The Effect And Mechanism Of PGC-1α On Acute Lung Injury

Background and objectives:Acute lung injury(ALI) and acute respiratory distress syndrome(ARDS) commonly induced by serious infection or trauma are characterized by refractory hypoxemia and decreased lung compliance. It is generally accepted that excessive inflammatory response is the main pathophysiology of ALI, which leads to endothelial or epithelial injury. This damage results in increased vascular permeability, alveolar ?ooding, hemorrhage and pulmonary edema. Although extensive efforts have been taken to elucidate the mechanisms underlying the occurrence and development of ALI/ARDS, effective therapies resulted from these efforts are rare and the mortality still remains 35-50%. Thus, exploration of new therapeutic target for ALI/ARDS is urgently needed.Our previous studies have confirmed that activation of PPARγ could inhibit the inflammatory response in lung of rats with ALI/ARDS and exrt protective effect via negatively regulate the expression and nuclear translocation of NF-κB. PGC-1α is an important coactivator for PPARγ, it was investigated that combination with coactivators is essential for the activation of PPARγ. Besides, many studies have reported that PGC-1α could elvate expression of PPARγ in many oxidative stress and metabolic disease. However, in acute lung injury, the expression of PGC-1α and the regulatory function of this coactivator on PPARγ remain to be elucidated.In this study, we firstly expored the expression change of PGC-1α during ALI/ARDS. To invistigate the the regulatory function of PGC-1α on PPARγ, we constructed a adenoviral vector which can sepecificly overexpress PGC-1α m RN A(Ad.v-PGC-1α). The expression of PGC-1α in macrophages and lung of mices with ALI/ARDS was up-regulated by using of this adenoviral vector. Then, the expression of PPARγ and proinflammatory cytokines were detected.Methods:1. Rats with sepsis ALI was induced by C LP(Cecum ligation and puncture). Eexpression of PGC-1α in lung tissues was detected by western-blot and RT-q PC R.2. Expression of PGC-1α in LPS stimulated macrophages was determined by western-blot. Based on this study, we up-regulated expression of PGC-1α in RAW264.7 macrophages by tansfected with an adenoviral vector which can express PGC-1α m RNA. Then, PPARγ expression was detected by western-blot and m RNA of proinflammatory genes IL-1β, IL-6, TNF-α was determined by RT-q PC R.3.To invistigate the effect of PGC-1α on the pathophysiology of ALI in vivo, expression of PGC-1α in lung of ALI mice was up-regulated via inhalation of Ad.v-PGC-1α. Then, PPARγ expression and IL-1β,TNF-α,IL-6 m RNA were detected by western-blot and RT-q PC R.Results:1.The expression of PGC-1α in lung tissues of the C LP group was higher than the control and sham group(P<0.05).2.Compared with the Ad.v group, the expressions of PGC-1α and PPARγ in the cell of the Ad.v+LPS group were remarkably decreased(P<0.05), and the expression of PPARγ of the Ad.v-PGC-1α group was remarkably increased(P<0.05). The m RNA expressions of IL-1β, IL-6, TNF-α of the Ad.v-PGC-1α+LPS group were lower than the Ad.v+LPS group(P<0.05), and the m RNA expressions of IL-1β, IL-6, TNF-α of the Ad.v-PGC-1α+LPS+GW9662 group were higher than the Ad.v-PGC-1α+LPS group(P<0.05).3.Compared with the Ad.v group, the expressions of PGC-1α and PPARγ in lung tissues of the Ad.v+LPS group mice were remarkably decreased(P<0.05), and the expression of PPARγ of the Ad.v-PGC-1α group was remarkably increased(P<0.05). The m RN A expressions of IL-1β, IL-6, TNF-α of the Ad.v-PGC-1α+LPS group were lower than the Ad.v+LPS group(P<0.05),, and the m RN A expressions of IL-1β, IL-6, TNF-α of the Ad.v-PGC-1α+LPS+GW9662 group were higher than the Ad.v-PGC-1α+LPS group(P<0.05). Compared with the the Ad.v group, the lung tissues of the Ad.v+LPS group mice were damaged histopathologically, and the lung injury degree of the Ad.v-PGC-1α+LPS group was alleviativer than the Ad.v+LPS group; and the lung injury degree of the Ad.v-PGC-1α+LPS+GW9662 group was aggravated again.Conclusions:1.The expression of PGC-1α in lung tissues of the septic lung injury rats was significantly decreased, suggesting that PGC-1α may participate in the development of ALI.2.The increased expression of PGC-1α in macrophages could increase the expression of PPARγ and inhibit the expression of inflammatory cytokines induced by LPS, and the effect could be attenuated by PPARγ antagonist. It shows that PGC-1α plays a role in anti- inflammatory through PPARγ pathway in vitro.3.Upregulation the expression of PGC-1α in mice lung tissue could increase the expression of PPARγ and inhibit the expression of inflammatory cytokines induced by LPS, and the lung injury degree was alleviated, and the effect could be attenuated by PPARγ antagonist. It shows that PGC-1α plays an anti- inflammatory effect through PPARγ pathway in vivo and has a protective effect for ALI.