sphingosine-kinase and diacerein

Acute lung injury (ALI) is a life-threatening clinical problem with high mortality rate and limited treatments or preventive options that represents a major challenge for clinicians. Diacerein (DIA) is a multi-target anthraquinone derivative with potent anti-inflammatory action. The aim of this study is to assess the protective effect of DIA and its potential molecular targets against lipopolysaccharide (LPS)-induced ALI in rats.. Adult male Sprague-Dawley rats were orally administrated DIA (50 mg/kg) for 5 consecutive days followed by a single intraperitoneal injection of LPS (5mg/kg).. DIA mitigated oxidative lung injury in LPS-challenged rats via significantly decreasing lung wet/dry (W/D) ratio, inflammatory cells infiltration, and lipid peroxidation, with concomitant elevation in enzymatic and non-enzymatic antioxidant levels in lung tissue. Likewise, DIA alleviated endoplasmic reticulum stress and markedly halted inflammation triggered by LPS challenge in pulmonary tissue by suppressing NLRP3/IL-1β and TLR4/NF-κB signaling with parallel decrease in proinflammatory cytokine levels. Interestingly, DIA down regulated Sphk1/S1P axis, reduced GSK-3β and STAT3 proteins expression, and markedly decreased caspase-3 besides increasing Bcl-2 levels in lung tissue of LPS-challenged animals. These biochemical findings was simultaneously associated with marked improvement in histological alterations of lung tissue.. These findings verify the protective effect of DIA against LPS-induced ALI through targeting oxidative stress, endoplasmic reticulum stress, and apoptosis. Importantly, DIA halted the hyperinflammatory state triggered by LPS via multi-faceted inhibitory effect on different signaling pathways, hence DIA could potentially reduce mortality in patients with ALI.

Topics: Acute Lung Injury; Animals; Anthraquinones; Anti-Inflammatory Agents; Antioxidants; Apoptosis; Caspase 3; Cytokines; Endoplasmic Reticulum Stress; Glycogen Synthase Kinase 3 beta; Lipopolysaccharides; Male; NF-kappa B; NLR Family, Pyrin Domain-Containing 3 Protein; Phosphotransferases (Alcohol Group Acceptor); Proprotein Convertases; Proto-Oncogene Proteins c-bcl-2; Rats; Rats, Sprague-Dawley; Serine Endopeptidases; Signal Transduction; Toll-Like Receptor 4