Fibrosis in connective tissue disease: the role of the myofibroblast and fibroblast-epithelial cell interactions

Thomas Krieg,David Abraham,Robert Lafyatis

doi:10.1186/ar2188

Abstract

Fibrosis, characterized by excessive extracellular matrix accumulation, is a common feature of many connective tissue diseases, notably scleroderma (systemic sclerosis). Experimental studies suggest that a complex network of intercellular interactions involving endothelial cells, epithelial cells, fibroblasts and immune cells, using an array of molecular mediators, drives the pathogenic events that lead to fibrosis. Transforming growth factor-β and endothelin-1, which are part of a cytokine hierarchy with connective tissue growth factor, are key mediators of fibrogenesis and are primarily responsible for the differentiation of fibroblasts toward a myofibroblast phenotype. The tight skin mouse (Tsk-1) model of cutaneous fibrosis suggests that numerous other genes may also be important.

Highlights

Fibrosis, the result of excess synthesis and deposition of collagen, is a feature of many connective tissue diseases (CTDs) and is the hallmark of scleroderma
As the experimental studies described here illustrate, myofibroblasts play a central role in mediating tissue fibrosis, which is the major clinical manifestation of CTDs such as SSc
transforming growth factor (TGF)-β, ET-1, and Connective tissue growth factor (CTGF) are among the most important molecular mediators of fibrogenesis, with TGF-β and ET-1 intimately involved in the differentiation of fibroblasts toward a myofibroblast phenotype, characterized by the presence of stress fibres containing α-stress fibres containing αsmooth muscle actin (SMA)

Summary

Introduction

The result of excess synthesis and deposition of collagen, is a feature of many connective tissue diseases (CTDs) and is the hallmark of scleroderma (systemic sclerosis [SSc]). Endothelin participates in stimulating the formation of myofibroblasts (the myofibroblast is a specialized type of fibroblast that is a normal cellular constituent of healing tissues) and increases levels of CTGF and matrix proteins [4] (Figure 1) It interacts with other profibrotic cytokines including TGF-β, which is a key component in the induction and progression of fibrosis [5] and is a potent stimulator of CTGF. A recent study has shown TGF-β preferentially induces ET-1 expression [34] Results from these experimental studies indicate that highly complex epithelial-mesenchymal crosstalk is involved in controlling the extent to which fibroblastic cells are induced in the underlying mesenchyma and in their subsequent differentiation to myofibroblasts

Conclusion

Mayes MD