Chronic mucus hypersecretion (CMH) is a common feature of chronic obstructive pulmonary disease (COPD). One of the major factors contributing to CMH is excessive mucin release by the airway epithelium. We hypothesized that fibroblasts support mucociliary differentiation and promote epithelial mucin release. Primary bronchial epithelial cells (PBECs) from COPD patients with CMH were cultured at air-liquid interface with and without primary airway fibroblasts (PAFs). mRNA expression of mucociliary markers and proinflammatory cytokines was assessed by qPCR. MUC5AC and MUC5B release in apical wash, and proinflammatory IL-6, CXCL8, and CCL20 release in basolateral supernatant were measured by ELISA. Immunohistochemical staining was performed on paraffin-embedded transwell inserts using alcian blue and acetylated α-tubulin. To assess the involvement of the proinflammatory mediator IL-6, cocultures of Calu-3 epithelial cells and PAFs were treated with a neutralizing antibody against IL-6. Upon coculture with PAFs, PBECs expressed more MUC5B mRNA and secreted higher levels of MUC5AC and MUC5B protein. These effects were accompanied by more pronounced mucous cell differentiation. PAFs expressed higher IL-6 mRNA and secreted more IL-6 upon coculture with airway epithelial cells (AECs), whereas IL-6 neutralization attenuated the increase in MUC5B expression by Calu-3 epithelial cells upon coculture with PAFs. This study demonstrates that fibroblasts support mucous cell differentiation and epithelial mucin release in vitro, and that IL-6 signaling contributes to this fibroblast-driven MUC5B expression. These findings support the notion that stromal-epithelium cross talk within the local niche may contribute to CMH in COPD.NEW & NOTEWORTHY Communication with airway fibroblasts promotes mucus production by COPD-derived airway epithelial cells. This mechanism, partly mediated by fibroblast-derived proinflammatory IL-6, may contribute to chronic mucus hypersecretion in COPD.
Keywords: COPD; MUC5B; chronic mucus hypersecretion; fibroblast-epithelium cross talk; mucin.