Echinacea Polyphenols Inhibit NLRP3-Dependent Pyroptosis, Apoptosis, and Necroptosis via Suppressing NO Production during Lipopolysaccharide-Induced Acute Lung Injury

PANoptosis is an intricate programmed death pathway that involves the interaction between pyroptosis, apoptosis, and necroptosis. We systematically explored the protective effect of Echinacea polyphenols (EPP) against the lipopolysaccharide (LPS)-induced acute lung injury (ALI) and the underlying mechanisms both in vitro and in vivo. We noted that EPP pretreatment could significantly alleviate LPS-induced lung tissue injury and pulmonary edema. EPP inhibited the PANoptosis by regulating the expression of nucleotide-binding oligomerization domain-like receptor protein 3 inflammasome, gasdermin D, caspase-8, caspase-3, and mixed lineage kinase domain-like protein. Meanwhile, a comparative study of EPP and inducible nitric oxide synthase inhibitor S-methylisothiourea sulfate indicated that EPP may play a preprotective role in inhibiting PANoptosis via reducing the activity of inducible nitric oxide synthase and the production of nitric oxide (NO) during ALI. Our results clearly indicated that PANoptosis existed in LPS-induced ALI, and EPP pretreatment could provide obvious protective effects to LPS-induced ALI by inhibiting PANoptosis, which may be related to NO production.