2. Academic Validation
  3. Mechanisms of Anti-Oxidants, N-Acetylcysteine and Elamipretide (SS-31), on Ozone-Induced Airway Hyperresponsiveness and Mucus Hypersecretion

Mechanisms of Anti-Oxidants, N-Acetylcysteine and Elamipretide (SS-31), on Ozone-Induced Airway Hyperresponsiveness and Mucus Hypersecretion

  • Lung. 2026 Mar 9;204(1):12. doi: 10.1007/s00408-026-00875-1.
Meiqin Xie # 1 2,  Jiali Weng # 2,  Chenfei Li 2,  Qi Liu 2,  Yi Feng 2,  Hai Zhang 2,  Qing Chang 2,  Kian Fan Chung 3,  Ian M Adcock 3,  Feng Li 4,  Xiaoyun Fan 5 6
Affiliations

Affiliations

  • 1 Department of Geriatric Respiratory and Critical Care Medicine, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, People's Republic of China.
  • 2 Department of Pulmonary and Critical Care Medicine, Shanghai Chest Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200030, People's Republic of China.
  • 3 Airway Disease Section, National Heart and Lung Institute, Imperial College, Dovehouse Street, London, SW3 6LY, UK.
  • 4 Department of Pulmonary and Critical Care Medicine, Shanghai Chest Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200030, People's Republic of China. [email protected].
  • 5 Department of Geriatric Respiratory and Critical Care Medicine, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, People's Republic of China. [email protected].
  • 6 Anhui Geriatric Institute, Hefei, 230032, People's Republic of China. [email protected].
  • # Contributed equally.
PMID: 41801306 DOI: 10.1007/s00408-026-00875-1
Abstract

Background: Ozone (O₃) exposure induces acute airway injury characterized by airway hyperresponsiveness (AHR) and airway mucus hypersecretion (AMH). Oxidative stress and mitochondria-derived Reactive Oxygen Species (mtROS) are key contributors. We investigated and compared the protective mechanisms of N-acetylcysteine (NAC) and the mitochondria-targeted antioxidant Elamipretide (SS-31) in O₃-induced airway inflammation, AHR and AMH.

Methods: Wild-type C57BL/6J mice received intraperitoneal NAC or SS-31 1 h before a single O₃ exposure. AHR, bronchoalveolar lavage (BAL) inflammatory cells, mucus production and Mucin expression, inflammatory mediators, oxidative stress indices, and PI3K/Akt and NLRP3/Caspase-1/GSDMD pathway activation were assessed in vivo. BEAS-2B cells were pretreated with NAC, SS-31, or the PI3K/Akt Inhibitor LY294002 before O₃ exposure, and pathway activation was evaluate d in vitro.

Results: NAC and SS-31 comparably attenuated O₃-induced AHR, reduced BAL inflammatory cell influx, and decreased AMH and MUC5B expression. Both treatments improved redox balance by reducing ROS/mtROS, lowering malondialdehyde (MDA), increasing superoxide dismutase (SOD) activity, and improving GSH/GSSG. NAC and SS-31 also suppressed O₃-induced inflammatory gene expression and inhibited activation of PI3K/Akt and NLRP3/Caspase-1/GSDMD signaling in mouse lungs and BEAS-2B cells. PI3K inhibition recapitulated these protective effects in vitro, supporting a mechanistic role for PI3K/Akt signaling during acute O₃ exposure.

Conclusions: NAC and SS-31 protect against acute O₃-induced AHR and AMH by alleviating oxidative stress and suppressing PI3K/AKT-driven inflammatory and pyroptotic pathways. Targeting oxidative stress, including mitochondrial ROS, may represent a viable strategy to mitigate airway damage caused by acute O₃ exposure.

Keywords

Airway hyperresponsiveness; Airway mucus hypersecretion; Antioxidants; Mitochondria; Oxidative stress; Ozone.

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