Diacerein attenuate LPS-induced acute lung injury via inhibiting ER stress and apoptosis: Impact on the crosstalk between SphK1/S1P, TLR4/NFκB/STAT3, and NLRP3/IL-1β signaling pathways

• Published in: Life sciences (1973) Vol. 308; p. 120915
• Main Authors: Youssef, Nagwa Salah, Elzaitony, Asmaa Samir, Abdel Baky, Nayira A.
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 01.11.2022
• Subjects: Acute lung injury; Diacerein; ER stress; GSK-3β; NF-κB; NLRP3; S1P; TLR-4; Acute lung injury; NF-κB; GSK-3β; TLR-4; S1P; ER stress; NLRP3; Diacerein
• ISSN: 0024-3205; 1879-0631
• DOI: 10.1016/j.lfs.2022.120915

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. Schematic diagram for protective molecular mechanisms of diacerein against lipopolysaccharide-induced acute lung injury. GSK-3β; glycogen synthase kinase-3 beta; IL-6: interleukin 6; IL-1β: interlukin-1β; LPS: lipopolysaccharide; NLRP3: NOD-like receptor pyrin domain-containing protein 3; NF-κB: nuclear factor-kappa B; ROS: reactive oxygen species; SOD: superoxide dismutase; SphK1, sphingosine kinase 1; S1P, sphingosine-1-phosphate; STAT3:signal transducer and activator of transcription 3;TLR4; toll-like receptor-4; TNF-α: tumor necrosis factor –α. [Display omitted]