Protective Effect of a Isothiazolinone Derivative on Acute Lung Injury by Regulating PI3K‐AKT Signaling Pathway

Abstract Acute lung injury (ALI) is a prevalent organ injury in sepsis, characterized by an inflammatory reactive disorder. Both the incidence and mortality rates of ALI have been steadily increasing. Isothiazolinone derivatives have displayed anti‐inflammatory activity and have shown effectiveness in treating pneumonia. The objective of the study is to assess the effects and mechanisms of the isothiazolinone derivative 4‐benzoyl‐2‐butyl‐5‐(ethylsulfinyl)isothiazol‐3( 2H )‐one (C6) on sepsis‐induced ALI.The analysis of biological function and signal pathway enrichment demonstrated that C6 primarily exhibited anti‐inflammatory effects. Administration of different doses of C6 through intraperitoneal injection significantly improved the survival rate, body temperature, and body mass of mice with ALI induced by cecal ligation and puncture (CLP). Additionally, it mitigated lung tissue injury, pulmonary edema, lung permeability, inflammatory cell infiltration, apoptosis, and the expression of inflammatory cytokines. Network targeting analysis and experimental validation in mouse leukemia cells of monocyte macrophage (RAW264.7) cells and CLP‐induced ALI mice revealed that the anti‐inflammatory effect of C6 was mediated by the inhibition of the phosphatidylinositol 3 kinase ‐protein kinase B (PI3K‐AKT) signaling pathway. The research suggest that C6 has protective effects against ALI by inhibiting the PI3K‐AKT signaling pathway. This information could be valuable in developing potential treatments for ALI.