Comparison of alveolar macrophages senescence between cigarette smoke-exposed and naturally aged mice and the role of P2X7R in CS-induced airway inflammation.

Authors

Ping Huang, Xichen Pang, Zhe Wang, Xiaofeng Li, Tingting Zhang, Sha Huang, Lulu Zhang, Xinrui Qiao, Xiaoli Zeng, Xiaoju Liu

Published in

Toxicology and applied pharmacology. Pages 118088. Oct 20, 2026. Epub Oct 20, 2026.

Abstract

Aging is intricately linked to chronic obstructive pulmonary disease (COPD). Alveolar macrophages (AMs) senescence-induced impaired phagocytosis may contribute to persistent airway inflammation in COPD. The P2X7 receptor (P2X7R) is a crucial modulator of cellular senescence. However, its roles in AMs senescence and phagocytosis remain unclear. In this study, naturally aged mice, cigarette smoke (CS)-exposed mice, and MH-S cells stimulated by cigarette smoke extract (CSE) were used to compare the degree of AMs senescence and phagocytosis between CS-exposed and naturally aged mice, and to confirm the function and mechanism of P2X7R. Results showed that pulmonary function gradually declined, AMs senescence increased, and phagocytosis decreased with increasing age. CS-exposed mice exhibited similar levels of AMs senescence and impaired phagocytosis as aged mice, but more severe pulmonary dysfunction, histopathological damage, and airway inflammation. P2X7R was elevated in AMs from CS-exposed mice and CSE-treated MH-S cells. Mechanistically, the P2X7R antagonist A438079 reduced ROS levels and p-p38 MAPK, restored SIRT1 expression, and reduced Ac-NF-κB p65, thereby alleviating cellular senescence and impaired phagocytosis in CSE-treated MH-S cells. Tert-butyl hydroperoxide, a ROS inducer, can reverse the protective effects of A438079. In vivo, treatment with A438079 alleviates AMs senescence and impaired phagocytosis, and improves pulmonary dysfunction, histopathological damage, and airway inflammation in CS-exposed mice. In conclusion, our findings demonstrate that the degree of AMs senescence and impaired phagocytosis is similar between CS-exposed and aged mice. Furthermore, CS may induce AMs senescence and impaired phagocytosis via the P2X7R-mediated ROS/p38 MAPK/SIRT1/NF-κB pathway, thereby driving airway inflammation.

PMID:
42901355
Bibliographic data and abstract were imported from PubMed on 21 Oct 2026.

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