Abstract
Fibrosis can occur in tissues in response to a variety of stimuli. Following tissue injury, cells undergo transformation or activation from a quiescent to an activated state resulting in tissue remodelling. The fibrogenic process creates a tissue environment that allows inflammatory and matrix-producing cells to invade and proliferate. While this process is important for normal wound healing, chronicity can lead to impaired tissue structure and function.This review examines the major factors involved in transforming or activating tissues towards fibrosis. The role of genetic variation within individuals affected by fibrosis has not been well described and it is in this context that we have examined the mediators of remodelling, including transforming growth factor-beta, T helper 2 cytokines and matrix metalloproteinases.Finally we examine the role of Toll-like receptors in fibrosis. The inflammatory phenotype that precedes fibrosis has been associated with Toll-like receptor activation. This is particularly important when considering gastrointestinal and hepatic disease, where inappropriate Toll-like receptor signalling, in response to the local microbe-rich environment, is thought to play an important role.
Highlights
Fibrosis is a wound-healing response by which the body attempts to repair itself following injury
In this review we focus on transforming growth factor (TGF)-β, IL-13, tissue inhibitor of metalloproteinases (TIMP) and matrix metalloproteinases (MMP), the major factors implicated in fibrogenesis
TGF-β plays a pivotal role in the fibrotic development through its influence on MMP/TIMP expression, T cell function and extracellular matrix (ECM) production
Summary
Fibrosis is a wound-healing response by which the body attempts to repair itself following injury. Yee et al reported carriage of the -308A allele was associated with a fivefold increased risk of cirrhosis following HCV infection [89] These findings were reported by Kusumoto et al, with carriage of 'A' at TNF-α -238 or -308 correlating with significantly higher serum levels of Type IV collagen 7S, which is a marker for advanced hepatic fibrosis [90]. A promoter polymorphism within the myeloperoxidase gene which is involved in activation of HSCs and the production of ECM-MPO G-463A has been shown to be associated with advanced fibrosis when the variant A allele was present [112]. Polymorphisms in genes involved in lipid transportation have been http://www.fibrogenesis.com/content/2/1/6 assessed within the context of HCV-induced liver fibrosis These pathways are thought to promote viral endocytosis. This view is supported by studies using gutsterilized mice that have shown a strong reduction in fibrogenesis compared to conventional mice [135]
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