[Mechanisms of Qibai Pingfei Capsules in inhibiting pyroptosis of pulmonaryartery adventitial fibroblasts via regulating NLRP3/Caspase-1/ GSDMD pathway to intervene in COPD complicated by pulmonary arterial hypertension].

This study investigated the mechanisms by which Qibai Pingfei Capsules(QBPF) intervene in chronic obstructive pulmonary disease(COPD) complicated by pulmonary hypertension(PH) through regulating the nucleotide-binding oligomerization domain-like receptor protein 3(NLRP3)/Caspase-1/gasdermin D(GSDMD) pathway to inhibit pyroptosis of pulmonary artery adventitial fibroblasts(PAAFs). A COPD-PH rat model was established using a combined protocol of forced swimming, passive smoking, and hypoxic exposure. Rats were divided into five groups(n=15 each), i.e., control, model, QBPF, QBPF + nigericin(NLRP3 activator), and simvastatin groups. After 4 weeks of continuous intervention, lung function was assessed. Mean pulmonary arterial pressure(mPAP) was measured by right heart catheterization. Hearts were weighed to calculate right ventricular hypertrophy index(RVHI). Serum inflammatory cytokines IL-8, IL-18, and tumor necrosis factor-α(TNF-α) were measured by ELISA. Lung histopathological changes were observed by hematoxylin-eosin(HE) staining. Western blot and immunohistochemistry were used to detect protein expression and localization of NLRP3, apoptosis-associated speck-like protein(ASC), Caspase-1, GSDMD, IL-1β, and IL-18 in lung tissues. Immunofluorescence examined co-localization of Vimentin(a PAAFs marker) and GSDMD. Ultrastructural changes of PAAFs were observed by transmission electron microscopy(TEM). RESULTS:: showed that QBPF treatment delayed the decline of FEV0.3, FVC, and FEV0.3/FVC in COPD-PH rats, reduced mPAP, RVHI, and serum levels of IL-8, IL-18, and TNF-α, improved emphysema, pulmonary arterial wall thickening, and inflammatory cell infiltration, decreased expression of NLRP3, ASC, Caspase-1, GSDMD, IL-1β, and IL-18 proteins in lung tissue and pulmonary artery adventitia, and inhibited pyroptosis of PAAFs. The NLRP3 activator nigericin antagonized the inhibitory effects of QBPF on pyroptosis-related protein expression and PAAF pyroptosis. In conclusion, QBPF attenuates lung function decline, suppresses inflammatory responses, alleviates pulmonary vascular remodeling, and intervenes in the disease progression of COPD complicated by PH in rats. Its mechanisms may be related to modulating the NLRP3/Caspase-1/GSDMD pathway to inhibit PAAF pyroptosis.