Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0036421 (PSS)
 10,989 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The expression of tenascin, a recently discovered extracellular matrix protein, was studied by immunohistochemical techniques in scleroderma skin and compared with its distribution in normal skin. In progressive systemic sclerosis, a marked increase in tenascin content was observed in the superficial reticular dermis. In localized scleroderma, the deposition of tenascin was increased both in the superficial and deep dermis of involved skin, whereas in clinically uninvolved skin the distribution of tenascin was the same as in normal control skin, i.e. the papillary dermis and peri-appendiceal zone. The distribution of tenascin did not strictly parallel that of fibronectin. These findings and the current knowledge of tenascin biology suggest that the overproduction of tenascin in scleroderma dermis could be secondary to stimulation of fibroblasts by immune cell-derived cytokines, or could be due to abnormal fibroblasts, or a subpopulation of fibroblasts, producing high levels of this extracellular matrix protein.
 ...
PMID:Increased expression of tenascin in the dermis in scleroderma. 138 45

Scleroderma fibrotic lesions demonstrate vascular disease, mononuclear cell infiltrates, and increased collagen. Fibroblasts in these lesions are activated to synthesize increased extracellular matrix substances, a phenotype that continues when these cells are removed and grown in tissue culture. Levels of messenger RNA for connective-tissue substances, measured directly in biopsies of scleroderma skin, show increased message for type I collagen, but not type III collagen or fibronectin. Increased procollagen type I in scleroderma skin occurs in the papillary dermis, perivascular areas, and deep interstitium, even in skin areas that are not yet fibrotic. Scleroderma fibroblasts express more intercellular adhesion molecule 1 on their surfaces than do normal cells, and this molecule is increased in endothelial cells, mononuclear cells, and fibroblasts. In vitro scleroderma fibroblasts adhere more frequently to extracellular matrix substances and retract collagen lattices to a greater extent. Peripheral blood lymphocytes from scleroderma patients produce excessive amounts of interleukin-2 when incubated with type I collagen, and circulating basophils release more histamine than do normal cells. There is evidence for activated eosinophils both in the dermis and pulmonary lesions in scleroderma, which may play a role in fibrosis. Transforming growth factor-beta is overexpressed by alveolar macrophages from patients with fibrotic pulmonary disease. Scleroderma fibroblasts, when exposed to transforming growth factor-beta, overexpress the alpha-type receptor for platelet-derived growth factor. Scleroderma sera more frequently contain measurable quantities of interleukin-4, interleukin-6, and interleukin-2. Interleukin-4 causes adult dermal fibroblasts to proliferate and to make interleukin-6. Interleukin-6 has been shown to stimulate fibroblast synthesis of collagen and glycosaminoglycans.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Connective tissue metabolism including cytokines in scleroderma. 145 83

Total RNA was extracted from skin biopsies of nine patients suffering from systemic sclerosis (SSc). Steady-state mRNA levels of collagen alpha 1(I) and alpha 1(III), collagenase, fibronectin, and beta-actin were studied using specific cDNA probes and compared to those of 12 sex- and age-matched healthy individuals. There was a more than three-fold elevation of collagen I mRNA levels in SSc skin compared to controls. No difference was found, however, for collagen III, collagenase, and fibronectin mRNA levels in SSc and control biopsies. The selective increase of collagen alpha 1(I) mRNA levels indicates a specific alteration of fibroblast metabolism in scleroderma. Analysis of mRNA levels in skin biopsies might not only offer a direct approach to the understanding of the pathophysiology of SSc, but also facilitate the monitoring of fibrotic activity in SSc patients during therapeutic trials.
 ...
PMID:Steady-state mRNA levels of collagens I, III, fibronectin, and collagenase in skin biopsies of systemic sclerosis patients. 164 27

A characteristic feature of systemic scleroderma is fibrosis of the skin and eventually of internal organs resulting from an overproduction of collagen and other connective tissue components by the resident fibroblasts. The balance between the cells and the amount of the surrounding extracellular matrix is then altered. Because cellular metabolism depends to a large extent on cellular contacts and communications with connective tissue molecules, we have therefore investigated the interactions with extracellular matrix components of fibroblasts obtained from skin of patients affected with scleroderma. In comparison to fibroblasts from healthy skin, all fibroblasts from scleroderma patients had an increased adhesion capacity to collagens I, IV, VI, fibronectin, and laminin. In addition, whereas adhesion of control fibroblasts was stimulated by a pre-treatment with transforming growth factor-beta, adhesion patterns of scleroderma fibroblasts remained unchanged. However, pre-incubation of the cells with interferon-gamma decreased the adhesion of both scleroderma and control fibroblasts.
 ...
PMID:Increased adhesion of fibroblasts from patients with scleroderma to extracellular matrix components: in vitro modulation by IFN-gamma but not by TGF-beta. 172 42

Cytokines are soluble informational polypeptides which modulate cellular functions by combining with specific membrane receptors in the originating cell (autocrine), a regional cell (paracrine) or a distant cell (endocrine). Cytokine-receptor complexes usually initiate signal transduction via protein kinase phosphorylation or G-protein dependent phospholinositol changes which further alter cell function. In the exuberant fibrosis of scleroderma, fibroblasts are activated to secrete several extracellular matrix molecules (collagens, fibronectin, proteoglycans) and they also fail to respond to the usual cell growth signals in vitro. We have studied the hypothesis that cytokines released through the T-cell dependent activation/injury of the vascular and microvascular endothelium initiate activation of the scleroderma fibroblast. Recalling that cell activation can occur either by removal of suppression or direct activation and that the locus of action can be transcriptional, translational or post-translational or a combination of these, our studies have focused on the cytokine transforming growth factor beta (TGF-beta) family of molecules, on the matrix gene expression abnormality of the scleroderma fibroblast and on the activation by TGF-beta of the platelet derived growth factor (PDGF) family of cytokines to explain the persistent cell growth abnormality. Our findings include: 1. Scleroderma fibroblasts are equally responsive to TGF-beta as are healthy fibroblasts with regard to collagen synthesis and they bind TGF-beta in all parameters similar to the binding to healthy fibroblasts. 2. TGF-beta is a stronger mitogenic signal to scleroderma fibroblasts than to control fibroblasts in the presence of serum.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Cytokines and human fibrosis. 196 52

The administration of Factor XIII (FXIII) produces a beneficial effect on the skin lesions in about 50% of the treated patients with progressive systemic sclerosis (PSS). The effect of FXIII on various skin fibroblast functions (proliferation, attachment, biosynthetic activity and mechanical properties) was investigated in vitro using normal and PSS strains. In cell culture, most of the PSS fibroblast strains synthesized excessive amounts of collagen. Other cell functions such as adhesion to collagen I or III, to fibronectin, retraction of collagen lattices, proliferation in low serum concentration and degradation of newly synthesized collagen were not significantly different. The addition of FXIII (I U/ml) inhibited the synthesis of collagen by normal fibroblasts and reduced it in PSS fibroblasts to a level similar to that of normal fibroblasts. This effect was observed for cells cultured on plastic or in a collagen lattice. In the latter, an increased amount of collagen degradation was observed. No significant effect of FXIII on the other cell functions was noted. Excessive collagen production by PSS fibroblasts can be repressed by FXIII in vitro by at least two distinct mechanisms: a reduction of collagen synthesis and an increased degradation of the newly synthesized collagen.
 ...
PMID:Factor XIII in scleroderma: in vitro studies. 196 47

Recently, a mutant fibronectin gene was identified in skin fibroblasts obtained from sclerotic lesions of 7 Japanese patients with systemic sclerosis (SSc). Two point mutations were found adjacent to the cell-attachment tetrapeptide DNA sequence in exon 7 of the fibronectin gene. In the present study, we investigated whether these point mutations are present in the fibronectin gene of Dutch patients with SSc. We were unable to demonstrate the point mutations in the Dutch SSc patients studied.
 ...
PMID:The mutations in the fibronectin gene described in Japanese patients with systemic sclerosis are not present in Dutch patients. 201 28

To determine whether enhanced matrix synthesis by systemic sclerosis (SSc) fibroblasts in vitro is due to increased responsiveness to transforming growth factor-beta (TGF-beta), fibronectin release by SSc and normal fibroblasts (7 pairs) was measured at various concentrations of TGF-beta. In the absence of TGF-beta, SSc fibroblasts released 30 +/- 22% more fibronectin than normal fibroblasts. While both SSc and normal fibroblasts increased fibronectin release at all concentrations of TGF-beta tested, the percentage increases were not statistically greater for the SSc fibroblasts even though 4 of the SSc fibroblasts strains were selectively sensitive to low concentrations of TGF-beta. TGF-beta increased cell numbers of both SSc and normal strains equally. Our data confirm abnormal regulation of fibronectin gene expression in SSc fibroblasts and suggest increased sensitivity to TGF-beta by some SSc fibroblast strains.
 ...
PMID:Fibronectin release by systemic sclerosis and normal dermal fibroblasts in response to TGF-beta. 202 18

The cause of systemic sclerosis remains unknown, but cellular and molecular mechanisms possibly responsible for the characteristic clinical manifestations of fibrosis and vascular damage (Raynaud's phenomenon, telangiectasis, digital infection, and renal arteriopathy) are becoming understood in greater detail. One possibly important cytokine is transforming growth factor-beta (TGF-beta); its involvement is reviewed here. With regard to vascular lesions, TGF-beta has variably been shown to inhibit endothelial cell growth in vitro but to promote angiogenesis in vivo, a paradox that remains unresolved. Nonetheless, an injurious activity of TGF-beta on microvascular endothelial cells could help to explain the intimal proliferation and microvascular obliteration seen. Whether as a result of or as a cause of endothelial cell damage, platelet activation has been well documented in systemic sclerosis and the platelet alpha granule pool contains a large quantity of TGF-beta. TGF-beta is also produced by activated macrophages and T cells, both of which are known to occur within systemic sclerosis lesions. An important effect of TGF-beta is its stimulation of fibroblast collagen and fibronectin synthesis and their deposition into the extracellular matrix. Stimulation by TGF-beta may therefore account for the fibrosis seen in the dermis and in the internal organs. Direct evidence of TGF-beta involvement in systemic sclerosis is scanty, and awaits discovery of either an abnormal expression of or response to TGF-beta. The biologic effects of TGF-beta appear to be regulated at the level of activation from a latent polypeptide precursor form. Descriptions of the importance of this cytokine in pathologic conditions will need to account for this activation and its regulation. Nonetheless, the physiologic effects so far attributed to TGF-beta make its involvement in systemic sclerosis an attractive possibility to explain some of the manifestations of this enigmatic disease.
 ...
PMID:A possible role for transforming growth factor-beta in systemic sclerosis. 225 29

Progressive systemic sclerosis is characterized by extensive generalized fibrotic destruction associated with increased accumulation of collagen and other extracellular macromolecules in the skin and other involved organs. It has been suggested that mediators released from mononuclear or endothelial cells play a critical role in the initial activation of connective tissue metabolism. Transforming growth factors beta(TGF-beta 1, TGF-beta 2) mediate the inhibition of epithelial cell proliferation and the induction of fibronectin and collagen gene expression. Therefore, we investigated the distribution of both TGF-beta 1 and TGF-beta 2 mRNA and the final proteins in PSS skin in comparison with other inflammatory dermatoses and healthy controls by means of in situ hybridization and immunohistochemistry. Our studies revealed TGF-beta 1 and -beta 2 mRNA in dermal and subcutaneous infiltrating cells in both acute and chronic PSS, but also in the other inflammatory skin disorders. In the vicinity of this infiltrate single TGF-beta positive fibroblasts could be found in acute PSS. The cytoplasm of epithelial cells of all skin adnexa showed TGF-beta transcripts and no apparent differences were seen in the distribution and number of autoradiographic grains between diseased and healthy skin samples. Especially, we could demonstrate abundant expression of TGF-beta 1/2 in epithelial hair follicle cells of the outer root sheath. Generally, the expression of TGF-beta 2 was less abundant than TGF-beta 1. Immunohistochemical studies revealed the same distribution pattern of the final proteins. Our data indicate that TGF-beta expression in infiltrating cells is not a specific feature of fibrotic disease, but seems to be associated with highly proliferating cells in general, perhaps functioning as common mediator in regulation of cellular physiology with special importance for negative control of cell growth.
 ...
PMID:Transcription and expression of transforming growth factor type beta in the skin of progressive systemic sclerosis: a mediator of fibrosis? 229 95


1 2 3 4 5 6 7 Next >>