Fibrosis in connective tissue disease: the role of the myofibroblast and fibroblast-epithelial cell interactions - PubMed (original) (raw)

Review

. 2007;9 Suppl 2(Suppl 2):S4.

doi: 10.1186/ar2188.

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Review

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

Thomas Krieg et al. Arthritis Res Ther. 2007.

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-beta 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.

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Figure 1

Figure 1

Effects of endothelin include stimulating myofibroblast formation, leading to a concomitant increase in collagen production and fibrosis. Binding of endothelin (ET)-1 to ET-1 receptor subtype A (ETA) and ETB has different effects in different cell types. The binding of ET-1 to smooth muscle cell ETA and ETB receptors leads to vasoconstriction and mitogenesis, and activation of ETB receptors on endothelial cells promotes the release of nitric oxide and prostacyclin, and plays a minor role in endothelial dependent vasodilatation. In fibroblasts ET-1 results in the increased production of collagen and leads to fibrosis. Reproduced with permission from Galiè et al. Cardiovascular Research © Elsevier 2004 [4].

Figure 2

Figure 2

Schematic diagram of the hierarchy and interplay between ET-1, TGF-β and CTGF. CTGF, connective tissue growth factor; ET, endothelin; NF-κB, nuclear factor-κB; TGF, transforming growth factor. Reproduced from [6] by permission of the publisher (Taylor & Francis Ltd,

).

Figure 3

Figure 3

TGF-β plays a pivotal role in the induction of ET-1. (a) Stellate (top panel) and sinusoidal endothelial (bottom panel) cells were isolated from normal rat livers or those injured by bile duct ligation (BDL). Transforming growth factor (TGF)-β1 was applied at the indicated concentration in serum-free medium for 24 hours. Endothelin (ET)-1 was measured by radioimmunoassay. *P < 0.05 versus no TGF-β1 (n = 5). (b) Stellate and endothelial cells were isolated from normal rat livers, and those after BDL and those after soluble TGF-β1 receptor (STR) antagonist during BDL (BDL + STR). *P < 0.05 versus normal and *P < 0.05 versus BDL (n = 8). Reproduced with permission from Shao et al. Mol Biol Cell 2003 © The American Society for Cell Biology [9].

Figure 4

Figure 4

The Tsk-1 model of cutaneous fibrosis exhibits increased MAGP-2, loss of fibulin-5 and increased fibulin-2 matrix. (a) Tissue sections from tight skin (Tsk) mice (panels 1 and 3) and control (panels 2 and 4) mice were immunostained for microfibril-associated glycoprotein (MAGP)-2. MAGP-2 is indicated by arrowheads. MAGP-2 was detected at higher levels in all dermal layers (panel 1 versus panel 2). Hypodermis (H) is shown (panel 3 versus panel 4). PC, panniculus carnosus; D, dermis. (b) Control (left panel) and Tsk (right panel) mice skin sections from 6-week-old mice were stained in parallel for fibulin-5 by immunohistochemistry. Positive staining is indicated by arrows at the muscle-connective tissue (M-CT) interface. Hypodermal connective tissue (HD) and hypodermal muscle (M) are indicated. Original magnification: 400×. (c) Control (panels 1 and 3) and Tsk (panels 2 and 4) mouse skin sections from 6-week-old mice were stained in parallel for fibulin-2 by immunohistochemistry. Positive staining is indicated by arrows (M-CT interface) and in panel 4 around hair follicles (F). (a) Reproduced with permission from Lemaire et al. Arthritis Rheum 2004 © John Wiley & Sons/American College of Rheumatology [18]. (b) and (c) Reproduced with permission from [19].

Figure 5

Figure 5

Synergistic effects of TGF-β and ET-1 in fibroblast activation. Signal intensities from Western blots of fibroblasts isolated from co-cultures of HaCaT keratinocytes and fibroblasts after 7 days in Dulbecco's modified Eagle medium/0.5% foetal calf serum. α-Smooth muscle actin (α-SMA) expression increased in co-cultures (see lane 1) as compared with fibroblasts alone (compare dotted line). Addition of an anti-transforming growth factor (TGF)-β antibody or the endothelin (ET)-1 inhibitor PD 156252 resulted in reduced α-SMA expression. Addition of anti-TGF-β and PD 156252 blocked α-SMA expression to almost basal levels [33].

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