Naltrexone attenuates airway remodeling by modulating neuromediators and sensory ion channels in cigarette smoke-induced COPD pathophysiology.

Chronic obstructive pulmonary disease (COPD) accompanied by inflammation contributes to airway obstruction, mucus hypersecretion, and other characteristic symptoms. The airways densely innervated by subsets of nerve fibers highlight the critical role of neuroimmune interactions in disease pathogenesis. The present study aimed to investigate the role of neurogenic inflammation in COPD and evaluate the therapeutic potential of naltrexone (NTX) at ultra-low doses (10  μg/kg 1  μg/kg 0.1  μg/kg) in modulating neuroimmune signaling in cigarette smoke (CS) induced COPD. CS exposure elevated inflammatory markers (COX-2 and LOX-5), activation of the hypothalamic-pituitary-adrenal axis (increased cortisol and ACTH), and enhanced neurogenic signaling marked by increased levels of neurotransmitters (substance P, serotonin, acetylcholine, and dopamine) and upregulation of their respective receptors. Further the increased sensory ion channels (TRPV1 and TRPM8), indicating elevated neurogenic inflammation. Furthermore, COPD mice exhibited elevated fibrotic markers, including TGF-β1, α-SMA, MMP-2, and MMP-9, and TIMP-1 expression, collagen deposition, and mucus hypersecretion. NTX at low doses (0.1  μg/kg) significantly attenuated these alterations by suppressing inflammatory mediators, reducing neurogenic signaling, downregulating TRP channel expression, and mitigating fibrosis. Importantly NTX modulated both µOR and TLR4 expression, suggesting that its protective effects are mediated through coordinated regulation of the µOR-TLR4 axis, attenuating neuroimmune crosstalk. Histopathological findings confirmed restoration of lung architecture and reduction of airway remodeling. The findings suggest that neuroimmune dysregulation contributes to COPD pathology, while NTX at ultra-low-dose exerts protective effects by targeting this axis. The study further highlights the µOR-TLR4 axis as a potential therapeutic target through which NTX modulates airway inflammation and remodeling.