The mTOR Inhibitor Rapamycin Attenuates Ozone-Induced Airway Inflammation and Emphysema In Mice

Background: Ozone exposure is a major risk factor for chronic obstructive pulmonary disease (COPD). In this study, we investigated the potential role of targeting mTOR signaling in the treatment of COPD induced by ozone exposure.

Methods: The public database was chosen to explore the expression of mTOR mRNA, S6K1 mRNA, and LC3B mRNA in COPD patients, and potential correlations with FEV₁(%pred). In an ozone-exposed mouse model, large airway and small airway function were evaluated by spirometry. After intraperitoneal injection of a mTOR Inhibitor known as rapamycin, the emphysema index, and inflammation scores in lung tissue were measured. Inflammatory cell infiltration in bronchoalveolar lavage fluid (BALF) and levels of cytokines in the lung tissue were also observed. Airway remodeling in the lung tissue was detected using Masson's trichrome stains and immunohistochemical staining. Mucus hypersecretion was evaluated by PAS staining. The protein expression of the mTOR pathway and Autophagy marker LC3B in the lung tissue was determined through Western blot.

Results: mTOR mRNA and S6K1 mRNA were upregulated in patients with COPD compared to the control subjects, whereas LC3B mRNA showed a downward shift in patients with COPD. Mice that received mTOR Inhibitor treatment displayed higher FEV₅₀/FVC, FEF₂₅, FEF₅₀, FEF₇₅, and MMEF. The mTOR Inhibitor rapamycin improved the emphysema index and inflammation scores in mice lung tissue. Moreover, it significantly inhibited inflammatory cell infiltration in BALF, IL-1β, TNF-α, and NF-κB in the lung tissue of ozone-exposed mice. The mTOR Inhibitor significantly suppressed mucus hypersecretion in large and small airways and decreased the protein expression of Collagen I and α-SMA in the lung tissue of ozone-exposed mice. Notably, mTOR repression also decreased the protein expression of S6K1 and increased LC3B expression in the lung tissue.

Conclusion: The mTOR Inhibitor rapamycin ameliorates ozone-induced airway inflammation and emphysema in a LC3B-dependent manner. mTOR inhibition may offer a promising therapeutic approach for preventing ozone-induced COPD by mitigating airway inflammation, reducing airway remodeling, and alleviating mucus hypersecretion.

airway inflammation; chronic obstructive pulmonary disease; emphysema; mTOR pathway; rapamycin.