Glucocorticoids exacerbate TGFß1 mediated fibrotic signalling in lung fibroblasts by inhibition of metalloproteinase expression and activity

Abstract

Excessive deposition of fibrillar collagen in the interstitial extracellular matrix (ECM) of tissues causes fibrosis. This leads to local disruption of tissue architecture, with ultimate organ failure. To this end, we conducted a high-throughput microscopy-based screen of an FDA approved drug library in primary human lung fibroblasts, aiming at discovering novel regulators of fibrillar collagen deposition in ECM. Here, TGFß1 was used as a pro-ECM depostion stimulating agent. In total 760 drugs were screened. Interestingly, the data analysis shows that glucocorticoids, a widely used anti-inflammatory class of drugs, enhances depostion of Collagen 1 relative to fibroblasts treated with TGFß1 alone. Multiomic analysis (transcriptomics and proteomics) of fibroblasts treated with TGFß1 and Prednisolone (a routinely prescribed glucocorticoid) showed downregulation of metalloproteinase expression. Using MMP activity assay, we confirm that the observed downregulation in MMP expression leads to corresponding decrease in pan MMP activity. We hypothesise, this inhibition of metalloproteinase activity when coupled to TGFß1 stimulation, enhances the depostion of fibrillar collagen in ECM. Furthermore, the observed glucocorticoid mediated enhanced depostion of collagen 1 might exacerbate lung dysfunction, in particular, in patients with Interstitial lung disease and inherently higher TGFß1 activity.