FR167653 attenuates ischemia and reperfusion injury of the rat lung with suppressing p38 mitogen-activated protein kinase

Background: FR167653 is a potent suppressant of tumor necrosis factor (TNF) -alpha and interleukin-1 (IL-1) production, and was shown to attenuate isch emia and reperfusion (IIR) organ injury in our previous experiment. Because p38 mitogen-activated protein (MAP) kinase has been reported to regulate t he production of TNF-alpha and IL-1, we examined the effects of FR167653 in the rat lung I/R model and determined the expression and activation of p38 MAP kinase. Methods: Experiment 1: After 1 hour of ischemia, p38 MAP kinase, phosphoryl ated p38 MAP kinase (active form), histologic changes of the lung, and seru m levels of TNF-alpha: and IL-1 beta were examined. Experiment 2: After 2 h ours of reperfusion, arterial oxygen content (Pao(2)) and saturation (Sao(2 )), serum TNF-alpha and IL-1 beta levels, and histologic changes in the lun g were examined. Rats were divided into three groups in Experiment 1. In th e control group, a saline solution was administered and, in the FR group, 0 .1 mg/kg per hour of FR167653 was administered, intravenously throughout th e experiment, beginning 30 minutes before ischemia. In the non-ischemic gro up, samples were taken soon after thoracotomy. The rats were divided into c ontrol and FR groups in Experiment 2. Results: Experiment 1: One hour of ischemia induced almost no changes in th e lung or serum cytokine levels. Meanwhile, FR167653 markedly attenuated th e expression of phosphorylated p38 MAP kinase, Experiment 2: Sao(2) and Pao (2) were improved, serum cytokines were lower, and lung damage was less ext ensive in the FR group than in the control group. Conclusion: FR167653 attenuates I/R injury of the lung and this attenuation is associated with suppression of p38 MAP kinase activation.