Influence of Liriodendrin on NLRP3-Mediated Pyroptosis and Proinflammatory Pathways in Mice Experiencing Acute Respiratory Distress Syndrome Induced by Lipopolysaccharide

Background: Acute respiratory distress syndrome (ARDS) is the major therapeutic dilemma associated with significant inflammation and severe pulmonary dysfunction. Liriodendrin is a bioactive compound extract from traditional Chinese medicine, historically utilized for modulating inflammatory responses and alleviating symptoms in multiple disease models. Methods: At present, BALB/c mice to explore the effects of liriodendrin on lipopolysaccharide (LPS)-induced ARDS. Before LPS was administered, the mice were treated with either liriodendrin or dexamethasone. Leukocyte infiltration, lung edema, and alveolar-capillary barrier integrity were evaluated in the bronchoalveolar lavage fluid (BALF) and pulmonary parenchyma. The expression of adhesion molecules and proinflammatory cytokines in BALF was evaluated by enzyme-linked immunosorbent assay. Western blotting assay facilitated the analysis of the expression or phosphorylation of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), NOD-like receptor family pyrin domain-containing 3 (NLRP3), apoptosis-associated speck-like protein containing a CARD (ASC), cleaved caspase-1 (CL-csapase-1), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), inhibitor of kappa B (IκB), mitogen-activated protein kinase (MAPK), and protein kinase B (Akt) in the lungs. In addition, the anti-inflammatory effects of liriodendrin were evaluated in LPS-stimulated RAW264.7 macrophages. Before LPS was administered, the RAW264.7 macrophages were treated with either liriodendrin or dexamethasone. Nitric Oxide (NO) production was measured using the Griess reaction assay, while ELISA assessed IL-1β, IL-6, and TNF-α levels. Western blot analysis evaluated NF-κB phosphorylation and the expression of NLRP3, ASC, and CL-caspase-1. Results: These outcomes revealed that liriodendrin intervention markedly ameliorated the pathological features of LPS-induced ARDS, including leukocyte infiltration, lung edema, and alveolar-capillary barrier disruption. Liriodendrin also reduced the LPS-induced secretion of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1), expression of iNOS and COX2, and production of proinflammatory cytokines. Finally, we further discovered that the concentration trend of liriodendron amelioration of ARDS was similar to those of NLRP3 formation, NF-κB pathway activation, and p38 MAPK, c-Jun N-terminal kinase (JNK), and Akt phosphorylation but not to that of extracellular signal-regulated kinase (ERK) phosphorylation. Liriodendrin inhibited LPS-induced inflammatory responses in RAW264.7 macrophages. It markedly reduced NO production, propro-inflammatorytokines, NF-κB phosphorylation, and NLRP3 formation. Conclusions: In summary, liriodendrin effectively ameliorated the pathological features of LPS-induced ARDS in mice, demonstrating significant anti-inflammatory properties attributed to NLRP3 formation through NF-κB pathway activation by p38 MAPK, JNK, and Akt phosphorylation. In LPS-treated RAW264.7 macrophages, liriodendrin reduced NO production, pro-inflammatory cytokines, and NLRP3 formation, suggesting its potential as an agent for ARDS and relative inflammation.