t0901317 and Acute-Lung-Injury

Topics: Acute Lung Injury; Animals; Antioxidants; Apoptosis; Disease Models, Animal; Humans; Hydrocarbons, Fluorinated; Inflammation; Interleukin-1beta; Lipid Peroxidation; Liver X Receptors; MAP Kinase Signaling System; Mice; NF-kappa B; p38 Mitogen-Activated Protein Kinases; Paraquat; Reactive Oxygen Species; Sulfonamides; Tumor Necrosis Factor-alpha

To investigate the potential role of synthetic liver X receptors (LXRs) agonists T0901317 in lung of rats with acute lung injury induced by lipopolysaccharide (LPS).. Rats infused with LPS served as acute lung injury (ALI) models. Specific mRNA was quantified by semi-quantitative reverse transcription polymerase (RT-PCR) and protein expression by western blotting. Inflammatory cytokine and MPO activity assays were studied by ELISA. Histopathology analysis was evaluated by hematoxylin and eosin.. The expressions of LXRα and LXRβ were gradually decreased after LPS challenge. T0901317 pretreatment efficiently reduced the production of TNF-α, IL-1β, and IL-6, while elevated the level of IL-10 in BALF of rats with ALI. T0901317 also decreased the number of inflammatory cells and the concentration of total proteins in the BALF. Compared with the LPS group, rats with ALI which were pretreated with T0901317 had lower pulmonary tissue MPO activity and lightened histopathologic changes of lung. Furthermore, the expressions of NF-κB and ICAM-1 were markedly reduced after T0901317 administration.. The expressions of LXRs were significantly decreased and synthetic agonist T0901317 suppresses lung inflammatory responses and lightened histopathologic changes of lung in rats with ALI. The mechanisms of this action for T0901317 may associate with the inhibition of NF-κB activation and downregulation of adhesion molecules ICAM-1 gene.

Topics: Acute Lung Injury; Animals; Bronchoalveolar Lavage Fluid; Cytokines; Hydrocarbons, Fluorinated; Intercellular Adhesion Molecule-1; Lipopolysaccharides; Liver X Receptors; Male; NF-kappa B; Orphan Nuclear Receptors; Peroxidase; Rats; Rats, Sprague-Dawley; Sulfonamides; Treatment Outcome

Liver x receptor alpha (LXRalpha) and beta (LXRbeta) are members of the nuclear receptor super family of ligand-activated transcription factors, a super family which includes the perhaps better known glucocorticoid receptor, estrogen receptor, thyroid receptor, and peroxisome proliferator-activated receptors. There is limited evidence that LXL activation may reduces acute lung inflammation. The aim of this study was to investigate the effects of T0901317, a potent LXR receptor ligand, in a mouse model of carrageenan-induced pleurisy.. Injection of carrageenan into the pleural cavity of mice elicited an acute inflammatory response characterized by: accumulation of fluid containing a large number of neutrophils (PMNs) in the pleural cavity, infiltration of PMNs in lung tissues and subsequent lipid peroxidation, and increased production of nitrite/nitrate (NOx), tumor necrosis factor-alpha, (TNF-alpha) and interleukin-1beta (IL-1beta). Furthermore, carrageenan induced the expression of iNOS, nitrotyrosine and PARP, as well as induced apoptosis (TUNEL staining and Bax and Bcl-2 expression) in the lung tissues.. Administration of T0901317, 30 min after the challenge with carrageenan, caused a significant reduction in a dose dependent manner of all the parameters of inflammation measured.. Thus, based on these findings we propose that LXR ligand such as T0901317, may be useful in the treatment of various inflammatory diseases.

Topics: Acute Lung Injury; Animals; Hydrocarbons, Fluorinated; Liver X Receptors; Male; Mice; Orphan Nuclear Receptors; Pleurisy; Pneumonia; Signal Transduction; Sulfonamides; Treatment Outcome