Distally derived lung fibroblasts from COPD patients show altered hypoxia-induced cellular responses and inflammatory profile

Chronic obstructive pulmonary disease (COPD) is a disease characterized by chronic bronchitis, emphysema and vascular remodeling. The disease is associated with hypoxia, inflammation and oxidative stress. Lung fibroblasts are important cells in remodeling processes in COPD, as main producers of extracellular matrix proteins and have a role in synthesis of inflammatory mediators and growth factors. We aimed to investigate if there are differences in how primary distal lung fibroblasts from COPD patients and healthy subjects respond to hypoxia (1% O2) and pro-fibrotic stimuli with TGF-β (10 ng/mL). Genes and proteins associated with oxidative stress, endoplasmic reticulum stress, remodeling and inflammation were analyzed with RT-qPCR and ELISA. Hypoxia induced differences in expression of genes involved in oxidative (SOD3, HIF-1α, and Nrf2) and ER stress (IRE1, PARK, and ATF6), apoptosis (c-Jun and Bcl2) and remodeling (5HTR2B, Collagen7, and VEGFR2) in lung fibroblasts from COPD subjects compared to healthy subjects, where COPD fibroblasts were less responsive. VEGF-C release was increased after hypoxia, whereas TGF-β significantly reduced VEGF response to hypoxia and release of HGF. COPD fibroblasts had a higher release of IL-6, IL-8, MCP and prostaglandin E2 compared to control subjects. The release of inflammatory mediators was less affected by hypoxia, whereas TGFβ1 induced differences in inflammatory profile between fibroblasts from COPD and control subjects. In conclusion, these results suggest that there is an alteration of gene regulation of various stress responses and remodeling associated mediator release that is related to COPD and hypoxia.