mortality. Aside from local injury, intestinal ischemia-reperfusion can result in remote organ damage, particularly in the lungs. Cold-inducible RNA-binding protein (CIRP) was identified as a novel inflammatory mediator. We hypothesized that a deficiency in CIRP would protect the lungs during intestinal ischemia-reperfusion injury.Intestinal ischemia was induced in adult male C57BL/6 wild-type and CIRP knock-out (CIRP−/−) mice via clamping of the superior mesenteric artery for 60 minutes. Reperfusion was allowed for 4 hours or 20 hours, and blood, gut, and lung tissues were harvested for various analyses.After intestinal ischemia-reperfusion, the elevated levels of serum lactate dehydrogenase and inflammatory cytokine interleukin-6 were reduced by 68% and 98%, respectively, at 20 hours after ischemia-reperfusion in CIRP−/− mice compared with the wild-type mice. In the gut, mRNA levels of inflammatory cytokine interleukin-6 were reduced by 67% at 4 hours after ischemia-reperfusion in CIRP−/− mice. In the lungs, inflammatory cytokine interleukin-6 protein and myeloperoxidase activity were reduced by 78% and 26% at 20 hours and 4 hours after ischemia-reperfusion, respectively, in CIRP−/− mice. Finally, the elevated lung caspase-3 was significantly decreased by 55%, terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling-positive cells decreased by 91%, and lung injury score decreased by 37% in CIRP−/− mice at 20 hours after ischemia-reperfusion.Increased levels of proinflammatory cytokines, myeloperoxidase, and apoptosis are the hallmarks of acute respiratory distress syndrome. We noticed after intestinal ischemia-reperfusion the proinflammatory milieu in lungs was elevated significantly, while the CIRP−/− mice had significantly decreased levels of proinflammatory cytokine, myeloperoxidase, and apoptotic cells leading to decreased lung injury. These findings strongly established a causal link between CIRP and acute respiratory distress syndrome during intestinal ischemia-reperfusion injuries. Targeting CIRP may therefore be beneficial for treatment of intestinal ischemia-reperfusion-associated acute respiratory distress syndrome acute respiratory distress syndrome.