Hydroxylase inhibition regulates inflammation-induced intestinal fibrosis through the suppression of ERK-mediated TGF-β1 signaling

Abstract

Fibrosis is a complication of chronic inflammatory disorders such as inflammatory bowel disease, a condition which has limited therapeutic options and often requires surgical intervention. Pharmacologic inhibition of oxygen-sensing prolyl hydroxylases, which confer oxygen sensitivity upon the hypoxia-inducible factor pathway, has recently been shown to have therapeutic potential in colitis, although the mechanisms involved remain unclear. Here, we investigated the impact of hydroxylase inhibition on inflammation-driven fibrosis in a murine colitis model. Mice exposed to dextran sodium sulfate, followed by a period of recovery, developed intestinal fibrosis characterized by alterations in the pattern of collagen deposition and infiltration of activated fibroblasts. Treatment with the hydroxylase inhibitor dimethyloxalylglycine ameliorated fibrosis. TGF-β1 is a key regulator of fibrosis that acts through the activation of fibroblasts. Hydroxylase inhibition reduced TGF-β1-induced expression of fibrotic markers in cultured fibroblasts, suggesting a direct role for hydroxylases in TGF-β1 signaling. This was at least in part due to inhibition of noncanonical activation of extracellular signal-regulated kinase (ERK) signaling. In summary, pharmacologic hydroxylase inhibition ameliorates intestinal fibrosis through suppression of TGF-β1-dependent ERK activation in fibroblasts. We hypothesize that in addition to previously reported immunosupressive effects, hydroxylase inhibitors independently suppress profibrotic pathways.

Hypoxia Inducible Factor (HIF) Hydroxylases as Regulators of Intestinal Epithelial Barrier Function

“…In recently published work, we described a role of hydroxylase inhibition as a negative regulator of transforming growth factor-β1–induced intestinal fibrosis. These effects were HIF independent and appear to be caused by hydroxylase-dependent modulation of the noncanonical transforming growth factor–extracellular regulated kinase signaling pathway 157 . Given the relevance of the extracellular regulated kinase pathway in fibrotic pathology, these observations may represent a first step toward investigating hydroxylase inhibition as antifibrotic therapy in IBD 158, 159, 160…”

Loss of Prolyl-Hydroxylase 1 Protects against Biliary Fibrosis via Attenuated Activation of Hepatic Stellate Cells

“…14 In fact, it could recently be shown that pharmacologic pan-hydroxlase inhibition significantly attenuated the development of intestinal fibrosis in mice exposed to experimental colitis. 47 However, because most of these drugs are neither specific for the oxygen-sensing PHD enzymes (PHD1, PHD2, and PHD3) nor for distinct cell populations, it remains to be investigated whether pharmacologic PHD enzyme inhibitors can be applied to rather specifically target PHD1 in HSCs.…”

Stromal and immune cells in gut fibrosis: the myofibroblast and the scarface

“…Acting upon human SEMFs, TGF-β enhances their migratory capacity and increases production of collagen and TIMP-1 [13,35,51]. TGF-β blockade ameliorated fibrosis in animal models of chronic colitis [52], whereas overexpression of TGF-β leads to intestinal stricture formation [53]. In a newly established model for fibrosis using human intestinal organoids, TGF-β treatment resulted in upregulation of fibrosis-related factors, such as collagen type I, fibronectin, α-SMA, actin contractile gene MYLK and fibrogenic transcription factor MLK1 [54].…”