Fibroblasts endothelin

ET-1 also stimulates anti-apoptotic signal cascades in fibroblasts, vascular smooth muscles and endothelial cells (via phosphatidylinositol-3-kinase and Akt/pro-tein kinase B). In prostate and ovarian cancer, upregulation of endothelin synthesis and ETA receptors has been associated with a progression of the disease. The inhibiton of ETA receptors results in a reduced tumour growth. In malignant melanoma, ETB receptors are associated with tumour progression. Endothelins can also stimulate apoptosis in stretch-activated vessels via the ETB receptor, which contrasts the above-mentioned effects. The molecular basis for these differential anti- and pro-apoptotic reactions mediated by endothelins remains elusive. 

In the interstitium, angiotensin II induces proliferation of mesangial cells and fibroblasts and the synthesis of collagen and other matrix molecules by these cells via the ATI receptor. Moreover, by the concomitant stimulation of chemoattractant cytokines, inflammation is induced. These processes are mediated by endothelin, transforming growth factor(3, and reactive oxygen species, and finally lead to interstitial fibrosis and glomerulosclerosis observed in hypertension and diabetes. 

Interleukin-6 (IL-6) is a small polypeptide with a molecular mass of 26 kDa (see Table 2). IL-6 can be induced in various cell types, including fibroblasts, macrophages/monocytes, epithelial cells, T cells, B cells, and diverse tumor cells (L4). TNF, IL-1, and LPS can stimulate IL-6 gene expression in macrophages/monocytes and fibroblasts. In vivo studies showed that systemic administration of TNF, LPS, and IL-1 was followed by a rapid induction of circulating IL-6 (B49, J2). Also, endothelin (ET) at concentrations observed pathophysiolog-ically may trigger production of IL-6 (Ml7). 

Resveratrol shows a direct inhibitory activity on heart fibroblasts and suppresses the spreading of heart fibrose (05MI1131). The vasoconstrictor peptide endothelin (ET-1) is controlled in its biosynthesis by polyphenols, and especially by resveratrol. Only 5 pmol causes an endothelin-depen-dent vasodilatation and lowers blood pressure (88NAT411, 01MI152, 01NAT863,06NAT566). 

Shi-Wen X, Chen Y, Denton CP, Eastwood M, Renzoni EA, Bou-Gharios G, Pearson JD, Dashwood M, du Bois RM, Black CM, Leask A, Abraham DJ. 2004. Endothelin-1 promotes myofibroblast induction through the ETA receptor via a rac/phosphoinositide 3-kinase/Akt-dependent pathway and is essential for the enhanced contractile phenotype of fibrotic fibroblasts. Mol Biol Cell 15 2707-2719. 

In 1991 inhibition of PKC activity was found to be at the basis of the vascular smooth muscle cell growth arrest induced by a-tocopherol [16,17]. A number of reports have subsequently confirmed the involvement of PKC in the effect of a-tocopherol on different cell types, including monocytes, macrophages, neutrophils, fibroblasts and mesangial cells [8,18-20]. a-Tocopherol, but not P-tocopherol, was found to inhibit thrombin-induced PKC activation and endothelin secretion in endothelial cells [21]. a-Tocopherol, and not P-tocopherol or trolox, inhibits the activity of PKC fi-om monocytes, followed by inhibition of phosphorylation and translocation of the cytosolic factor p47(phox) and by an impaired assembly of the NADPH-oxidase and of superoxide production [22]. a-Tocopherol has the important biological effect of inhibiting the release of the proinflammatory cytokine, IL-lp, via inhibition of the 5-lipoxygenase pathway [23]. 

Endothelin-1, a peptide initially purified from porcine aortic endothelial cells, has been shown to be expressed by human pneumocytes type II in lung fibrosis (Giaid et al. 1993), by rat pneumocytes II (Crestani et al. 1994), and a cell line derived from rat pneumocytes II (L2 Markevitz et al. 1995). ET-1 has potent vascular and bronchial smooth muscle cell constrictor properties, acts as a mitogen for different cell types, such as fibroblasts or smooth muscle cells (Battistini et al. 1993), and is involved in the modulation of the inflammatory response through a direct effect on alveolar macrophages (Na-GASE et al. 1990) or mast cells (Ehrenreich et al. 1992). ET-1 production is inhibited by IL-ip (Odoux et al. 1997). IL-ip effect was dependent on protein synthesis, was partially prevented by indomethacin, and was totally prevented by dexamethasone. 

Platelet derived growth factor Insulin-like growth factors Epidermal growth factor Transformation growth factor- Fibroblast growth factor Interleukin-1 Endothelin-1 Tumor necrosis factor-a MCP-1 VMAP-1 Selectins ICAM-1 VCAM-1 LFA-1... 

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