Inhibition of pyroptosis by belnacasan: A potential strategy for mitigating acute lung injury and multiple organ dysfunction

Introduction: Acute lung injury (ALI) caused by infections and trauma poses a significant public health concern. The activation of caspase-1 triggers the expression of interleukin-1 beta (IL-1(3), leading to pyroptosis. Targeting pyroptosis may offer therapeutic benefits in ALI. This study evaluates the therapeutic potential of belnacasan (Bel), a caspase-1 inhibitor, in reducing pyroptosis and mitigating multi-organ failure in a murine ALI model induced by lipopolysaccharide (LPS). Methods: Thirty BALB/c mice were divided into five groups (n = 6): control, LPS, LPS+Bel, Bel, and DMSO. The LPS group received 5 mg/kg LPS, while the LPS+Bel group was treated with 50 mg/kg belnacasan one hour post-LPS. Histopathological, immunohistochemical, and ultrastructural analyses were conducted on lung tissues. Organ damage was assessed through histopathological evaluation and biochemical markers, including ALT/AST for livers and BUN/creatinine for kidneys. Inflammation was evaluated through C-reactive protein (CRP) levels. IL-1(3 levels in bronchoalveolar lavage fluid (BALF) were measured using ELISA, and alveolar macrophages were analysed via confocal microscopy. Results: The findings suggest that belnacasan treatment may reduce multiple organ dysfunction by inhibiting pyroptosis and preserving tissue morphology. The CRP, ALT, AST, BUN, and creatinine levels corroborate the histopathological results. Immunofluorescence and ELISA findings indicate that belnacasan treatment can inhibit IL-1(3 and reduce both pyroptotic and non-pyroptotic alveolar macrophages in BALF. Transmission electron microscopy (TEM) analyses revealed that belnacasan preserved the integrity of the blood-air barrier. Conclusions: Belnacasan inhibits pyroptosis, reduces inflammation, and preserves organ morphology in ALI. These findings underscore its potential as a therapeutic agent for preventing multiple organ dysfunction in ALI.