The study shows that a natural protein called cathelicidin (LL‑37) makes airway cells change shape and become more like scar‑forming cells when people smoke, which contributes to lung damage in COPD. Turning down cathelicidin in mice reduced this harmful change, while increasing it made it worse. The effect works through a chain of signals called TACE, TGF‑α, and EGFR.

Epithelial-mesenchymal transition (EMT) is an important characteristic in the remodeling of airways that occurs in chronic obstructive pulmonary disease (COPD). Cigarette smoke is a potential driving factor of this EMT in COPD. However, the mechanisms by which cigarette smoke induce EMT remain uncertain. Cathelicidin has been implicated as a causal factor of airway inflammation and mucus hypersecretion in smoking-related COPD. This study aimed to investigate whether cathelicidin induces EMT to promote airway remodeling in this disease. Human lung tissue was collected from smokers with COPD and smokers without COPD. The EMT markers E-cadherin and vimentin were examined by immunohistochemistry. Mouse models of COPD were established by taking mice with airway cathelin-related antimicrobial peptide (CRAMP), the murine homologue of cathelicidin, either upregulated or downregulated by intranasal introduction of lentiviral vectors and then exposing them to cigarette smoke. E-cadherin and vimentin expression in the airways of the model mice was examined using immunofluorescence. Tumor necrosis factor alpha (TNF-&#x3b1;) converting enzyme (TACE), transforming growth factor alpha (TGF-&#x3b1;), and epidermal growth factor receptor (EGFR) expression was analyzed by Western blot. Additionally, NCI-H292 human airway epithelial cells, both with and without cathelicidin downregulation, were stimulated with cigarette smoke extract (CSE) and LL-37 synthetic peptide, a bioactive fragment of cathelicidin. This was done to confirm that the TACE/TGF-&#x3b1;/EGFR signaling pathway is activated in humans exposed to cigarette smoke. Significant EMT was found in the small airways of smokers both with and without COPD, as well as in the airways of COPD model mice. Downregulation of CRAMP in COPD mice, however, ameliorated airway EMT induced by cigarette smoke. Conversely, upregulation of CRAMP enhanced airway EMT <i>in vivo</i>; TACE, TGF-&#x3b1;, and EGFR were found to be involved in this process. <i>In vitro</i>, EMT induced by CSE and LL-37 was inhibited by blocking TACE, TGF-&#x3b1;, and EGFR expression. Cathelicidin promotes airway EMT by activating the TACE/TGF-&#x3b1;/EGFR signaling pathway. This mediates smoking-induced airway remodeling in the pathogenesis of COPD.