Background: Chronic Obstructive Pulmonary Disease (COPD) is characterized by airflow limitation and inflammation resulting from genetic and environmental factors, notably cigarette smoke. Pyroptosis, a cell death process, is implicated in COPD, but its mechanisms are unclear. SHP2, a phosphatase, modulates inflammatory pathways, suggesting a role in COPD pathogenesis and potential therapeutic avenues.
Objective: This study investigates the mechanism by which SHP2 regulates cell pyroptosis in bronchial epithelial cells in COPD patients.
Methods: In this prospective study, we employed in vivo and in vitro models to investigate the mechanisms underlying COPD progression. Hematoxylin and eosin (H&E) staining were utilized to assess the morphological changes characteristic of COPD. Electron microscopy enabled precise quantification of pyroptotic bodies to highlight cellular changes associated with COPD pathogenesis. Immunofluorescence analysis facilitated the measurement of protein fluorescence intensity, allowing for the assessment of inflammatory responses within bronchial epithelial cells. Additionally, Western blot analysis was conducted to evaluate the expression levels of key pathway proteins involved in COPD progression.
Results: In the COPD model, lesions worsened in SHP2-KD mice compared to SHP2-NC. Western blot results showed increased p22, p47, p-IRE1α, XBP1, STING, p-TBK1, NLRP3, Caspase1, and IL-1β expression levels in both in vivo and in vitro models. Transmission electron microscopy revealed more pyroptotic bodies in SHP2-KD+CSE than in SHP2-NC+CSE. Immunofluorescence demonstrated significantly higher NLRP3 and GSDMD fluorescence intensities in SHP2-KD+CSE versus SHP2-NC+CSE. Additionally, Western blot analysis indicated increased expression of Bax, Caspase3, Caspase8, and Caspase9 proteins in the in vitro model. No differences were observed between SHP2 NC and SHP2-KD groups without CSE stimulation in immunofluorescence, electron microscopy, and Western blot findings in the cellular model.
Conclusions: SHP2 promotes COPD progression by inducing oxidative stress, endoplasmic reticulum stress, and pyroptosis.