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Query: UMLS:C0036421 (PSS)
 10,989 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Scleroderma is a complex disease characterized by activation of the immune system, small-vessel vasculopathy, and fibrosis of the skin and other organs. This review is limited to the discussion of scleroderma fibroblast biology and the cellular and molecular mechanisms that contribute to the abnormal deposition of collagen. Selected aspects of abnormal extracellular matrix (ECM) regulation by scleroderma fibroblasts are critically reviewed. These include the role of transforming growth factor-beta (TGF-beta) and connective tissue growth factor (CTGF) and their receptors in the fibrotic process in scleroderma and the overview of the transcription factors involved in regulation of the human alpha2 (I) collagen (COL1A2) gene.
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PMID:Molecular aspects of scleroderma. 1186 Dec 21

Several distinct entities associated with dermal fibrosis can mimic scleroderma/systemic sclerosis. The list of scleroderma-like conditions or scleroderma variants includes eosinophilic fasciitis, localized forms of scleroderma, scleredema and scleromyxedema, keloids, and environmental exposure-associated conditions including eosinophilia-myalgia syndrome and pseudosclerodermas induced by various drugs. Although these conditions are relatively uncommon, their accurate recognition is essential to avoid misdiagnosis and inappropriate therapy. The pathogenesis of these scleroderma variants appears to share similarities with each other and with that of scleroderma. Better understanding of scleroderma-like disorders is emerging through epidemiologic investigations, and in vivo and in vitro experimental research. Activation of eosinophils and disordered regulation of fibroblast collagen synthesis, apoptosis, and proliferation are recurrent findings in these disorders. The etiologic role of infection with Borrelia species or other microorganisms remains controversial. Cytokines such as transforming growth factor-beta, interleukin-4, interleukin-13, and connective tissue growth factor contribute to fibrosis in these disorders by inducing an accentuated and persistent fibrogenic response to tissue injury. The role of genetic factors in susceptibility and clinical expression of scleroderma-like conditions remains to be systematically addressed. Because of the relative rarity of these conditions, few well-controlled clinical treatment trials have been performed. In addition, there is no consensus on optimal management. Much anecdotal information and small clinical series indicate that phototherapy may have a role in the treatment of scleroderma-like conditions.
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PMID:Scleroderma-like cutaneous syndromes. 1189 Aug 76

We conducted this study to analyze endothelial cell function within intact thoracic aorta of the systemic sclerosis murine model, the heterozygous tight-skin mice 1: (i) assessing the distribution and activation intensity of endothelial cells, responsive to endothelium-dependent vasodilators (acetylcholine, adenosine triphosphate, bradykinin, and substance P) and Iloprost, using laser line confocal microscopy in combination with two Ca2+ fluorescent dyes; (ii) evaluating en-dothelium-dependent vasodilator- and Iloprostinduced relaxation, using isometric tension measurement; and (iii) investigating the role of nitric oxide in mediating relaxation to acetylcholine and adenosine triphosphate. The number of activated endothelial cells was significantly lower in heterozygous tight-skin mice 1, compared with controls, for adenosine triphosphate and Iloprost. Maximal increase of Ca2+ fluorescence intensity ratio in activated endothelial cells was decreased for adenosine triphosphate, bradykinin, and Iloprost, in heterozygous tight-skin mice 1. Adenosine triphosphate- and Iloprost-mediated aortic relaxation was further impaired in heterozygous tight-skin mice 1. Finally, aortic relaxation to acetylcholine and adenosine triphosphate was markedly decreased by nitric oxide synthase inhibitor in heterozygous tight-skin mice 1. This study suggests that endothelial cell receptors for endothelium-dependent vasodilators and Iloprost may not be homogeneously distributed or continuously expressed in thoracic aorta of heterozygous tight-skin mice 1, resulting in endothelium-dependent vasodilatation dysfunction. Moreover, because endothelium-dependent relaxation was highly dependent on nitric oxide release in heterozygous tight-skin mice 1, endothelium-dependent relaxation may differ from that of controls by increased production of nitric oxide. In turn, in heterozygous tight-skin mice 1, the resulting elevated nitric oxide levels may contribute to nitric oxide-mediated free radical endothelial cytotoxicity, although endothelium impairment may be related to other factors, particularly: Fbn-1 gene mutation and transforming growth factor-beta.
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PMID:Endothelial dysfunction in murine model of systemic sclerosis: tight-skin mice 1. 1248 43

A 65-year-old female began experiencing arthralgia, morning stiffness and psychroesthesia in April 2000. She visited a rheumatologist and was suspected of having early-stage rheumatoid arthritis. She was referred to our hospital, and was admitted in December 2000. At that time, sclerosis of the skin was advanced, and Raynaud's phenomenon was confirmed. The patient also exhibited nailfold bleeding, and was diagnosed as having systemic scleroderma. She visited a gynecologist for screening and cervical uteri carcinoma was confirmed. She underwent surgery in March 2001, and subsequently, sclerosis in her skin was almost stopped. We believe that these clinical symptoms were related to paraneoplastic syndrome. We therefore immunochemically investigated the pathogenesis of paraneoplastic syndrome and found that connective tissue growth factor (CTGF) might be involved and transforming growth factor-beta (TGF-beta) might not be involved in this case.
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PMID:[A case of pseudoscleroderma as paraneoplastic syndrome due to carcinoma of cervical uteri]. 1463 3

Acute and chronic renal diseases remain common complications of systemic sclerosis. Although treatment for acute scleroderma renal crisis may arrest the rapid progression of renal disease, many patients develop persistent renal dysfunction. Based on recent insights gained from progressive renal diseases of diverse etiologies, novel approaches to understanding the pathobiology of scleroderma renal disease may be applicable. Key factors involved in progression of renal disease include accumulation of extracellular matrix in the glomerular and tubulointerstitial compartments, epithelial to mesenchymal transformation, and vascular changes. The relevant factors mediating these events include the renin-angiotensin system, the profibrotic growth factors, transforming growth factor-beta and connective tissue growth factor, and reactive oxygen species. Much of the molecular details of the role of these factors have been revealed and promise to alter the practice of therapy of progressive renal disease.
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PMID:The pathogenesis of fibrosis and renal disease in scleroderma: recent insights from glomerulosclerosis. 1501 45

We sought to determine whether the spontaneous production of transforming growth factor-beta (TGF-beta) by peripheral blood mononuclear cells (PBMC) is increased in patients with systemic sclerosis (SSc). Culture supernatants of PBMC from SSc patients (n = 88) and healthy controls (n = 44) were analyzed by enzyme-linked immunosorbent assay. The production of active TGF-beta1 and total (active and latent) TGF-beta1 by PBMC from patients with limited cutaneous SSc (lSSc) and by PBMC from patients with diffuse cutaneous SSc (dSSc) was significantly elevated compared to the production by PBMC from normal controls. Production of active TGF-beta1 by dSSc PBMC was higher than that by lSSc PBMC, although not significantly. Patients with PBMC with increased active or total TGF-beta1 production showed significantly shorter disease duration than patients with PBMC with normal production levels. PBMC from patients without anticentromere antibody showed enhanced active TGF-beta1 production more frequently than those from patients with anticentromere antibody. PBMC from SSc patients more frequently showed enhanced total TGF-beta2 production than PBMC from normal controls. Among each leukocyte subset, spontaneous production of total TGF-beta1 was significantly higher in cultured peripheral monocytes/macrophages, but not in T cells, B cells, or NK cells, from patients than from normal controls. Thus, the enhanced production of TGF-beta by PBMC may contribute to the disease process in SSc
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PMID:Augmented production of transforming growth factor-beta by cultured peripheral blood mononuclear cells from patients with systemic sclerosis. 1513 94

Skin fibrotic disorders such as systemic sclerosis (SSc) are characterized by an excessive production of extracellular matrix (ECM) and understood to develop under the influence of certain growth factors. Connective tissue growth factor (CTGF) is a cysteine-rich mitogenic peptide that is implicated in various fibrotic disorders and induced in fibroblasts after activation with transforming growth factor-beta (TGF-beta). To better understand the mechanisms of persistent fibrosis seen in SSc, we previously established an animal model of skin fibrosis induced by exogenous application of growth factors. In this model, TGF-beta transiently induced subcutaneous fibrosis and serial injections of CTGF after TGF-beta caused persistent fibrosis. To further define the mechanisms of skin fibrosis induced by TGF-beta and CTGF in vivo, we investigated in this study, the effects of growth factors on the promoter activity of the proalpha2 (I) collagen (COL1A2) gene in skin fibrosis. For this purpose, we utilized transgenic reporter mice harboring the -17 kb promoter sequence of the mouse COL1A2 linked to either a firefly luciferase gene or a bacterial beta-galactosidase gene. Serial injections of CTGF after TGF-beta resulted in a sustained elevation of COL1A2 mRNA expression and promoter activity compared with consecutive injection of TGF-beta alone on day 8. We also demonstrated that the number of fibroblasts with activated COL1A2 transcription was increased by serial injections of CTGF after TGF-beta in comparison with the injection of TGF-beta alone. Furthermore, the serial injections recruited mast cells and macrophages. The number of mast cells reached a maximum on day 4 and remained relatively high up to day 8. In contrast to the kinetics of mast cells, the number of macrophages was increased on day 4 and continued to rise during the subsequent consecutive CTGF injections until day 8. These results suggested that CTGF maintains TGF-beta-induced skin fibrosis by sustaining COL1A2 promoter activation and increasing the number of activated fibroblasts. The infiltrated mast cells and macrophages may also contribute to the maintenance of fibrosis.
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PMID:Connective tissue growth factor causes persistent proalpha2(I) collagen gene expression induced by transforming growth factor-beta in a mouse fibrosis model. 1560 79

Systemic sclerosis (SSc) is characterized by autoimmunity and tissue fibrosis. There is a close association between specific autoantibodies and clinical features in patients with SSc. A number of studies have demonstrated that various cytokines, such as transforming growth factor-beta, modulate the synthesis of extracellular matrix by fibroblasts. However, it is not clear as to how autoimmunity and tissue fibrosis interact with each other. Recent studies have revealed that B cells play a critical role in various systemic autoimmune disorders. CD19 is a central regulator of B cell signaling threshold, and B cells from SSc patients exhibit an increased expression of CD19 that induces SSc-specific autoantibody production in transgenic mice. Furthermore, SSc patients have intrinsic B cell abnormalities characterized by decreased but activated memory B cells, which is possibly due to CD19 overexpression. Similarly, B cells from a tight-skin mouse, a model of SSc, show augmented CD19 signaling and chronic B cell activation. Remarkably, CD19 loss results in inhibition of chronic B cell hyper-reactivity and elimination of autoantibody production, which is associated with improvement in skin fibrosis and a parallel decrease in IL-6 production by B cells. Therefore, augmented cytokine production by B cells is a potential candidate for the induction of skin sclerosis. Alternatively, B cells may influence tissue fibrosis by regulating T cell activation and cytokine production through their antigen-presenting and co-stimulatory abilities. Thus, altered B cell function may result in tissue fibrosis, as well as autoimmunity, in SSc.
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PMID:Pathogenesis of systemic sclerosis: altered B cell function is the key linking systemic autoimmunity and tissue fibrosis. 1588 84

Systemic sclerosis (SSc) is characterized by extensive fibrosis, vasculopathy and activation of the immune system. Fibrosis can be caused by profibrotic cytokines, such as transforming growth factor-beta (TGFbeta), interleukin-4 (IL-4), platelet-derived growth factor (PDGF), and connective tissue growth factor. Vasculopathy can be caused by TGFbeta, PDGF, while paucity of vessels in skin lesions can be attributed to anti-endothelial cell autoantibodies. Recent studies have suggested that the activation of the immune system is of paramount importance in the pathogenesis of SSc. T Cells are activated by antigen, infiltrate early the skin lesions in SSc, and produce the profibrotic cytokine IL-4. They are also required for autoantibody production. B cells may contribute to fibrosis, as deficiency of CD19, a B cell transduction molecule, results in decreased fibrosis in animal models of fibrosis. These new developments have direct impact on the treatment of SSc. Medications directed against immune cells or harmful soluble factors in small trials in SSc are encouraging.
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PMID:New developments in the pathogenesis of systemic sclerosis. 1604 Mar 30

Since trunk skin (or non-palmoplantar skin) is less durable under mechanical stress than sole skin (palm, plantar or palmoplantar skin), conventional trunk-derived skin grafts (including the trunk dermis) commonly result in erosion and ulceration when transplanted on to plantar wounds caused by various injuries including, diabetes mellitus or collagen diseases (including systemic sclerosis, polyarthritis nodosa and rheumatoid arthritis). However, trunk-derived epidermis can adopt a plantar phenotype, characterized by keratin 9 expression, hypopigmentation and thick suprabasal layers, through factors derived from plantar dermal fibroblasts in the wounds. Thus, intractable plantar wounds with exposed bones can be treated with the combination of bone marrow exposure, occlusive dressing and epidermal grafting. The higher expression of dickkopf 1 (DKK1), an inhibitor of canonical Wnt/beta-catenin signals, in the plantar dermis partly explains these phenomena. Thus, mesenchymal-epithelial interactions play important roles not only in embryogenesis (the embryonic development) but also in maintaining the homeostasis of adult tissue. The topographical (site-specific) interactions of growth factors and substances, including DKKs, fibroblast growth factors (FGFs) and transforming growth factor-beta (TGF-beta) family proteins including bone morphogenetic proteins (BMPs), may explain the site-specific differences in the skin in addition to the expression patterns of HOX genes and sonic hedgehogs (Shhs). We review the importance of dermal-epidermal interactions in tissue homeostasis and regeneration, especially in palms and soles.
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PMID:Mesenchymal-epithelial interactions in the skin: aiming for site-specific tissue regeneration. 1615 76


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