Acriflavine protects against LPS-induced sepsis via regulation of pyroptosis, inflammation, and endoplasmic reticulum stress

BackgroundLipopolysaccharide (LPS) is a glycolipid that constitutes the Gram-negative bacteria outermost membrane main portion. LPS is frequently of concern in medicine because of nearly all severe sepsis patients have elevated LPS plasma levels, which cause life-threatening organ dysfunction. Consequently, the potential protective benefit of acriflavine (Ac) in limiting LPS-induced acute inflammatory response and the possible underlying mechanisms were investigated.MethodsMale <i>a</i><i>lbino</i> mice were treated with <i>i.p</i>. Ac 4 or 8 mg/kg/day for 2 weeks, then received a single <i>i.p</i>. LPS (10 mg/kg) at day 14.ResultsAc administration ameliorated hepatic, pulmonary, and testicular dysfunction, as confirmed by attenuation of pathological changes and amendment of oxidative stress parameters. This was associated with inhibition of protein kinase R-like endoplasmic reticulum kinase/phosphatidylinositol 3-kinase (PERK/PI3K) endoplasmic reticulum (ER) stress pathway; toll-like receptor 4/nuclear factor kappa B (TLR4/NF-κB) and active caspase-1/gasdermin D (GSDMD)-N-terminal as well as interleukin-1 beta (IL-1β) inflammatory and pyroptotic signals.ConclusionOur results highlighted the protective potential of Ac in a mouse model of LPS-mediated systemic inflammatory response, which paves the way for its clinical application in sepsis.