Small airway remodeling (SAR) is a key phenomenon of airfow obstruction in smokers, leading to chronic obstructive pulmonary disease (COPD). SAR results in an increased thickness of small airway walls, with a combination of peribronchiolar fbrosis with increased fbrous tissue and accumulation of mesenchymal and epithelial cells. SAR pathogenesis is still unclear but recent data suggest that alterations in telomerase activity could represent a possible underlying mechanism of SAR. Our study was dedicated to identify a potential protective role of TA-65, a pharmacological telomerase activator, in a cigarette smoke (CS) model of SAR in mice, and to further precise if extra-telomeric efects of telomerase, involving oxidative stress modulation, could explain it. C57BL/6J mice were
daily exposed to air or CS during 4 weeks with or without a concomitant administration of TA-65 starting 7 days before CS exposure. Morphological analyses were performed, and mucus production, myofbroblast diferentiation, collagen deposition, as well as transforming growth factor-β1 (TGFβ1) expression in the small airway walls were examined. In addition, the efects of TA-65 treatment on TGF-β expression, fbroblast-to-myofbroblast diferentiation, reactive oxygen species (ROS) production and catalase expression and activity were evaluated in primary cultures of pulmonary fbroblasts and/or mouse embryonic fbroblasts in vitro. Exposure to CS during 4 weeks induced SAR in
mice, characterized by small airway walls thickening and peribronchiolar fbrosis (increased deposition of collagen, expression of α-SMA in small airway walls), without mucus overproduction. Treatment of mice with TA-65 protected them from CS-induced SAR. This efect was associated with the prevention of CS-induced TGF-β expression in vivo, the blockade of TGF-β-induced myofbroblast diferentiation, and the reduction of TGF-β-induced ROS production that correlates with an increase of catalase expression and activity. Our fndings demonstrate that telomerase is a critical player of SAR, probably through extra-telomeric anti-oxidant efects, and therefore provide new insights in the understanding and treatment of COPD pathogenesis.