Background: Acute intestinal ischemia/reperfusion (AII/R) broadly affects critically ill patients in the areas of trauma, transplantation, cardiac surgery, shock, and sepsis. The mortality rates from intestinal ischemia range from 60-80% and has not changed in past 70 years. The high mortality rates from intestinal ischemia are due to the severity of the disease and development of remote organ injury. AII/R results in a remarkable systemic inflammatory response, and lung injury is frequently implicated. However, the mechanisms by which AII/R results in lung injury are not clearly understood. The high mortality rates of intestinal ischemia are also related to the failure to make the diagnosis.

Objective: To search for biomarkers of AII/R that would aid in earlier diagnosis, treatment, and prevention of further systemic injury in critically ill patients.

Methods: C57BL/6 mice were subjected to intestinal ischemia by occlusion of the superior mesenteric artery (SMA). A time course of intestinal ischemia from 0.5 to 3h was performed and followed by reperfusion for 2h. In separate experiments, N-acetyl-cysteine (NAC) was given prior to reperfusion. Intestinal injury was assessed by myeloperoxidase (MPO) levels and serum measurements of neutrophil, lactate, and I-FABP. Lung injury was measured by wet/dry ratio, neutrophil and protein influx in the bronchoalveolar lavage (BAL), and MPO levels. A pathologist, blinded to the study, performed the histopathologic grading of the intestinal and lung tissue.

Results: Neutrophil sequestration (MPO) in the intestine increased from <0.01 U/g to a peak of 0.074 U/g at 2h of intestinal ischemia. Intestinal pathology revealed normal mucosal villi at 0.5h. Pathologic signs of ischemia were then evident at 1h and by 3h of ischemia demonstrated areas of full thickness coagulative necrosis. Importantly, I-FABP was able to identify intestinal ischemia by 0.5h even prior to pathological changes. I-FABP levels directly correlated with ischemia time with levels of 5, 71, 238, and 2295 ng/mL at 0, 0.5, 2, 3h of intestinal ischemia respectively. Intestinal ischemia resulted in evidence of lung injury in a time dependent manor. The neutrophil sequestration in the lung, measured in lung homogenate, directly correlated with intestinal ischemia time. Lung MPO was <2 U/g at 0.5h of intestinal ischemia which increased to >6 U/g by 3h of ischemia (Figure 1). This was confirmed by pathologic examination. Pretreatment with NAC showed a decrease in MPO levels demonstrating oxidants are involved in the process of intestinal I/R induced-lung injury. Serum measurements of I-FABP also directly correlated with lung injury (R2=0.88, p=0.037).

Conclusion: I-FABP predicted AII/R prior to pathological evidence of ischemia and also directly correlated with resultant lung injury. Pretreatment of AII/R with the antioxidant NAC prevented lung injury, suggesting a role for oxidants in this mechanism. I-FABP is a promising biomarker for AII/R and may guide the treatment with antioxidant in early intestinal and distal organ injury.