A review of research advances in the modulation of olfactory receptors for COPD inflammation and airway remodeling

Abstract

Chronic obstructive pulmonary disease (COPD), as the third leading cause of global mortality, presents complex pathological mechanisms and imposes a substantial health burden. Emerging evidence reveals that olfactory receptors (ORs), traditionally associated with odor detection, exhibit non-canonical regulatory functions in COPD pathogenesis. This review systematically explores ORs' multidimensional roles: environmental triggers activate specific ORs in specific cells, initiating chronic inflammatory cascades. Persistent inflammation drives irreversible airway remodeling through smooth muscle proliferation and extracellular matrix reorganization. Preclinical and clinical studies demonstrate that OR agonists/antagonists modulate the inflammation-remodeling axis to influence pulmonary function, though their pleiotropic effects complicate therapeutic targeting. The cell type-specific expression patterns and diverse ligand profiles of ORs create unique opportunities for precision interventions, while posing challenges in tissue delivery and receptor efficacy optimization. Future investigations should integrate single-cell omics and artificial intelligence to elucidate OR-mediated dynamic networks, downstream signaling pathways, and their interplay with microbiome-gut-lung axis regulation. This review not only advances our understanding of OR biology in respiratory diseases but also proposes a novel theoretical framework for developing OR-based diagnostic and therapeutic strategies in the early management of COPD.

Keywords: airway remodeling; chronic inflammation; chronic obstructive pulmonary disease; olfactory receptors; therapeutic targets.

Figure 1

Ligands and ORs in COPD. Common olfactory receptor ligands (e.g., nonanal, farnesol and citronellal) originate from fragrance products, industrial solvents, microbial metabolites, endogenous sources and so on. These ligands act on cell type-specific ORs (e.g., OR2AT4, OR51E2, OR2W1 and OR1A2) expressed in airway ECs, airway smooth muscle cells (SMCs), macrophages (Mφ), and PNECs within lung tissue. They directly influence COPD through mechanisms involving chronic inflammation and airway remodeling.

Figure 2

Effects of ORs on chronic inflammation in COPD. Multiple odorants activate ORs on the surface of airway epithelial cells, neutrophils, A549 cells, and alveolar macrophages. Then, they can trigger pulmonary inflammatory injury in COPD.

Figure 3

Effects of ORs on airway remodeling in COPD. (A) In airway smooth muscle cells (SMCs), OR2W3, OR51E2, OR1D2, and OR2AG1 can be activated. OR2W3 induces relaxation by Ca²⁺ influx and activating TMEM16A and CFTR; OR51E2 induces cytoskeletal remodeling and cell proliferation; OR1D2 induces contraction and release of IL-8/GM-CSF by ERK signaling pathway; OR2AG1 induces contraction by blocking histamine pathway. (B) In airway ECs, OR2AT4 and OR2J3 can be activated. OR2AT4 promotes wound healing by Ca²⁺ influx; OR2J3 promotes wound healing and inhibits release of IL-8 by Ca²⁺ influx and the cAMP/PKA pathway.