| ObjectiveAcute lung injury (ALI) is a critical clinical syndrome with high mortality. The pathological feature are mainly alveolar-capillary endothelial cell injury and Alveolar epithelial cells injury. The previous studies had indicated that ALI is a kind of inflammation, in which many inflammatory mediators and cytokines play a key role in the pathological process. Although many clinical efforts about the therapy for ALI were carried out, the mortality has not been markedly decreased. It is now well known that liver X receptors (LXRs) has the anti-inflammatory effects and is involved in lipopolysaccharide-induced inflammation in liver, kidney and adipose tissue. However, a few studies on the protective effects of LXR-αon acute lung injury in rat lung were done. Another study shows that the nuclear receptor superfamily peroxisome proliferator-activated receptors (PPARs) include three kinds of subtypes: PPAR-α, PPAR-β, and PPAR-γ. PPAR-γis associated with the regulation of pulmonary inflammation.The study of the dynamics characteristics between LXR / PPAR shows that LXRs combine with the three kinds of subtypes in different binding affinity.The ligands combining with the LXR also regulate the interaction and activity between LXR and PPAR. So we suppose that LXRs and PPARs possibly have protective effects on lung tissue in ALI. However, the anti-inflammatory mechanism of LXR agonists on ALI has not been completely elucidated. In this study, we detected the expressions of LXR-αand PPAR-γafter LPS challenge in the lung tissue of rats, and observed the effects of LXR-αagonist T0901317 on the expression of LXR-αand PPAR-γin rats lung during development of ALI. The study provided a theoretical basis and experimental evidence for clinical application of LXR-αagonist in the treatment of ALI .MethodsA rat model of ALI was established by intravenous injection of LPS at a dose of 5mg/kg. 72 male Wistar rats were randomly divided into three goups: control group (C group), LPS group (L group), T0901317 group (LT group). Each group were divided into four subgroups: 1h, 2h, 4h, 8h .Method: C group was injected with normal saline; L group was injected with LPS ; LT group was injected with T0901317 30 minutes after intravenous injection with LPS. The rats were killed at 1h, 2h, 4h, 8h after treatment. The lung tissue was collected and the wet/dry weight ratio and lung histopathological change were observed. Expression of LXR-α,PPAR-γand TNF-αmRNA were detected. The immunohischemistry (IHC) was used to detect the protein expression of LXR-αand PPAR-γin the lung tissues of rats in all groups. ELISA was used to measure the concentration of TNF-αin the supernatants of lung and arterial serum, respectively.Results1. In the Control group, LXR-αand PPAR-γwere expressed in the alveolar epithelial cells,macrophages and vascular endothelial cells of lung. The expression of LXR-αand PPAR-γdeclined significantly in the lung tissues of injury rats induced by LPS than those in Control group both at the mRNA and the protein level (P < 0.05).2. The expression of LXR-αand PPAR-γin rat lung tissues in LT group were significantly higher than those in L group both at the mRNA and the protein level (P < 0.05), especially, at 2h and 4h.3. T0901317 inhibited remarkably the expression of TNF-αof ALI rat lung at the mRNA level and reduced the protein level of TNF-αin arterial serum than L group (P <0.05).4. T0901317 increased PaO2, decreased W/D ratio and pathomorphological score of lung tissue, inhibited the activity of MPO, attenuated pathological damage of the lung tissue and the infiltration and aggregation of inflammatory cells (mainly neutrophils) in lung tissue.Conclusion1. The expression of LXR-αmRNA and protein of lung tissues in control group is significantly higher than that in the rats with ALI, which suggest that LXR-αmight be involved in the inflammation induced by LPS and the decreased expressions of LXR-αmRNA and protein might be related with the inflammation out of control.2. Compared with the lipopolysaccharide group, the activation of LXR-αby T0901317 markedly improved respiratory distress symptom, increased PaO2, reduced lung tissue pathological scores, the activation of myeloperoxidase and W / D ratio , these data indicated that T0901317 have protective effect on the lung tissues of the rats with ALI .3. T0901317 has played an anti-inflammatory effect through up-regulating the expression of LXR-αand PPAR-γin rats lung tissues with ALI both at the mRNA and the protein level. suppressing the expression of TNF-α,and reducing the infiltration and aggregation of inflammatory cells (mainly neutrophils) in lung tissue.
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