About this Research Topic
The development of fibrotic strictures requiring surgical excision is a debilitating complication of Crohn's disease with around 60% of sufferers undergoing surgery at least once in the 20 years following their initial diagnosis. Fibrosis occurs due to excessive deposition of extracellular matrix (ECM), particularly fibrous collagen, and dysregulated turnover of ECM. The tissue becomes hardened and thickened, leading to a loss of function. Fibrogenesis is a multifactorial process and it is not known how or why fibrosis develops in such a high proportion of patients. Fibrosis follows the pattern of inflammation and inflammation is required to initiate fibrogenesis but does not propagate disease. Cytokines, such as TGF-β, TNF-alpha and IL-13, produced during the inflammatory response are known to drive fibrosis by increasing collagen synthesis and simultaneously preventing its normal breakdown by reducing levels of matrix metalloproteinases.
Mesenchymal cells are predominantly responsible for the excessive deposition of ECM seen in fibrosis. During inflammation it is these cells which cytokines act upon to increase ECM synthesis. Additionally, inflammation induces recruitment, proliferation and differentiation of mesenchymal cells, further amplifying the pro-fibrotic effect. Once fibrosis becomes established the resulting tissue stiffness causes mechanical stress which, in turn, drives colonic fibroblasts to take on a fibrogenic phenotype. Thus, following the inflammation-induced early cellular changes, fibrosis becomes self-propagating.
Since inflammation is key to the initiation of fibrosis, targeting this inflammation at an early stage might be an effective mechanism to reduce the progress of fibrogenesis. Certainly, in experimental models of disease, control of inflammation has been shown to reduce fibrosis but the picture in patients is less clear. As yet, there is no convincing evidence for the effectiveness of systemic anti-inflammatory drugs, including biologicals, in preventing fibrosis but there is some evidence to suggest that administration of anti-TNF-alpha directly into fibrosed areas may dilate the stricture. New therapeutic options are being explored but more data is needed.
This Research Topic aims to summarise the main pro-fibrotic pathways in Crohn's disease and discuss possible mechanisms for disrupting these pathways, which could be used therapeutically.
Mesenchymal cells are predominantly responsible for the excessive deposition of ECM seen in fibrosis. During inflammation it is these cells which cytokines act upon to increase ECM synthesis. Additionally, inflammation induces recruitment, proliferation and differentiation of mesenchymal cells, further amplifying the pro-fibrotic effect. Once fibrosis becomes established the resulting tissue stiffness causes mechanical stress which, in turn, drives colonic fibroblasts to take on a fibrogenic phenotype. Thus, following the inflammation-induced early cellular changes, fibrosis becomes self-propagating.
Since inflammation is key to the initiation of fibrosis, targeting this inflammation at an early stage might be an effective mechanism to reduce the progress of fibrogenesis. Certainly, in experimental models of disease, control of inflammation has been shown to reduce fibrosis but the picture in patients is less clear. As yet, there is no convincing evidence for the effectiveness of systemic anti-inflammatory drugs, including biologicals, in preventing fibrosis but there is some evidence to suggest that administration of anti-TNF-alpha directly into fibrosed areas may dilate the stricture. New therapeutic options are being explored but more data is needed.
This Research Topic aims to summarise the main pro-fibrotic pathways in Crohn's disease and discuss possible mechanisms for disrupting these pathways, which could be used therapeutically.
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