Endothelin, an endothelial‐dependent vasoconstrictor in scleroderma. Enhanced production and profibrotic action

Kahaleh, M. Bashar

doi:10.1002/art.1780340807

Cited by 225 publications

(103 citation statements)

References 29 publications

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“…ET-1 is a potent activator of fibroblast proliferation and ECM synthesis, and its enhanced production has been well described in SSc (3,10). We found a marked overexpression of all these key profibrotic factors in the stomach of patients with SSc, mostly in the small vessel wall and focally in the fibrotic areas of muscle layers, suggesting their active role in inducing and perpetuating the fibrotic response.…”

Section: Discussionsupporting

confidence: 57%

“…In the present study, we analyzed endoscopic and surgical gastric samples from SSc patients with gastroesophageal involvement to evaluate the extent of collagen deposition, the presence of myofibroblasts, and the expression of key fibrogenic cytokines (TGF␤ and CTGF), as well as of endothelin 1 (ET-1), a mediator of fibroblast proliferation and ECM synthesis, whose role in the pathogenesis of SSc is the subject of worldwide interest (2,10).…”

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confidence: 99%

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Severe fibrosis and increased expression of fibrogenic cytokines in the gastric wall of systemic sclerosis patients

Manetti¹,

Neumann²,

Milia³

et al. 2007

Arthritis & Rheumatism

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Objective. Systemic sclerosis (SSc) is a connective tissue disorder characterized by fibrosis of the skin and internal organs. Although the esophagus is the most frequently affected part of the gastrointestinal tract, all other segments can be involved. The present study was undertaken to evaluate the fibrotic process and the expression of fibrogenic cytokines in the gastric wall of SSc patients with gastroesophageal involvement.Methods. Full-thickness surgical and endoscopic gastric biopsy samples were obtained from 14 SSc patients and 10 controls. Tissue sections were either stained with Masson's trichrome or by immunohistochemistry and analyzed for the expression of types I, III, and IV collagen, ␣-smooth muscle actin (␣-SMA), transforming growth factor ␤ (TGF␤), connective tissue growth factor (CTGF), and endothelin 1 (ET-1).Results. In the gastric wall of SSc patients, Masson's trichrome staining and immunohistochemistry for types I and III collagen revealed a high amount of collagen in the lamina propria that increased toward the muscularis mucosae. In addition, muscle layers showed features of atrophy, with wide areas of focal fibrosis surrounding smooth muscle cells. Type IV collagen was present around glands and small vessels, suggesting a thickening of the basal lamina. The expression of the fibrogenic cytokines TGF␤ and CTGF, ET-1, and the myofibroblast marker ␣-SMA was stronger in SSc patients than in controls.Conclusion. A pronounced deposition of collagen, the presence of myofibroblasts, and increased expression of several profibrotic factors are important hallmarks in the stomach of patients with SSc. The fibrotic involvement of the gastric wall may account for muscle atrophy leading to stomach hypomotility in SSc.

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Section: Discussionsupporting

confidence: 57%

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confidence: 99%

Severe fibrosis and increased expression of fibrogenic cytokines in the gastric wall of systemic sclerosis patients

Manetti¹,

Neumann²,

Milia³

et al. 2007

Arthritis & Rheumatism

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“…The vascular lesions, which consist of both endothelial cell damage and proliferation of myointimal cells, result in elevated levels of von Willebrand factor antigen [31] and endothelin [32], and are associated with raised levels of -thromboglobulin as an indicator of platelet activation [33].…”

Section: Discussionmentioning

confidence: 99%

Antibodies to membranes of endothelial cells and fibroblasts in scleroderma

Hill¹,

Phipps²,

Cartwright

et al. 1996

Clinical and Experimental Immunology

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SUMMARYAnti-endothelial and other cell membrane-reactive antibodies in scleroderma were characterized by immunoblotting sera with membrane and cytosol preparations of human umbilical vein endothelial cells (HUVEC), dermal fibroblasts and a T cell lymphoma HUT78. Antibodies reactive with HUVEC membranes were found in 17 of 20 patients with scleroderma (33 bands) in contrast to only two of 20 controls (two bands; P<0 . 01) and three of 11 patients with myocardial infarction (four bands). Eleven of the 20 patients possessed antibodies that were specific for HUVEC membrane and did not cross-react with other cell lines. Analysis of patient subgroups showed that HUVEC membrane antibodies were present in nine of 11 patients with systemic sclerosis and in all nine with the CREST syndrome, and were HUVEC-specific in five and six of these cases, respectively. Although considerable heterogeneity was seen, antibodies to an 18-19-kD membrane epitope were found in 11 of the 20 patients but in none of the controls (P<0 . 01). This antibody which reacted particularly with HUVEC (n 9) and HUT78 membranes (n 9) was associated with CREST syndrome rather than systemic sclerosis (9/9 versus 1/ 11; P<0 . 01), and after elution was shown to possess anticentromere activity. In addition, antibodies reactive with both fibroblast (n 11; 18 bands) and HUT78 membranes (n 18; 42 bands) were detected and were specific for either fibroblast or HUT78 membranes in nine and 14 patients, respectively. There was no significant difference in the incidence of these fibroblasts and HUT78 membrane antibodies in the two patient subgroups. These findings support the concept that membranereactive antibodies, including anticentromeric antibodies, may play a central role in the pathogenesis of scleroderma, through their ability to react with endothelial cells.

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“…A recent report describes high levels of circulating endothelin, a potent endothelialderived vasoconstrictor substance, in patients with diffuse SSc (26). Endothelin levels were partially augmented by exposure of the patients to cold, and endothelin had potent effects on fibroblast proliferation and collagen synthesis in culture.…”

Section: Discussionmentioning

confidence: 99%

Immunocytochemical Localization and Serologic Detection of Transforming Growth Factor β1

Higley¹,

Persichitte²,

Chu³

et al. 1994

Arthritis & Rheumatism

155

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Objective. To determine the presence of transforming growth factor β1 (TGFβ1) and inflammatory cell markers (HLA–DR and Factor XIIIa) and to compare these with the presence of type I procollagen, in clinically uninvolved and involved skin from patients with different subsets of systemic sclerosis (SSc), and to analyze circulating levels of TGFβ1 in SSc patients. Methods. TGFβ1, HLA‐DR, Factor XIIIa, and type I procollagen were detected in skin biopsy sections using a biotin–streptavidin–peroxidase system. Levels of circulating TGFβ1 were measured using a capture enzyme‐linked immunosorbent assay technique. Results. Patients with active diffuse cutaneous SSc (dcSSc) showed minimal TGFβ1 but significant type I procollagen staining in involved skin, while the clinically uninvolved skin of these patients showed moderate extracellular and intra‐epidermal TGFβ1 immunoreactivity. Patients with limited cutaneous SSc (IcSSc) showed elevated TGFβ1 staining in both involved and uninvolved skin, as well as procollagen staining. Significant TGFβ1 reactivity, HLA–DR and Factor XIIIa immunoreactivity, numerous inflammatory cells, and procollagen staining were seen in specimens from patients with morphea. Sequential biopsies suggested the presence of cytokine activity at the earliest stages of disease, which was not maintained with progression of sclerosis. Among the disease groups studied, elevated levels of circulating TGFβ1 were seen only in patients with morphea. Conclusion. The pattern of TGFβ1 staining in dermal sections from patients with dcSSc, IcSSc, and morphea suggests that this cytokine is important in the pathogenesis of scleroderma. Furthermore, the presence of TGFβ1 prior to the onset of fibrosis indicates an early involvement of this growth factor, possibly in the inflammatory stage of the disease.

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Endothelin, an endothelial‐dependent vasoconstrictor in scleroderma. Enhanced production and profibrotic action

Cited by 225 publications

References 29 publications

Severe fibrosis and increased expression of fibrogenic cytokines in the gastric wall of systemic sclerosis patients

Severe fibrosis and increased expression of fibrogenic cytokines in the gastric wall of systemic sclerosis patients

Antibodies to membranes of endothelial cells and fibroblasts in scleroderma

Immunocytochemical Localization and Serologic Detection of Transforming Growth Factor β1

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