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Published on: May 21, 2018
Tianlong kechuanling ameliorated COPD-PH through DNMT3A-GSDMD axis-dependent regulation of endothelial cell
Huihua Li1, Zhenqiu Li1, Jing Gong1
1Traditional Chinese Medicine, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, 510120, China.
Ethnopharmacological Relevance:
COPD-PH is a common and severe complication of COPD, posing significant challenges to patient survival and quality of life due to its poor prognosis. However, current treatment options remain clinically unsatisfactory. Tianlong kechuanling (TL), a traditional Chinese medicine compound hospital preparation, has been clinically employed for treating cor pulmonale, although its underlying mechanisms remain elusive.
Purpose:
This study aimed to investigate the therapeutic effects of TL on COPD-PH and elucidate its molecular mechanisms.
Materials And Methods:
A murine COPD-PH model was established through cigarette smoke exposure, intratracheal lipopolysaccharide instillation, and chronic hypoxia. The therapeutic effects of TL were evaluated by measuring pulmonary function parameters, lung index, right ventricular systolic pressure (RVSP), right ventricular hypertrophy index (RVHI), total cell count in bronchoalveolar lavage fluid (BALF), levels of TNF-α, IL-1β, IL-6, and IL-18, along with histopathological analyses. Immunohistochemistry was performed to examine DNMT3A, GSDMD, Caspase1and NLRP3 expression for mechanistic studies. A pyroptosis model was established using TNF-α-stimulated human pulmonary arterial endothelial cells (HPAECs), with Scanning electron microscopy, qPCR, immunofluorescence, and Western blot analyses conducted to assess TL's effects. To further elucidate the therapeutic mechanism of TL, pharmacological inhibition of DNMT3A was systematically employed.
Results:
TL administration significantly improved pulmonary function, reduced RVSP and RVHI in COPD-PH mice, attenuated pulmonary inflammation, reduced DNMT3A expression and ameliorated pyroptosis. In HPAECs, TL suppressed the expression of mitigated cellular pyroptosis, revealing a regulatory correlation between DNMT3A and GSDMD.
Conclusion:
TL attenuated COPD-PH progression via inhibiting endothelial pyroptosis by targeting the DNMT3A-GSDMD signaling pathway, offering potential therapeutic avenues for COPD-PH management.
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