Suppression of NOD-like receptor protein 3 inflammasome activation and macrophage M1 polarization by hederagenin contributes to attenuation of sepsis-induced acute lung injury in rats

Abstract

Acute lung injury (ALI) is a major leading cause of death in sepsis patients. Hederagenin (HG), derived from Hedera helix Linné , has anti-inflammatory effects, while its role in sepsis-induced ALI has not been elucidated. In vivo , rats were subjected to cecal ligation and puncture to induce ALI and then treated with HG (12.5, 25, or 50 mg/kg) by gavage. Administration of HG raised survival rate, ameliorated lung injury, and decreased lung wet/dry ratio and inflammatory cell accumulation in bronchoalveloar lavage fluid (BALF) of ALI rats. HG inhibited macrophage polarization toward the M1 phenotype as evidenced by decreased CD86 expression in rat lung tissues. Moreover, HG decreased the secretion of TNF-α, IL-6 and monocyte chemoattractant protein-1 (MCP-1) in BALF and the levels of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) in lung tissues. In vitro , phorbol-12-myristate-13-acetate (PMA)-differentiated THP-1 macrophages were stimulated with 100 ng/mL lipopolysaccharide. HG treatment inhibited M1 macrophage polarization and the production of M1-related pro-inflammatory mediators (IL-6, MCP-1, iNOS, and COX-2). Mechanistically, HG inhibited NLRP3 inflammasome activation and subsequent release of IL-18 and IL-1β, and suppressed NF-κB signaling pathway both in vivo and in vitro . Notably, HG treatment further emphasized the inhibitory effect of NF-κB inhibitor BAY11-7082 on NLRP3 inflammasome activation and macrophage M1 polarization. Taken together, HG exerts a protective effect against sepsis-induced ALI by reducing the inflammatory response and macrophage M1 polarization, which may involve NF-κB pathway-modulated NLRP3 inflammasome activation.

Hederagenin inhibits high glucose‐induced fibrosis in human renal cells by suppression of NLRP3 inflammasome activation through reducing cathepsin B expression

“…Previous reports have identified the anti‐inflammatory activity of hederagenin (Kim et al, 2017; Lee et al, 2015), while the relationship between hederagenin and NLRP3 inflammasome is largely unknown in diabetic nephropathy. In this study, we found that hederagenin mitigated NLRP3 inflammasome activation in HRMCs and HRPTEpiCs under HG conditions, which was also consistent to that in sepsis‐induced acute lung injury (Wang & Zhao, 2022).…”

Heparin-Binding Protein Aggravates Acute Lung Injury in Septic Rats by Promoting Macrophage M1 Polarization and NF-κB Signaling Pathway Activation

“…However, the molecular mechanism of sepsis complicated by ALI remains unclear. Wang et al showed that hederagenin inhibition by inhibiting the NF- κ B pathway and NLRP3 inflammasome activation reduces inflammatory response and macrophage M1 polarization, thereby playing a protective role against sepsis-induced ALI [ 6 ]. Jiao et al found that exosomal miR-30d-5p from polymorphonuclear neutrophils contributed to sepsis-related ALI by inducing M1 macrophage polarization and priming macrophage pyroptosis through activating NF- κ B signaling [ 7 ].…”

Exploring the mechanism of Tingli Pill in the treatment of HFpEF based on network pharmacology and molecular docking

“…[13,14] Hederagenin is a kind of pentacyclic triterpenoid compound with natural biological activity, which can be extracted and separated from a variety of medicinal plants. It has many pharmacological effects, such as anti-oxidation, enhancing immunity, promoting apoptosis and anti-fibrosis, [15,16] while it can also protect blood vessels from atherosclerosis by improving lipid metabolism and inhibiting lipid deposition. [17] In addition, hederagenin can also inhibit the expression of nitric oxide synthase, cyclooxygenase-2, and nuclear factor κB (NF-κB) induced by lipopolysaccharide stimulation, thus alleviating the inflammatory reaction.…”