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)

Scleroderma is a fibrotic disease occurring in a localized or systemic form. The pathogenesis of scleroderma remains poorly understood. Recent studies revealed that various cytokines and growth factors were involved in the development of scleroderma fibrosis. Platelet-derived growth factor (PDGF) is a potent growth factor for mesenchymal cells, especially fibroblasts. It can promote fibroblasts proliferation, enhance extracellular matrix synthesis. It is also a chemoattractant to fibroblasts. To better understand the role of PDGF in pathogenesis of scleroderma, we performed both in vivo studies on the expression of PDGF beta-receptor protein in scleroderma tissue and in vitro studies on the expression of PDGF B-chain and PDGF beta-receptor mRNA in cultured fibroblasts derived from both lesions of scleroderma and normal skin. Immunohistochemistry staining showed that PDGF beta-receptor expression was greatly elevated in the dermis of scleroderma lesion whereas PDGF beta-receptor were expressed at low levels in normal skin. Northern blot analysis showed that cultured fibroblasts from scleroderma had higher expression of PDGF B-chain and PDGF beta-receptor mRNA than those from normal control. Two PDGF B-chain mRNA transcripts, 2.8 and 4.0 kb, were expressed. The 2.8 kb transcripts which had more efficient translation ability was the more predominantly expressed one. These results indicate that PDGF B-chain/PDGF beta-receptor signal pathway might be involved in the development of fibrosis in scleroderma, and that the 2.8 kb PDGF B-chain mRNA transcript may be the main modulation gene.
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PMID:Expression of platelet-derived growth factor B-chain and platelet-derived growth factor beta-receptor in fibroblasts of scleroderma. 983 75

1. Changes in the environmental oxygen tension to which cells are exposed in vivo result in physiological and sometimes pathological consequences that are associated with differential expression of specific genes. 2. Low oxygen tension (hypoxia) affects endothelial cellular physiology in vivo and in vitro in a number of ways, including the transcriptionally regulated expression of vasoactive substances and matrix proteins involved in modulating vascular tone or remodelling the vasculature and surrounding tissue. 3. Hypoxia results in the transcriptional induction of genes encoding vasoconstrictors and smooth muscle mitogens (PDGF-B, endothelin-1, VEGF, thrombospondin-1) and genes encoding matrix or remodelling molecules (collagenase IV (MMP-9), thrombospondin-1) and reciprocal transcriptional inhibition of vasodilatory or anti-mitogenic effectors (eNOS). 4. Oxygen appears to signal through a novel haem-containing sensor and signals initiated by this sensor alter the levels and DNA-binding activity of transcription factors such as activating protein (AP)-1, nuclear factor-kappa B and hypoxia-inducible transcription factor-1. 5. The genes encoding vasoactive factors regulated by oxygen tension are themselves also regulated by the vasoactive agent nitric oxide (NO). 6. Nitric oxide and oxygen transduce similar signals (i.e. their absence results in identical patterns of gene expression in endothelial cells and other cell types). 7. Thus, NO can feedback on and modulate signals induced by hypoxia and vice versa. For example, NO, which can act directly on smooth muscle cells as a vasodilator, can also facilitate vasodilation indirectly by reversing the production of vasoconstrictors induced by hypoxia. 8. Short-term exposure of endothelial cells to low oxygen tension results in the elaboration of predominantly vasoconstricting effectors, while longer-term and more severe hypoxic exposure generates factors that can induce smooth muscle proliferation and remodelling. 9. Thus, the endothelial cell response to hypoxic stress can result in two different consequences in the surrounding tissues, depending on the duration of the exposure: short-term exposure causes physiological and reversible modulation of vascular tone and blood flow; chronic hypoxic stress results in irreversible remodelling of the vasculature and surrounding tissues, with smooth muscle proliferation and fibrosis. 10. This dichotomy of responses to hypoxia may explain, in part, both the acute and chronic pathophysiological sequelae of diseases characterized by regional hypoxia, including atherosclerosis, pulmonary hypertension, sickle cell disease and systemic sclerosis (scleroderma).
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PMID:Endothelial cell responses to hypoxic stress. 1090 94

Systemic sclerosis (SSc) is a connective tissue disease with unknown etiology characterized by excessive deposition of collagen in the skin as well as various internal organs. One of the characteristic histological features is the presence of infiltrating mononuclear cells in the dermis in its early stage. As well as T cells, macrophages are implicated to play an important role in the initial pathologic changes associated with SSc by releasing fibrogenic cytokines, including transforming growth factor-beta or platelet-derived growth factor. However, the precise mechanism for increased monocyte/macrophage recruitment in the lesional skin of SSc is still not completely elucidated. Monocyte chemoattractant protein-1 (MCP-1) is a predominant monocyte chemoattractant secreted by various cells types including mononuclear cells, fibroblasts, smooth muscle cells, endothelial cells, or keratinocytes. In this study, we examined the expression of MCP-1 protein and mRNA in the lesional skin of seven patients with SSc by immunohistochemistry and in situ hybridization. Results of immunohistochemistry showed that MCP-1 was detected on infiltrating mononuclear cells and fibroblastic cells in scleroderma skin, whereas normal skin showed only minimal MCP-1 expression. We demonstrated the expression of MCP-1 mRNA in infiltrating mononuclear cells and keratinocytes in scleroderma and contact dermatitis skin. In addition, signals were also detected in fibroblasts in the lesional skin of scleroderma, whereas fibroblasts in normal skin and contact dermatitis skin did not express MCP-1 mRNA. These findings suggest that MCP-1 plays a role in recruiting monocyte/macrophages in the lesional skin of scleroderma and that activated fibroblasts in scleroderma are involved in this process.
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PMID:Expression of monocyte chemoattractant protein-1 in the lesional skin of systemic sclerosis. 1137 30

Skin ulcers can be very painful and detrimental in patients with systemic sclerosis, or systemic scleroderma. A brief review of scleroderma skin ulcers is presented, as well as a case study that demonstrates the effectiveness of becaplermin gel supplemented by oral immunosuppressive agents in the treatment of ulcers resulting from systemic sclerosis. The time to healing (approximately 3 months) was comparable to that associated with the oral agents and surgical interventions specifically designed to help heal scleroderma ulcers. Except for incisional biopsy, no surgical procedures were performed.
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PMID:Treatment of scleroderma skin ulcers using becaplermin gel and hydrocolloid membrane. 1207 Feb 35

Idiopathic pulmonary fibrosis (IPF) is a lung disease that is characterized by epithelial cell damage and areas of denuded basement membrane resulting in inflammation, fibroblast proliferation, excessive extracellular matrix (ECM) deposition, and remodeling of alveolar gas exchange units. The progressive loss of lung gas exchange units in patients with IPF leads to respiratory failure and eventually to death. While the etiology of this disease is unknown, for many years studies suggested that chronic inflammation was the underlying factor that caused fibroproliferation and structural alterations of the lung. Recent data show that fibroproliferation and fibrosis can occur independently of inflammation, suggesting that IPF is a disease caused by a mesenchymal, rather than an immune disorder. Mesenchymal growth factors, including transforming growth factor (TGF)-beta, insulin-like growth factor (IGF)-I, platelet-derived growth factor, connective tissue growth factor, fibroblast growth factors, and keratinocyte growth factors, as well as proinflammatory cytokines such as tumor necrosis factor-alpha and interleukin-1beta, have been shown to be exaggerated in several fibrotic lung disorders including IPF, ARDS, sarcoidosis, and bronchopulmonary dysplasia, as well as pulmonary manifestations of systemic diseases such as rheumatoid arthritis or progressive systemic sclerosis (scleroderma). We argue that inflammation is required to initiate growth factor production and repair of the damaged alveolar epithelial lining in fibrotic lung diseases and that exaggerated TGF-beta production may be responsible for the fibrotic response seen in diseases such as IPF. We recognize the potential role of several growth factors in the fibroproliferative process in the lung, and in this brief report we focus on the possible roles of the growth factors IGF-I and TGF-beta in cell migration, proliferation, and ECM synthesis in patients with IPF.
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PMID:Roles for insulin-like growth factor I and transforming growth factor-beta in fibrotic lung disease. 1247 2

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

The levels of Ras proteins in human primary fibroblasts are regulated by PDGF (platelet-derived growth factor). PDGF induced post-transcriptionally Ha-Ras by stimulating reactive oxygen species (ROS) and ERK1/2. Activation of ERK1/2 and high ROS levels stabilize Ha-Ras protein, by inhibiting proteasomal degradation. We found a remarkable example in vivo of amplification of this circuitry in fibroblasts derived from systemic sclerosis (scleroderma) lesions, producing vast excess of ROS and undergoing rapid senescence. High ROS, Ha-Ras, and active ERK1/2 stimulated collagen synthesis, DNA damage, and accelerated senescence. Conversely ROS or Ras inhibition interrupted the signaling cascade and restored the normal phenotype. We conclude that in primary fibroblasts stabilization of Ras protein by ROS and ERK1/2 amplifies the response of the cells to growth factors and in systemic sclerosis represents a critical factor in the onset and progression of the disease.
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PMID:Platelet-derived growth factor and reactive oxygen species (ROS) regulate Ras protein levels in primary human fibroblasts via ERK1/2. Amplification of ROS and Ras in systemic sclerosis fibroblasts. 1608 26

Extensive chronic graft-versus-host disease (ecGVHD) is characterized by fibrosis similar to that of patients with systemic sclerosis (scleroderma). Since stimulatory autoantibodies against the platelet-derived growth factor (PDGF) receptor (PDGFR) have been found in patients with scleroderma and are responsible for the activation of skin fibroblasts, we tested the hypothesis that these autoantibodies are also present in patients affected by ecGVHD. Serum from 39 patients subjected to allogeneic stem cell transplantation for hematologic malignancies (22 with ecGVHD and 17 without cGVHD) and 20 healthy controls was assayed for the presence of stimulatory autoantibodies to the PDGFR by incubating purified IgG with mouse-embryo fibroblasts lacking PDGFR alpha or beta chains or with the same cells expressing PDGFR alpha. Stimulatory antibodies to the PDGFR were found selectively in all patients with ecGVHD but in none of the patients without cGVHD. Higher levels were detected in patients with generalized skin involvement and/or lung fibrosis. Antibodies recognized native PDGFR, induced tyrosine phosphorylation, accumulation of reactive oxygen species (ROS), and stimulated type 1 collagen gene expression through the Ha-Ras-ERK1/2-ROS signaling pathway. The biologic activity of these autoantibodies suggests a role in the development of fibrosis and argues for a common pathogenetic trait in ecGVDH and scleroderma phenotypes.
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PMID:Stimulatory autoantibodies to PDGF receptor in patients with extensive chronic graft-versus-host disease. 1736 28

Abelson kinase (c-abl) and platelet-derived growth factor (PDGF) are key players in the pathogenesis of systemic sclerosis (SSc). The aim of the present study was to evaluate the antifibrotic potential of dasatinib and nilotinib, 2 novel inhibitors of c-abl and PDGF, which are well tolerated and have recently been approved. Dasatinib and nilotinib dose-dependently reduced the mRNA and protein levels of extracellular matrix proteins in human stimulated dermal fibroblasts from SSc patients (IC(50) of 0.5-2.0 nM for dasatinib and 0.8-2.5 nM for nilotinib). In a mouse model of bleomycin-induced dermal fibrosis, dasatinib and nilotinib potently reduced the dermal thickness, the number of myofibroblasts, and the collagen content of the skin in a dose-dependent manner at well-tolerated doses. These data indicate that dasatinib and nilotinib potently inhibit the synthesis of extracellular matrix in vitro and in vivo at biologically relevant concentrations. Thus, we provide the first evidence that dasatinib and nilotinib might be promising drugs for the treatment of patients with SSc.
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PMID:Dual inhibition of c-abl and PDGF receptor signaling by dasatinib and nilotinib for the treatment of dermal fibrosis. 1832 84

A patient with therapy-resistant and progressive systemic sclerosis (SSc) with pulmonary involvement who was treated with imatinib mesylate is described herein. Prior to treatment, pulmonary fibroblasts obtained from the patient were cultured and incubated with imatinib mesylate. Preincubation of the fibroblasts for 16 hours with 2.5 microg/ml imatinib mesylate efficiently abrogated platelet-derived growth factor BB-induced fibroblast proliferation. Furthermore, transforming growth factor beta1-induced type I collagen gene transcription was blocked. During treatment, the patient's pulmonary involvement stabilized and her skin tightness improved. To our knowledge, this is the first report of a patient with therapy-refractory SSc responding to treatment with imatinib mesylate.
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PMID:Is imatinib mesylate a promising drug in systemic sclerosis? 1866 75


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