cyclin-d1 and Respiratory-Distress-Syndrome

1. Pravastatin is best known for its antilipidemic action. Recent studies have shown that statins have immunomodulatory and anti-inflammatory effects. The present study aimed to determine whether or not pravastatin can attenuate acute lung injury and fibrosis in a mouse model. 2. Bleomycin was given to C57BL6 mice through intratracheal instillation. Pravastatin was given through intraperitoneal injection. To study the effect of pravastatin on the early inflammatory phase and the late fibrotic phase, mice were killed on days 3, 7, 14 and 21. 3. Pravastatin attenuated the histopathological change of bleomycin-induced lung injury and fibrosis. The accumulation of neutrophils and increased production of tumor necrosis factor-α in bronchoalveolar lavage fluid were inhibited in the early inflammatory phase. Pravastatin effectively inhibited the increase of lung hydroxyproline content induced by bleomycin. Furthermore, pravastatin reduced the increased expression of transforming growth factor (TGF)-β1, connective tissue growth factor (CTGF), RhoA and cyclin D1. The increased levels of TGF-β1 and CTGF mRNA expression were also significantly inhibited by pravastatin. 4. Pravastatin effectively attenuated bleomycin-induced lung injury and pulmonary fibrosis in mice. Our results provide evidence for the therapeutic potential of pravastatin in the treatment of acute lung injury and pulmonary fibrosis.

Topics: Acute Lung Injury; Animals; Anti-Inflammatory Agents; Bleomycin; Blotting, Western; Bronchoalveolar Lavage Fluid; Connective Tissue Growth Factor; Cyclin D1; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Female; Gene Expression; Hydroxyproline; Mice; Mice, Inbred C57BL; Pravastatin; Pulmonary Fibrosis; Respiratory Distress Syndrome; Reverse Transcriptase Polymerase Chain Reaction; rho GTP-Binding Proteins; rhoA GTP-Binding Protein; Transforming Growth Factor beta1

Resolution of alveolar epithelial/capillary membrane damage after acute lung injury requires coordinated and effective tissue repair to reestablish a functional alveolar epithelial/capillary membrane barrier. We hypothesized that signaling pathways important in lung alveolar bud ontogeny are activated in the recovery and remodeling phases after profound oxidant stress lung injury in a murine model. To test this, we characterized the expression of noncanonical beta-catenin pathway proteins E-cadherin, integrin-linked kinase-1, and beta-catenin in mice undergoing normoxic recovery after exposure to butylated hydroxytoluene (BHT, ionol) and concomitant sublethal (75% O2) hyperoxia. Mice developed early acute lung injury with subsequent inflammation, collagen deposition, interstitial cellular proliferation, and lung architectural distortion. Reduced E-cadherin expression after 6 d of BHT and hyperoxia was accompanied by enhanced expression and nuclear localization of beta-catenin and increased integrin-linked kinase-1 expression during subsequent normoxic recovery. This resulted in increased expression of the cotranscriptional regulators TCF-1 and -3 and cyclin D1. Proliferation of murine lung epithelial-12 cells in vitro after 8 h of treatment with BHT quinone-methide and hyperoxia and 48 h of normoxic recovery was enhanced 2.7-fold compared with vehicle-treated control mice at the same time point. BHT/hyperoxia-exposed mice treated with the pan-caspase inhibitor z-ASP had increased acute lung injury and reduced survival despite the presence of TUNEL-positive cells, suggesting enhanced lung cell necrosis. Beta-catenin expression was reduced in z-ASP-co-treated lungs after BHT/hyperoxia. The noncanonical cadherin-beta-catenin axis is associated with fibroproliferative repair after BHT/hyperoxia exposure and may regulate epithelial proliferation and lung matrix remodeling and repair in response to lung injury.

Topics: Animals; Apoptosis; Asparagine; beta Catenin; Butylated Hydroxytoluene; Cadherins; Caspase Inhibitors; Caspases; Cell Line, Transformed; Cell Proliferation; Collagen; Cyclin D1; Epithelial Cells; Lung; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Necrosis; Oxidative Stress; Oxygen; Protein Serine-Threonine Kinases; Pulmonary Fibrosis; Respiratory Distress Syndrome