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

To assess potential abnormalities in collagen metabolism in systemic scleroderma, skin fibroblast lines from patients with this disease were established and compared to control cell lines derived from healthy subjects. For studies on the biosynthesis of procollagen, the cells were incubated with [(14)C]proline in a medium supplemented with ascorbic acid and beta-aminopropionitrile, and the synthesis of nondialyzable [(14)C]hydroxyproline, in relation to DNA or cell protein, was taken as an index of procollagen formation. Five of eight scleroderma fibroblast cell lines demonstrated procollagen biosynthesis rates significantly higher than the controls, and the mean rate of procollagen synthesis by scleroderma fibroblasts was about twice that of the control cells. Control experiments demonstrated that the specific activity of the intracellular free proline was not different in scleroderma and control fibroblasts, and the mean population doubling times of the scleroderma and the control fibroblast cell lines were the same. The relative synthesis of the genetically distinct procollagens was examined by isolating type I and type III procollagens from the cell culture medium using DEAE-cellulose chromatography. The ratios of type I/III procollagens in scleroderma cell lines did not differ from the controls. The helical stability of the collagenous portion of type I and type III procollagens, estimated by the resistance of (14)C-collagen to limited proteolytic digestion with pepsin under nondenaturing conditions, was the same in both scleroderma and control cultures. The capacity of the cells to synthesize enzymatically active and immunologically reacting collagenase was also studied; no marked differences in these parameters could be observed. The results suggest that cultured skin fibroblasts from patients with scleroderma demonstrate a metabolic abnormality expressed as increased synthesis of type I and type III procollagens in a normal ratio. This abnormality may play a role in the excessive accumulation of collagen in the skin and other organs affected in scleroderma.
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PMID:Scleroderma: increased biosynthesis of triple-helical type I and type III procollagens associated with unaltered expression of collagenase by skin fibroblasts in culture. 9 59

Collagenase activity was measured by direct assay in skins from 12 patients afflicted with systemic sclerosis. In seven of those cases where extensive involvement of the forearm and trunk skin existed, collagenase activity of the involved skin was minimal or absent. Moreover, in the same patient, regions of marked skin involvement (e.g., forearm) showed no collagenase activity, when clinically uninvolved areas (thigh) exhibited normal or nearly normal levels of enzyme activity. In other patients where clinical symptoms were systemic and not associated significantly with the skin, collagenase activity approximated normal levels. Measurements of collagenase activity and tensile strength in another condition (basal cell carcinoma) that includes changes in mechanical properties of skin that any be regarded as the opposite end of the spectrum from those of sclerodermatous skin support a general correlation between collagenase activity and tensile strength. These studies indicate that the major defect responsible for the hidebound skin lesions of scleroderma may be decreased collagenase activity.
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PMID:Collagenase in scleroderma. 17 Dec 82

Lymphokine-rich supernates from normal human peripheral blood mononuclear cells, stimulated by the mitogen phytohemagglutinin, have been shown to cause enhanced collagen accumulation by human embryonic lung fibroblasts (WI-38), as measured by hydroxyproline content of fibroblast monolayers, [14C] proline incorporation into soluble collagen and collagenase release of radioactivity in supernates and monolayers of cultures incubated with [14C] proline. This fibroblast-stimulating activity, demonstrable by suitable dilutions of the supernates, coexisted with a number of other lymphokine activities such as lymphotoxin, proliferation inhibitory factor, and cloning inhibitory factor, which tend to reduce the numbers of function of fibroblasts. The increased content of collagen appeared to be the product of selected surviving and responding fibroblasts. The factor causing this increased collagen accumulation was nondialyzable and stable at -70 degrees C. It represents the first described lymphoid cell-derived activity capable of enhancing collagen accumulation. Fibroblast-stimulating activity may be implicated in the abnormal fibrosis seen in association with chronic inflammation in a variety of disease states. It may have special relevance to progressive systemic sclerosis.
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PMID:Lymphokine stimulation of collagen accumulation. 93 8

Owing to the wide variety of symptoms, the long clinical course, the inadequate knowledge of the points at which therapeutic action is appropriate and the difficulty of obtaining objective measurements of the treatment results, therapy for systemic sclerosis has to be planned individually. Besides basic recommendations (avoidance of noxious substances, sensible diet, keeping warm, active exercises), physiotherapy and psychological guidance, the therapy is directed at three pathogenetic complexes. Among the vasoactive substances the prostacyclins, calcium channel blockers and angiotensin-converting-enzyme inhibitors (in the case of complicated renal involvement) are recommended. They inhibit the thrombocyte hyperaggregation and lead to vasodilatation. The anti-inflammatory substances prednisolone and azathioprine also exert immunosuppressant (and cytotoxic) effect. Their use is indicated in inflammatory, immunologically active forms of systemic sclerosis. Antifibrotic agents inhibit cross-link formation, prolylhydroxylase, extrusion of collagen from fibroblasts and, thus, collagen synthesis. In addition, they favour the degradation of collagen via the activation of collagenase. Good results have been reported with penicillamine and penicillin G. Pentoxyphyllin leads to vasodilatation and also inhibits collagen metabolism. Promising agents and procedures for future use include cyclosporin A, CD4 antibodies, photopheresis, interferon gamma and factor XIII. A critical attitude to therapy and a great deal of patience are necessary to avoid harming the patients, especially as it is often some months before any effects of the treatment are seen.
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PMID:[Current status and trends in treatment of scleroderma]. 138 Apr 94

Extracorporeal photopheresis (ExP) has been shown to be an efficacious and well-tolerated therapy in the treatment of cutaneous T-cell lymphoma (CTCL) and systemic sclerosis. However, the precise mechanisms of its action have not been defined. Because of a correlation between the development of fever in the early phase of treatment of CTCL and subsequent anti-tumor responses, we examined the production of the proinflammatory, pyrogenic cytokines tumor necrosis factor-alpha (TNF), IL-6, IL-1 alpha, and IL-1 beta before and after ExP. Monocytes were purified from peripheral blood specimens of normal volunteers (n = 4) or from peripheral blood specimens of CTCL (n = 6) or systemic sclerosis (n = 3) patients that were obtained immediately prior to ExP and also directly from the photopheresis unit after ExP, just prior to reinfusion into the patient. Monocytes were then cultured under various conditions for 16 h, after which the culture supernatants were collected and assayed for specific cytokine production. ExP induced a significant increase in the production of TNF (p less than 0.008) and IL-6 (p less than 0.05) as compared to non-ExP-treated cells, whereas no significant differences were observed in IL-1 alpha (p less than 0.5) and IL-1 beta (p less than 0.2) production following ExP. Exposure of monocyte cultures to IFN-gamma (100 U/mL) either before or after ExP further enhanced TNF production by 4 to 28 times. In contrast, incubation with IFN-alpha (100 U/mL) had no significant effect on TNF production. Addition of TNF (500 U/ml) to monocyte cultures obtained prior to ExP resulted in a slight but insignificant increase in TNF production in 2 of 10 cases. However, when monocytes obtained prior to ExP were incubated with 8-methoxypsoralen (8-MOP, 100 ng/ml), exposed to ultraviolet light A (UVA, 2J/cm2), washed, and then incubated with TNF, a significant increase (p less than 0.01) in TNF production was observed in 8 of 10 cases, suggesting that the combination of 8-MOP and UVA may sensitize cells to TNF. Based on studies of endotoxin (LPS)-stimulated production of TNF by monocytes, levels of endotoxin in culture reagents or photopheresis equipment could not account for the increased production of TNF following treatment by ExP. Increased TNF production as a result of ExP may have important implications for treating both CTCL and systemic sclerosis because, in the case of CTCL, it could mediate numerous anti-tumor effects, whereas, in the case of systemic sclerosis, it could suppress collagen synthesis and induce collagenase production.
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PMID:Extracorporeal photochemotherapy induces the production of tumor necrosis factor-alpha by monocytes: implications for the treatment of cutaneous T-cell lymphoma and systemic sclerosis. 156 19

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.
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PMID:Steady-state mRNA levels of collagens I, III, fibronectin, and collagenase in skin biopsies of systemic sclerosis patients. 164 27

Clones of dermal fibroblasts from the skin of 4 normal subjects and 5 patients with progressive systemic sclerosis (PSS; scleroderma) were established, and their synthetic and proliferative characteristics were compared. A limiting-dilution assay was used to determine frequencies of cloning in the microcultures of dermal fibroblasts plated. The clones derived from single cells were expanded in vitro and examined (in passages C-H) for growth and synthesis of glycosaminoglycan (GAG) and collagenase-sensitive protein (CSP). The clonogenicity of PSS fibroblasts was not significantly different from that of normal fibroblasts. Normal fibroblast clones were characterized by low levels of GAG and CSP synthesis, and there was a correlation between the GAG and CSP phenotypes. In contrast, clones of PSS fibroblasts were often, but not always, high producers of GAG and CSP, but there was no correlation between the levels of GAG and CSP synthesis. It appears that scleroderma skin is composed of fibroblast clones that are unable to regulate the synthesis of connective tissue components and often synthesize large amounts of connective tissue macromolecules.
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PMID:Heterogeneous synthetic phenotype of cloned scleroderma fibroblasts may be due to aberrant regulation in the synthesis of connective tissues. 284 98

Collagen production and collagenase activity were measured in dermal fibroblast cultures obtained from eight patients with diabetes with digital sclerosis and three normal controls. Total collagen synthesis in patients with diabetes was reduced in comparison with controls. DNA replication was also reduced in patients with diabetes. No differences in collagenase activity were noted. Our results suggest that, in contrast to systemic sclerosis, increased synthesis does not contribute to the collagen accumulation of diabetic digital sclerosis. Decreased degradation related to nonenzymatic glucosylation of collagen is a more likely mechanism.
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PMID:Collagen synthesis and collagenase activity in dermal fibroblasts from patients with diabetes and digital sclerosis. 298 79

Lung involvement (LI) was studied by lung function (LF) in 101 scleroderma patients (circumscribed scleroderma, n = 17; progressive systemic scleroderma [PSS], n = 84; with the subtypes I, acroscleroderma [n = 19]; 2, proximal ascending scleroderma [n = 61]; 3, trunk scleroderma [n = 4]). Eighteen percent of morphea, 32 percent of type 1, 56 percent of type 2, and 75 percent of type 3 patients had impaired LF. The LI was more frequent (57 percent vs 45 percent) and more severe (20 percent vs 3 percent) in PSS with systemic inflammation (form A) compared to those without (form B). Elevated lymphocytes/neutrophils in bronchoalveolar lavage (BAL) were found associated with form A and severe LI. The LF of patients showing an inflammatory cell pattern in initial BAL (n = 3) worsened, whereas those with normal BAL findings (n = 4) did not. Collagenase activity in BAL was significantly elevated in those with elevated lymphocytes/neutrophils in lavage. Patients with type 2 or 3 of PSS, especially form A, carry a higher risk of developing severe LI than circumscribed scleroderma, type 1, or form B patients. Differential cell count and collagenase activity in BAL is correlated with active disease and provides prognostic information.
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PMID:Lung involvement in scleroderma. 632 Nov 13

Various dermal fibrotic conditions, such as progressive systemic sclerosis, localized morphea and familial cutaneous collagenoma, are characterized by excessive deposition of collagen in the skin. In the present study, we examined the possibility that a circulating serum factor(s) is responsible for increased collagen production in these diseases. The effects of human serum on the synthesis of procollagen were examined by incubating normal human dermal fibroblasts with [3H]proline and varying concentrations of dialyzed heat-inactivated serum. The synthesis of procollagen was measured as formation of nondialyzable [3H]hydroxyproline and collagenase-digestible 3H]polypeptides. In the absence of serum little procollagen was formed but the synthesis was markedly stimulated by the addition of normal serum in a concentration-dependent manner. THe ratio of genetically distinct 3H-procollagens of type I and type III, assayed by DEAE-cellulose chromatography and SDS-polyacrylamide gel electrophoresis after limited pepsin proteolysis, was unaffected by the addition of serum. Thus, normal human serum contains a nondialyzable factor(s) which stimulates the synthesis of procollagens type I and type III equally. Sera from 5 patients with progressive systemic sclerosis, 3 with localized scleroderma, and 2 with familial cutaneous collagenoma were also tested. Sera from these patients failed to stimulate 3H-procollagen production more than sera from healthy age-matched controls. Therefore, no increased quantities or qualitatively aberrant factors were shown to be present in the sera of these patients.
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PMID:Human skin fibroblasts in culture: procollagen synthesis in the presence of sera from normal human subjects and from patients with dermal fibroses. 724 Jul 93


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