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<p>Cigarette smoke (CS) is a major risk factor for chronic obstructive pulmonary disease (COPD). CS exposure disrupts the oxidant‑antioxidant balance in the lungs, which may contribute to cellular senescence – a process implicated in the initiation and progression of COPD. Club cell secretory protein 16 (CC16) is produced by the airway epithelium, and reduced CC16 levels have been associated with COPD pathogenesis. In this study, we investigated the potential anti‑senescence effect of recombinant human CC16 (rhCC16) using both <i>in vitro</i> and <i>in vivo</i> models and explored the underlying mechanisms. A cellular senescence model was established by exposing A549 type II alveolar epithelial cells to cigarette smoke extract (CSE). Senescence markers were assessed in the presence or absence of rhCC16 treatment. A mouse model of COPD was generated by chronic CS exposure, and rhCC16 was administered intranasally. Senescence markers in lung tissues were evaluated by immunohistochemistry. Our results indicate that the protective effect of rhCC16 is associated with inhibition of the PI3K‑AKT‑mTOR pathway and restoration of autophagic flux. Furthermore, the anti‑senescence action of rhCC16 in A549 cells may involve integrin α4β1 and clathrin‑mediated endocytosis. In the CS‑exposed mouse model, rhCC16 treatment improved pulmonary function and attenuated lung pathological injury. Collectively, these findings suggest that rhCC16 alleviates CS‑induced cellular senescence through modulation of the PI3K‑AKT‑mTOR/autophagy axis, and may therefore represent a potential candidate for senescence‑targeted therapy in COPD.</p>

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Pharmacological effect of rhCC16 on COPD: anti-senescence via the PI3K-AKT-mTOR pathway

  • 期刊论文

  • 发表日期：

    2026年6月20日

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  • Rui Gao,
  • Shuo Wu,
  • Chu-lin Zhang,
  • Chao-feng Liu,
  • Ting Li,
  • Min Guo,
  • Zhao-yang Chen,
  • Hai-long Wang,
  • Min Pang

摘要

Cigarette smoke (CS) is a major risk factor for chronic obstructive pulmonary disease (COPD). CS exposure disrupts the oxidant‑antioxidant balance in the lungs, which may contribute to cellular senescence – a process implicated in the initiation and progression of COPD. Club cell secretory protein 16 (CC16) is produced by the airway epithelium, and reduced CC16 levels have been associated with COPD pathogenesis. In this study, we investigated the potential anti‑senescence effect of recombinant human CC16 (rhCC16) using both in vitro and in vivo models and explored the underlying mechanisms. A cellular senescence model was established by exposing A549 type II alveolar epithelial cells to cigarette smoke extract (CSE). Senescence markers were assessed in the presence or absence of rhCC16 treatment. A mouse model of COPD was generated by chronic CS exposure, and rhCC16 was administered intranasally. Senescence markers in lung tissues were evaluated by immunohistochemistry. Our results indicate that the protective effect of rhCC16 is associated with inhibition of the PI3K‑AKT‑mTOR pathway and restoration of autophagic flux. Furthermore, the anti‑senescence action of rhCC16 in A549 cells may involve integrin α4β1 and clathrin‑mediated endocytosis. In the CS‑exposed mouse model, rhCC16 treatment improved pulmonary function and attenuated lung pathological injury. Collectively, these findings suggest that rhCC16 alleviates CS‑induced cellular senescence through modulation of the PI3K‑AKT‑mTOR/autophagy axis, and may therefore represent a potential candidate for senescence‑targeted therapy in COPD.