Crosstalk between epithelium and fibroblasts; implications for COPD

Background: We hypothesized that disturbed communication between lung epithelial cells and fibroblasts contributes to tissue remodelling and airway inflammation in COPD. We studied the interaction in a co-culture model with human bronchial cells epithelial cells (16HBE and primary cells from COPD and control) in the upper well and human fibroblasts (MRC-5 and primary cells from COPD and control) in the lower well of a transwell system. We harvested cell-free supernatants to measure pro-inflammatory cytokine IL-8, and cells for mRNA analysis of IL-8 and extracellular matrix (ECM) proteins, including fibronectin, decorin, and collagen. Also, we tested effects of epithelium-conditioned medium on fibroblast inflammatory and ECM responses. Results: IL-8 levels were significantly higher upon co-culture than single culture in cell lines as well as primary cells from COPD and control subjects, with fibroblasts being the main source as revealed by mRNA analysis. In contrast, fibroblast mRNA expression of ECM proteins significantly decreased upon co-culture. 16HBE-conditioned medium also strongly increased IL-8 secretion and decreased ECM expression in fibroblasts. This could be blocked by the use of neutralizing IL-1α antibody, suggesting that IL-1α drives the observed changes in fibroblasts. In line with this role for epithelium-derived IL-1α, we observed that both 16HBE and primary epithelial cells secrete substantial levels of IL-1α, in contrast to fibroblasts. Conclusion: Together, our data suggests that epithelial cells regulate fibroblast responses by secreting soluble factors (e.g. IL-1α), inducing a switch towards a more inflammatory and less regenerative phenotype, which may have implications for COPD.