CD146 Antigen ; immunology ; Fibroblasts ; immunology ; pathology ; Humans ; Scleroderma, Systemic ; drug therapy ; immunology ; pathology

Female ; Humans ; Middle Aged ; Sarcoidosis ; diagnosis ; pathology ; Scleroderma, Systemic ; diagnosis ; pathology

OBJECTIVE: To investigate the expression of tumor-transforming gene-1 (PTTG1) in systemic sclerosis (SSc) and its role in fibrosis. METHODS: Skin biopsy samples were collected from 21 patients with SSc and 22 patients with healthy skin for detecting the mRNA and protein expressions of PTTG1 using real-time PCR (RT-PCR) and immunohistochemistry, respectively. In cultured primary human dermal fibroblasts, PTTG1 expression was knocked down via RNA interference (siRNA), and the mRNA expression levels of PTTG1 and the fibrosis-related genes RESULTS: Compared with those in normal skin samples, the mRNA and protein expressions of PTTG1 increased significantly in the skin tissue of patients with SSc ( CONCLUSIONS PTTG1 is highly expressed in skin tissues of patients with SSc, and PTTG1 knockdown can reduce the activity of the dermal fibroblasts, suggesting a close correlation of PTTG1 with fibrosis in SSc.
Cells, Cultured ; Fibroblasts ; Fibrosis ; Humans ; Scleroderma, Systemic/pathology* ; Securin ; Skin/pathology*

Actins ; metabolism ; Adult ; Amyloidosis ; pathology ; Diagnosis, Differential ; Female ; Humans ; Intestinal Pseudo-Obstruction ; metabolism ; pathology ; Lupus Erythematosus, Systemic ; pathology ; Muscular Atrophy ; pathology ; Scleroderma, Systemic ; pathology ; Young Adult

Lysophosphatidic acid (LPA) is a signaling lipid that binds to six known lysophosphatidic acid receptors (LPARs), named LPA1-LPA6. These receptors initiate signaling cascades relevant to development, maintenance, and healing processes throughout the body. The diversity and specificity of LPA signaling, especially in relation to cancer and autoimmune disorders, makes LPA receptor modulation an attractive target for drug development. Several LPAR-specific analogues and small molecules have been synthesized and are efficacious in attenuating pathology in disease models. To date, at least three compounds have passed phase I and phase II clinical trials for idiopathic pulmonary fibrosis and systemic sclerosis. This review focuses on the promising therapeutic directions emerging in LPA signaling toward ameliorating several diseases, including cancer, fibrosis, arthritis, hydrocephalus, and traumatic injury.
Arthritis ; Autoimmune Diseases ; Fibrosis ; Hydrocephalus ; Idiopathic Pulmonary Fibrosis ; Pathology ; Pharmacology ; Receptors, Lysophosphatidic Acid ; Scleroderma, Systemic ; Sensitivity and Specificity

OBJECTIVETo explore the role of the fibroblast transdifferentiation into myofibroblasts (MFBs) in the pathogenesis of systemic sclerosis (SSc) and investigate the influence of transforming growth factor β(1) (TGF-β(1)) and blocking of its signal transduction on fibroblast transdifferentiation.

METHODSFibroblasts derived from the skin lesions of SSc patients and normal skin tissue were cultured in vitro. The proportion of MFBs in the fibroblast culture was analyzed qualitatively using immunocytochemistry and quantitatively with ELISA for α-smooth muscle actin (α-SMA). The changes in fibroblast transdifferentiation were observed after addition of TGF-β(1) in the cell culture and after blocking the signal transduction of TGF-β(1).

RESULTSThe fibroblasts isolated from SSc patients and control subjects showed a similar morphology. The mean number of cells positive for α-SMA in SSc group was significantly higher than that in the control group (P<0.01). As culture time extended, α-SMA levels of the two groups both increased gradually (P<0.01), but the increments were significantly greater in SSc group than in the control group at 24, 48, and 72 h (P<0.05 all). Addition of TGF-β(1) resulted in significantly increased α-SMA levels in both groups (P<0.05), and SSc group showed significantly higher α-SMA levels than the control group at 24, 48, and 72 h (P<0.01). In the presence of TGF-β(1), blocking of Smads, ERK/MAPK, and p38MAPK pathways, but not JNK/MAPK pathway, caused an obvious decrease in α-SMA levels in the fibroblasts in both groups.

CONCLUSIONThe fibroblasts in the skin lesion of SSc patients have strong potential of transdifferentiation into MFBs, and TGF-β(1) can promote this transdifferentiation process possibly involving Smads, and ERK/MAPK, and p38MAPK signalling pathways.

Actins ; metabolism ; Adult ; Cell Transdifferentiation ; physiology ; Cells, Cultured ; Female ; Fibroblasts ; pathology ; Humans ; Male ; Myofibroblasts ; pathology ; Scleroderma, Systemic ; pathology ; Signal Transduction ; Skin ; pathology ; Transforming Growth Factor beta1 ; metabolism

OBJECTIVETo assess the occurrence of stressful life events in the year before the initiation of systemic sclerosis.

METHODSA consecutive series of 40 patients with systemic sclerosis (mean age (56.3+/-11.9) years, mean disease duration (4.3+/-3.1) years; 32 females and 8 males), including 28 with diffuse cutaneous scleroderma and 12 with limited cutaneous scleroderma, were evaluated. A control group of 40 healthy subjects free of systemic sclerosis also was included. Socioeconomic status was investigated and Paykel's interview for recent life events (a semi-structured research interview covering 64 life events) was conducted.

RESULTSPatients with systemic sclerosis showed higher percentages of lower education (72.5%) and working class (82.5%), and reported more stressful life events (P<0.05), such as exits (P<0.05), undesirable events (P<0.01), and uncontrolled events (P<0.001), when compared with the control. More events that had an objective negative impact (P<0.001) were also reported in systemic sclerosis patients than in the control. These results are in accordance with a multifactorial model of pathogenesis in systemic sclerosis.

CONCLUSIONWe reported a strong relationship between stressful life events and the initiation of systemic sclerosis. Our findings are consistent with current understanding of the extensive links of behavioral responses to stress with neurophysiological and biochemical processes.

Female ; Humans ; Interviews as Topic ; Life Change Events ; Male ; Middle Aged ; Scleroderma, Systemic ; etiology ; pathology ; psychology ; Socioeconomic Factors ; Stress, Psychological ; complications ; pathology ; psychology

The hallmark of scleroderma is fibrosis by excessive extracellular matrix (ECM) deposition in the skin, lung, and other organs. Increasing evidence suggests that overexpression of transforming growth factor-beta (TGF-beta) and its receptors play a key pathogenic role in the development of tissue fibrosis in scleroderma. TGF-beta is known to induce the expression of ECM proteins in the pathogenesis of fibrosis in systemic sclerosis. Investigations into TGF-beta pathways will suggest new treatment strategies for fibrotic diseases.
Animals ; Extracellular Matrix ; metabolism ; pathology ; Extracellular Matrix Proteins ; metabolism ; Fibroblasts ; metabolism ; Fibrosis ; Humans ; Receptors, Transforming Growth Factor beta ; metabolism ; Scleroderma, Systemic ; etiology ; metabolism ; Transforming Growth Factor beta ; metabolism

The elastin metabolism in systemic sclerosis (SSc) has been known to be abnormal. The authors investigated relationship between the clinical manifestations of systemic sclerosis (SSc) and serum levels of soluble elastin-derived peptide (S-EDP) and anti-elastin antibodies. Serum samples were obtained from 79 patients with SSc and 79 age- and sex-matched healthy controls. Concentrations of serum S-EDP and anti-elastin antibodies were measured by ELISA. The serum concentrations of S-EDP in SSc patients were significantly higher than in healthy controls (median, 144.44 ng/mL vs 79.59 ng/mL, P < 0.001). Serum EDP concentrations were found to be correlated with disease duration in SSc (P = 0.002) and particularly in diffuse cutaneous SSc (P = 0.005). Levels of anti-elastin antibodies were found to be more elevated in SSc patients than in healthy controls (median, 0.222 U vs 0.191 U, P = 0.049), more increased in diffuse cutaneous SSc than limited cutaneous SSc (median, 0.368 U vs 0.204 U, P = 0.031). In addition, levels of anti-elastin antibodies were also found to be negatively associated with presence of anti-centromere antibody (P = 0.023). The S-EDP levels were not found to be correlated with levels of anti-elastin antibodies. The increased S-EDP and anti-elastin antibody levels and association with clinical and laboratory characteristics may reflect the abnormal metabolism in SSc.
Adult ; Antibodies, Anti-Idiotypic/*blood/immunology ; Centromere/immunology ; Elastin/*blood/immunology ; Enzyme-Linked Immunosorbent Assay ; Female ; Humans ; Male ; Middle Aged ; Peptides/*blood/immunology ; Scleroderma, Systemic/*metabolism/pathology

OBJECTIVETo study the effects of artemether and dihydroarteannuin on the mouse model of scleroderma.

METHODSixty mice were randomly divided into 8 groups: PBS control group, model group, menstruum group (20% Tween-80, 0.4%CMC-Na), positive medicine group (penicillamine 200 mg kg(-1)), low-dose artemether group (5 mg kg(-1)), high-dose artemether group (20 mg kg(-1)), low-dose dihydroarteannuin group (5 mg kg(-1)), high-dose dihydroarteannuin group (25 mg kg(-1)). We have established a mouse model for scleroderma in Balb/c mice by subcutaneous injections of bleomycin 0.1 mL per day (200 mg L(-1) BLM) for 3 weeks. Meanwhile, the administration lasted for 4 weeks. The back skin was removed in the next day after the final administration. Treated skins and lungs were harvested and analyzed for histological sclerosis. The thickness of the skin and fibrosis degree of derma were observed and made an analysis of the contents of collagen and hydroxyproline.

RESULTCompared with the model groups, the high-dose groups markedly inhibited the thickness of derma (P<0.001), furthermore, the contents of collagen and hydroxyproline in the skin were also significantly reduced (P<0.05). Other groups of mice showed improvement on scleroderma.

CONCLUSIONOur results suggest that administration of artemether or dihydroarteannuin may be an effective approach in preventing systemic sclerosis.

Animals ; Artemisinins ; pharmacology ; Collagen ; metabolism ; Female ; Hydroxyproline ; metabolism ; Lung ; drug effects ; pathology ; Mice ; Mice, Inbred BALB C ; Scleroderma, Systemic ; metabolism ; pathology ; prevention & control ; Sesquiterpenes ; pharmacology ; Skin ; drug effects ; metabolism ; pathology