Protective effects of fenofibrate against acute lung injury induced by intestinal ischemia/reperfusion in mice

Zhu, Qiankun; He, Guizhen; Wang, Jie; Wang, Yukang; Chen, Wei

Oxidative stress is another facet of the mechanism of I/R injury. To confirm the effectiveness of fenofibrate in the model of I/R injury, we applied the NO as the oxidative marker which is closely related to I/R 29 . In physiological conditions, NO inhibits the neutrophil release and the platelet accumulation. But in I/R state, NO in the lung tissue is dramatically increased, leading to mitochondria inhibition and energy metabolism dysfunction 30 . The reduced NO concentration in the lung tissue of the fenofibrate treated group is consistent with the ameliorated morphologic presentations of the lung tissue. Therefore, the beneficial effect of fenofibrate in I/R-caused ALI can be partly attributed to its anti-oxidative property. NF-κ B p65 is a widely-acknowledged transcriptional factor regulating the distinct inflammatory cytokines in I/R 20 . In normal state, the NF-κ B p65 is combined with its inhibitor Iκ Bα within the cytoplasm in an inactive form. When being stimulated under pathological conditions, Iκ Bα becomes phosphorylated and ubiquitinated, and then NF-κ B p65 is released and aggregated into the nucleus, activating the related genes to transcript 31 . We demonstrated that fenofibrate markedly inhibited the activation of the NF-κ B p65 pathway in the lungs and intestines of mice during intestinal I/R injury, while the Iκ Bα activity was up-regulated compared to the vehicle group, unveiling that the anti-inflammatory property of fenofibrate in the intestinal I/R injury is through an NF-κ B p65 dependent pathway. Since the NF-κ B p65 activation is reported to be associated with alveolar macrophage activity which is the major source of inflammatory cytokines 4 , the NF-κ B p65 pathway in the macrophage seems a reasonable explanation for the mechanism of anti-inflammation of fenofibrate in the protection against ALI in I/R.