| Endotoxic shock is one of the major causes of death induced by acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) which are devastating syndromes that account for high morbidity and mortality among critically ill patients [1]It is well known that HO-1for the induction of type, is a stress protein, also known as heat shock protein32(HSP32), which can be found in most cells and tissues. It is well known that HO-1is the rate-limiting enzymes in the oxidative catabolism of heme to carbon monoxide (CO), bilirubin and iron. All of the end-product formation has been shown to be association with the protective effect in modulating physiologic functions. Therefore, the HO-1system is regarded as an endogenic defense mechanism of organism and plays an important role in maintaining cellular homeostasis and regulating the imflammatory response. HO-1is induced not only by the substrate heme but also by a variety of nonheme substance such as endotoxin, shock, stress, and hyperxia. The protective effect of Alpha-Lipoic Acid in lipopolysaccharide-induced acute lung injury is mediated by heme oxygenase-1. We have also demonstrated previously that The upregulation of HO-1protein may resistance to increased oxidative stress and contribute to the protection of lung during endotoxic shock in rats.AP-1is a major transcription factor that can activate HO-1by binding to the promoter region of the gene.The treatment of RAW264.7cells with LPS has been shown that the AP-1family of transcription factors plays a critical role in regulating HO-1gene activation. However, there are few studies investigating whether the up-regulation of HO-1protein can protect the lung during endotoxic shock in rats by AP-1. The effect of AP-1on LPS-induced HO-1expression in the lung of endotoxic shock rats has not yet been elucidated. Therefore, the goal of the present study was designed to investigate if AP-1via up-regulation of heme oxygenase-1confers protection of lung against endotoxic shock in rats. To better understand HO-1expression mechanisms in lung tissue of endotoxic shock rats, the potential role of HO-1for therapeutic applications in inflammatory conditions of lung during endotoxic shock in rats.Objective To evaluate the role of activator protein-1(AP-1) in the up-regulation of heme oxygenase-1(HO-1) expression during during endotoxic shock-induced acute lung injury (ALI) in rats.Methods Forty-eight healthy and clean male Sprague-Dawley rats, weighing200-220g,2.5-3.0months, were randomly divided into four groups by the random number table method (n=12each):normal control group (group C), endotoxic shock-induced acute lung injury group (group ES), curcumin plus endotoxic shock-induced acute lung injury group (group Cur+ES), curcumin group(group Cur). In groups C and ES, normal saline0.5ml and LPS10mg/kg (0.5ml) were injected respectively30min after0.1%dimethyl sulfoxide (the vehicle for curcumin)0.5ml was injected intraperitoneally. In groups Cur+ES and Cur, curcumin20mg/kg (0.5ml) was injected intraperitoneally, and30min later LPS10mg/kg and normal saline0.5ml were injected respectively. To monitor the general condition, mean arterial pressure(MAP) and heart rate of the rats for6hours were recorded. MAP was monitored continuously, the MAP decrease at least an initial25%within2h after iv injection of LPS the endotoxic shock model can be successfully established, if the MAP did not decrease within2h or die within6h, the animal was excluded from the study. Arterial blood gas analysis was performed and the rats were then sacrificed and the lung were removed at6h after iv injection of LPS. The lungs were removed for microscopic examination, the lung water ratio, oxygenation index, malondialdehyde (MDA) content, superoxide dismutase (SOD) activity the expression of HO-1and AP-1protein (by western blot analysis), and HO-1mRNA (by RT-PCR) were measured.Results Compared with group C, the pathological score, the lung water ratio, oxygenation index and MDA content were significantly increased, SOD activity was significantly decreased, and the expression of HO-1, AP-1and HO-1mRNA was up-regulated in groups ES and Cur+ES (P<0.05), and no significant change was found in the parameters mentioned above in group Cur (P>0.05). Compared with group ES, the pathological score, the lung water ratio and MDA content were significantly increased, SOD activity was significantly decreased, and the expression of HO-1, AP-1and HO-1mRNA was down-regulated in group Cur+ES (P<0.05). Compared with group Cur+ES, the pathological score, the lung water ratio and MDA content were significantly decreased, oxygenation index and SOD activity was significantly increased, and the expression of AP-1, HO-1and HO-1mRNA was down-regulated in group Cur (P<0.05).Conclusion Transcription factor AP-1is involved in the up-regulation of HO-1expression during endotoxic shock-induced acute lung injury (ALI) in rats. |
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