Regulation of pathologic fibroblast functions in digestive diseases: a role for hypoxia?

The recent uncovering of fibroblast heterogeneity has given great insight into the versatility of the stroma. Among other cellular processes, fibroblasts are now thought to contribute to the coordination of immune responses in a range of chronic inflammatory diseases and cancer. Although the pathologic roles of myofibroblasts, inflammatory fibroblasts, and cancer-associated fibroblasts in disease are reasonably well understood, the mechanisms behind their activation remain to be uncovered. In the gastrointestinal (GI) tract, several interleukins and tumor necrosis factor superfamily members have been identified as possible mediators driving the acquisition of inflammatory and fibrotic properties in fibroblasts. In addition to cytokines, other microenvironmental factors such as nutrient and oxygen availability are likely contributors to this process. In this respect, the phenomenon of low cellular oxygen levels known as hypoxia is common in a plethora of GI diseases. Indeed, the cross talk between hypoxia and inflammation is well-documented, with an abundance of studies suggesting that oxygen-sensing enzymes may have regulatory effects on inflammatory signaling pathways such as NF-κB. However, the impact that this has in GI fibroblasts in the context of chronic diseases has not been fully uncovered. Here we discuss the role of fibroblasts in GI diseases, the mediators that have emerged as regulators of their functions and the potential impact of hypoxia in this process, highlighting areas that require further investigation.