14 results on '"Serena, Guiducci"'
Search Results
2. A loss of telocytes accompanies fibrosis of multiple organs in systemic sclerosis
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Lidia Ibba-Manneschi, Luca Messerini, Marco Matucci-Cerinic, Serena Guiducci, Mirko Manetti, and Irene Rosa
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Pathology ,medicine.medical_specialty ,Muscularis mucosae ,Stromal cell ,systemic sclerosis ,Gene Expression ,Antigens, CD34 ,Cell Count ,Biology ,telocytes ,lung ,Extracellular matrix ,Interstitial space ,Fibrosis ,Submucosa ,Telocyte ,myocardium ,medicine ,Humans ,scleroderma ,skin and connective tissue diseases ,Scleroderma, Systemic ,Lung ,Cell Death ,Tissue Embedding ,integumentary system ,Stomach ,fibrosis ,Endothelial Cells ,Microtomy ,Original Articles ,Cell Biology ,Anatomy ,medicine.disease ,Immunohistochemistry ,Platelet Endothelial Cell Adhesion Molecule-1 ,gastric wall ,medicine.anatomical_structure ,Gastric Mucosa ,Molecular Medicine ,CD34 ,Stromal Cells ,Biomarkers - Abstract
Systemic sclerosis (SSc) is a complex connective tissue disease characterized by fibrosis of the skin and various internal organs. In SSc, telocytes, a peculiar type of stromal (interstitial) cells, display severe ultrastructural damages and are progressively lost from the clinically affected skin. The aim of the present work was to investigate the presence and distribution of telocytes in the internal organs of SSc patients. Archival paraffin-embedded samples of gastric wall, myocardium and lung from SSc patients and controls were collected. Tissue sections were stained with Masson's trichrome to detect fibrosis. Telocytes were studied on tissue sections subjected to CD34 immunostaining. CD34/CD31 double immunofluorescence was performed to unequivocally differentiate telocytes (CD34-positive/CD31-negative) from vascular endothelial cells (CD34-positive/CD31-positive). Few telocytes entrapped in the fibrotic extracellular matrix were found in the muscularis mucosae and submucosa of SSc gastric wall. In the muscle layers and myenteric plexus, the network of telocytes was discontinuous or even completely absent around smooth muscle cells and ganglia. Telocytes were almost completely absent in fibrotic areas of SSc myocardium. In SSc fibrotic lung, few or no telocytes were observed in the thickened alveolar septa, around blood vessels and in the interstitial space surrounding terminal and respiratory bronchioles. In SSc, the loss of telocytes is not restricted to the skin, but it is a widespread process affecting multiple organs targeted by the fibrotic process. As telocytes are believed to be key players in the regulation of tissue/organ homoeostasis, our data suggest that telocyte loss might have important pathophysiological implications in SSc.
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- 2014
3. Agonistic anti-human Fas monoclonal antibody induces fibroblast-like synoviocyte apoptosis in haemophilic arthropathy: potential therapeutic implications
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Marco Matucci-Cerinic, Massimo Innocenti, Eloisa Romano, Lidia Ibba-Manneschi, Massimo Morfini, Daniela Melchiorre, Silvia Bellando-Randone, Kusuki Nishioka, Silvia Linari, Mirko Manetti, F. Peruzzi, Christian Carulli, Serena Guiducci, and Anna Franca Milia
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Adult ,Male ,musculoskeletal diseases ,Fibroblast-like synoviocyte ,Cell Survival ,medicine.drug_class ,Basic fibroblast growth factor ,Apoptosis ,Hemophilia A ,Monoclonal antibody ,Arthritis, Rheumatoid ,Antibodies, Monoclonal, Murine-Derived ,Young Adult ,chemistry.chemical_compound ,Antigen ,Synovitis ,Hemarthrosis ,medicine ,Humans ,Cytotoxic T cell ,fas Receptor ,Viability assay ,skin and connective tissue diseases ,Genetics (clinical) ,Caspase 3 ,business.industry ,Synovial Membrane ,Antibodies, Monoclonal ,Hematology ,General Medicine ,Fibroblasts ,Middle Aged ,musculoskeletal system ,medicine.disease ,Immunoglobulin M ,chemistry ,Immunology ,Cancer research ,business - Abstract
Summary Haemophilic arthropathy (HA) is characterized by chronic proliferative synovitis leading to cartilage destruction and shares some pathological features with rheumatoid arthritis (RA). Apoptosis has been implicated in RA pathogenesis, and an agonistic anti-Fas monoclonal antibody (mAb) was found to induce RA fibroblast-like synoviocyte (FLS) apoptosis and suppress synovial hyperplasia in animal models of RA. The aim of this study was to evaluate the effect of anti-Fas mAb on HA-FLS. FLS were isolated from knee synovial biopsies from six HA patients, six RA patients and six healthy subjects. The expression of Fas in synovial biopsies was investigated by immunohistochemistry. FLS were stimulated with anti-Fas mAb at different concentrations, alone or in combination with tumour necrosis factor-α (TNF-α) and basic fibroblast growth factor (bFGF). Fas expression in FLS was assessed by Western blot. Cell viability was studied with the WST-1 assay. Active caspase-3 levels were measured using ELISA and Western blot. A strong Fas-immunoreactivity was observed in different cells of HA synovium, including FLS, inflammatory cells and endothelial cells. Fas antigen was constitutively overexpressed in cultured HA-FLS. Anti-Fas mAb had a significant cytotoxicity on HA-FLS in a dose-dependent manner, either alone or in combination with TNF-α and bFGF. These cytotoxic effects were due to the ability of anti-Fas to induce HA-FLS apoptosis, as shown by the increased active caspase-3 levels. Anti-Fas mAb exhibited a more pronounced pro-apoptotic effect on HA-FLS than RA-FLS. Fas antigen is highly expressed on HA-FLS and its stimulation by anti-Fas mAb may be an effective strategy to induce HA-FLS apoptosis.
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- 2013
4. 2013 Classification Criteria for Systemic Sclerosis: An American College of Rheumatology/European League Against Rheumatism Collaborative Initiative
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Bashar Kahaleh, Christopher P. Denton, Philip J. Clements, Sindhu R Johnson, Gabriele Valentini, Murray Baron, Douglas J. Veale, Armando Gabrielli, Yannick Allanore, Janet E. Pope, Mary Ellen Csuka, Sergio A. Jimenez, Robert W. Simms, Peter A. Merkel, Madelon C. Vonk, Ulrich A Walker, Barri J. Fessler, Ulf Müller-Ladner, Thomas A. Medsger, Otylia Kowal-Bielecka, Vivien Hsu, László Czirják, Patricia Carreira, Frank H J van den Hoogen, Daniel E. Furst, John Varga, Maureen D. Mayes, Serena Guiducci, Alan Tyndall, Gabriela Riemekasten, Jacob M van Laar, Stanislav Sierakowski, Jaap Fransen, Murat Inanc, Raymond P. Naden, Dinesh Khanna, Oliver Distler, Marco Matucci-Cerinic, Lorinda Chung, Ariane L. Herrick, Richard M. Silver, James R. Seibold, David H. Collier, and Virginia D. Steen
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musculoskeletal diseases ,medicine.medical_specialty ,integumentary system ,business.industry ,Skin thickening ,Immunology ,Interstitial lung disease ,medicine.disease ,Acr criteria ,Rheumatology ,Point system ,Expert opinion ,Internal medicine ,medicine ,Physical therapy ,Immunology and Allergy ,Pharmacology (medical) ,Capillary microscopy ,skin and connective tissue diseases ,business ,Rheumatism - Abstract
OBJECTIVE: The 1980 American College of Rheumatology (ACR) classification criteria for systemic sclerosis (SSc) lack sensitivity for early SSc and limited cutaneous SSc. The present work, by a joint committee of the ACR and the European League Against Rheumatism (EULAR), was undertaken for the purpose of developing new classification criteria for SSc. METHODS: Using consensus methods, 23 candidate items were arranged in a multicriteria additive point system with a threshold to classify cases as SSc. The classification system was reduced by clustering items and simplifying weights. The system was tested by 1) determining specificity and sensitivity in SSc cases and controls with scleroderma-like disorders, and 2) validating against the combined view of a group of experts on a set of cases with or without SSc. RESULTS: It was determined that skin thickening of the fingers extending proximal to the metacarpophalangeal joints is sufficient for the patient to be classified as having SSc; if that is not present, 7 additive items apply, with varying weights for each: skin thickening of the fingers, fingertip lesions, telangiectasia, abnormal nailfold capillaries, interstitial lung disease or pulmonary arterial hypertension, Raynaud's phenomenon, and SSc-related autoantibodies. Sensitivity and specificity in the validation sample were, respectively, 0.91 and 0.92 for the new classification criteria and 0.75 and 0.72 for the 1980 ACR classification criteria. All selected cases were classified in accordance with consensus-based expert opinion. All cases classified as SSc according to the 1980 ACR criteria were classified as SSc with the new criteria, and several additional cases were now considered to be SSc. CONCLUSION: The ACR/EULAR classification criteria for SSc performed better than the 1980 ACR criteria for SSc and should allow for more patients to be classified correctly as having the disease.
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- 2013
5. Evidence for progressive reduction and loss of telocytes in the dermal cellular network of systemic sclerosis
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Irene Rosa, Lidia Ibba-Manneschi, Maria Simonetta Faussone-Pellegrini, Martina Ruffo, Serena Guiducci, Marco Matucci-Cerinic, and Mirko Manetti
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Adult ,Male ,skin ,Pathology ,medicine.medical_specialty ,Stromal cell ,systemic sclerosis ,Population ,CD34 ,Antigens, CD34 ,Human skin ,Biology ,telocytes ,Extracellular matrix ,Microscopy, Electron, Transmission ,Dermis ,transmission electron microscopy ,Telocyte ,medicine ,Humans ,scleroderma ,education ,education.field_of_study ,Scleroderma, Systemic ,integumentary system ,fibrosis ,Endothelial Cells ,Original Articles ,Cell Biology ,Fibroblasts ,Middle Aged ,dermis ,Proto-Oncogene Proteins c-kit ,medicine.anatomical_structure ,immunohistochemistry ,Molecular Medicine ,Female ,Stromal Cells ,Myofibroblast - Abstract
Telocytes, a peculiar type of stromal cells, have been recently identified in a variety of tissues and organs, including human skin. Systemic sclerosis (SSc, scleroderma) is a complex connective tissue disease characterized by fibrosis of the skin and internal organs. We presently investigated telocyte distribution and features in the skin of SSc patients compared with normal skin. By an integrated immunohistochemical and transmission electron microscopy approach, we confirmed that telocytes were present in human dermis, where they were mainly recognizable by their typical ultrastructural features and were immunophenotypically characterized by CD34 expression. Our findings also showed that dermal telocytes were immunophenotypically negative for CD31/PECAM-1 (endothelial cells), α-SMA (myofibroblasts, pericytes, vascular smooth muscle cells), CD11c (dendritic cells, macrophages), CD90/Thy-1 (fibroblasts) and c-kit/CD117 (mast cells). In normal skin, telocytes were organized to form three-dimensional networks distributed among collagen bundles and elastic fibres, and surrounded microvessels, nerves and skin adnexa (hair follicles, sebaceous and sweat glands). Telocytes displayed severe ultrastructural damages (swollen mitochondria, cytoplasmic vacuolization, lipofuscinic bodies) suggestive of ischaemia-induced cell degeneration and were progressively lost from the clinically affected skin of SSc patients. Telocyte damage and loss evolved differently according to SSc subsets and stages, being more rapid and severe in diffuse SSc. Briefly, in human skin telocytes are a distinct stromal cell population. In SSc skin, the progressive loss of telocytes might (i) contribute to the altered three-dimensional organization of the extracellular matrix, (ii) reduce the control of fibroblast, myofibroblast and mast cell activity, and (iii) impair skin regeneration and/or repair.
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- 2013
6. Differential expression of junctional adhesion molecules in different stages of systemic sclerosis
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Mirko Manetti, Lidia Ibba-Manneschi, Irene Rosa, Eloisa Romano, Marco Matucci-Cerinic, Maria Letizia Conforti, Claudia Ceccarelli, Serena Guiducci, Tommaso Mello, and Anna Franca Milia
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Male ,endocrine system ,Pathology ,medicine.medical_specialty ,Junctional Adhesion Molecules ,Angiogenesis ,Blotting, Western ,Immunology ,Cell ,Cell Culture Techniques ,Enzyme-Linked Immunosorbent Assay ,Vascular permeability ,Inflammation ,Biology ,Pathogenesis ,Rheumatology ,medicine ,Humans ,Immunology and Allergy ,Pharmacology (medical) ,skin and connective tissue diseases ,Skin ,Scleroderma, Systemic ,Neovascularization, Pathologic ,integumentary system ,medicine.diagnostic_test ,Endothelial Cells ,Immunohistochemistry ,humanities ,Endothelial stem cell ,medicine.anatomical_structure ,Skin biopsy ,cardiovascular system ,Female ,medicine.symptom ,Transcriptome - Abstract
Objective Systemic sclerosis (SSc) is characterized by early perivascular inflammation, microvascular endothelial cell (MVEC) activation/damage, and defective angiogenesis. Junctional adhesion molecules (JAMs) regulate leukocyte recruitment to sites of inflammation and ischemia-reperfusion injury, vascular permeability, and angiogenesis. This study was undertaken to investigate the possible role of JAMs in SSc pathogenesis. Methods JAM-A and JAM-C expression levels in skin biopsy samples from 25 SSc patients and 15 healthy subjects were investigated by immunohistochemistry and Western blotting. Subcellular localization of JAMs in cultured healthy dermal MVECs and SSc MVECs was assessed by confocal microscopy. Serum levels of soluble JAM-A (sJAM-A) and sJAM-C in 64 SSc patients and 32 healthy subjects were examined by enzyme-linked immunosorbent assay. Results In control skin, constitutive JAM-A expression was observed in MVECs and fibroblasts. In early-stage SSc skin, JAM-A expression was strongly increased in MVECs, fibroblasts, and perivascular inflammatory cells. In late-stage SSc, JAM-A expression was decreased compared with controls. JAM-C was weakly expressed in control and late-stage SSc skin, while it was strongly expressed in MVECs, fibroblasts, and inflammatory cells in early-stage SSc. Surface expression of JAM-A was higher in early-stage SSc MVECs and increased in healthy MVECs stimulated with early-stage SSc sera. JAM-C was cytoplasmic in resting healthy MVECs, while it was recruited to the cell surface upon challenge with early-stage SSc sera. Early-stage SSc MVECs exhibited constitutive surface JAM-C expression. In SSc, increased levels of sJAM-A and sJAM-C correlated with early disease and measures of vascular damage. Conclusion Our findings indicate that JAMs may participate in MVEC activation, inflammatory processes, and impaired angiogenesis in different stages of SSc.
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- 2012
7. The relationship between plasma microparticles and disease manifestations in patients with systemic sclerosis
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Serena Guiducci, Jörg H. W. Distler, Astrid Jüngel, Dörte Huscher, Lars C. Huber, Beat A. Michel, Renate E. Gay, David S. Pisetsky, Steffen Gay, Marco Matucci-Cerinic, and Oliver Distler
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Adult ,Blood Platelets ,Male ,Pathology ,medicine.medical_specialty ,Systemic disease ,Immunology ,Cell Separation ,Severity of Illness Index ,Statistics, Nonparametric ,Flow cytometry ,Pathogenesis ,Plasma ,Rheumatology ,Cell-Derived Microparticles ,Blood plasma ,Humans ,Immunology and Allergy ,Medicine ,Pharmacology (medical) ,Platelet ,Microparticle ,Aged ,Autoimmune disease ,Scleroderma, Systemic ,integumentary system ,medicine.diagnostic_test ,business.industry ,Endothelial Cells ,Middle Aged ,Flow Cytometry ,medicine.disease ,Connective tissue disease ,C-Reactive Protein ,Multivariate Analysis ,Regression Analysis ,Female ,business - Abstract
Objective Microparticles are small, membrane-coated vesicles that can serve as novel signaling structures between cells. The aim of the present study was to analyze the profile of microparticles in the blood of patients with systemic sclerosis (SSc; scleroderma) and healthy controls. Methods The study population consisted of 37 patients with SSc and 15 healthy subjects of comparable sex and age. Microparticles were isolated from plasma by high-speed differential centrifugation. Microparticles were stained with monoclonal antibodies against cell type–specific markers and were quantified by fluorescence-activated cell sorting analyses. Results The total number of microparticles was strongly increased in patients with SSc compared with healthy controls (mean ± SEM 88.0 ± 4.8 × 105 microparticles/ml plasma versus 42.3 ± 9.4 × 105 microparticles/ml plasma; P < 0.001). Similarly, significant increases were found for microparticles derived from platelets, endothelial cells, monocytes, and T cells, reflecting the activation of these cells in SSc. Platelets were the most common source of microparticles in the blood of patients with SSc (66.9 ± 5.2% of all microparticles) and healthy donors, followed by microparticles derived from endothelial cells (8.8 ± 0.9% in SSc patients). The modified Rodnan skin thickness score (MRSS) was inversely correlated with the total number of microparticles. Furthermore, patients with cutaneous ulcers showed a significantly lower total number of microparticles. In multivariate analysis, an additive model of age, C-reactive protein, MRSS, and subtype of disease accounted for 55% of the variability of the total microparticle count (r = 0.744). Conclusion The number of microparticles from different cellular sources is increased in the blood of SSc patients. Considering their role as important mediators of intercellular communication, microparticles could be a novel link between activated cellular compartments in the pathogenesis of SSc.
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- 2008
8. Autoantibodies to the translational suppressors T cell intracytoplasmic antigen 1 and T cell intracytoplasmic antigen 1–related protein in patients with rheumatic diseases: Increased prevalence in systemic lupus erythematosus and systemic sclerosis and correlation with clinical features
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Elisabeth Hoefler, Franz Karlhofer, Nancy Kedersha, Georg Stummvoll, Walter Ulrich, Josef S Smolen, Georg Schett, Marco Matucci-Cerinic, Günter Steiner, Esther Jimenez-Boj, Makiyeh Tohidast-Akrad, Christof Zimmermann, Serena Guiducci, and Martin Aringer
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Pathology ,medicine.medical_specialty ,Systemic disease ,Immunology ,Lupus nephritis ,medicine.disease_cause ,Poly(A)-Binding Proteins ,Autoimmunity ,Rheumatology ,Antigen ,parasitic diseases ,medicine ,Humans ,Lupus Erythematosus, Systemic ,Immunology and Allergy ,Pharmacology (medical) ,cardiovascular diseases ,skin and connective tissue diseases ,Autoantibodies ,Scleroderma, Systemic ,Lupus erythematosus ,business.industry ,Autoantibody ,RNA-Binding Proteins ,medicine.disease ,Connective tissue disease ,T-Cell Intracellular Antigen-1 ,nervous system diseases ,business ,Anti-SSA/Ro autoantibodies - Abstract
Objective T cell intracytoplasmic antigen 1 (TIA-1) and TIA-1–related protein (TIAR) are involved in posttranscriptional regulation of the expression of tumor necrosis factor α (TNFα) and other proteins. Given the pivotal role of TNFα in chronic inflammatory diseases, this study was undertaken to analyze sera from patients with systemic autoimmune diseases for the presence of autoantibodies to TIA proteins and to investigate the expression of these proteins in inflamed tissue. Methods The presence of autoantibodies to TIA proteins in sera from 385 patients with rheumatic diseases and healthy controls was determined by immunoblotting using recombinant antigens. Expression of TIA proteins in skin and kidney tissue was analyzed by immunohistochemistry. Serum levels of TNFα were measured by enzyme-linked immunosorbent assay. Results Autoantibodies to TIA-1 and/or TIAR were detected in 61% of patients with systemic lupus erythematosus (SLE), 42% of patients with systemic sclerosis (SSc), 15–31% of patients with other rheumatic diseases, and 6% of healthy controls. Compared with patients negative for anti-TIA antibody, anti-TIA antibody–positive SLE patients had higher disease activity (P = 0.01), elevated antibodies to double-stranded DNA (P = 0.0003), and increased serum TNFα levels (P = 0.018). In SLE patients, anti-TIAR antibodies were associated with lupus nephritis (P = 0.02), while in patients with SSc, anti–TIA-1 was associated with lung involvement (P = 0.02). Immunohistochemical analysis of skin and kidney tissue revealed aberrant expression of TIA proteins in skin lesions from SLE and SSc patients, as well as in glomerular cells from SLE patients. Conclusion Aberrant expression of TIA proteins in inflammatory tissue may lead to systemic autoantibody responses, particularly in SLE and SSc. Increased occurrence of anti-TIA autoantibodies in patients with severe organ involvement may point to a possible pathogenetic role.
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- 2008
9. Exercise Doppler Echocardiography Identifies Preclinic Asymptomatic Pulmonary Hypertension in Systemic Sclerosis
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Ginevra Fiori, Alberto Moggi Pignone, Roberto Fedi, Leonardo Gramigna, Angela Del Rosso, Sergio Generini, Andrea Oddo, Chiara Arcangeli, Alessio Tempestini, R. Livi, Pasquale Bernardo, Maria Letizia Conforti, Martina Minelli, Francesco Pieri, Marco Matucci Cerinic, Federico Perfetto, A Becucci, M Cinelli, Chiara Benvenuti, Serena Guiducci, Gianna Galeota, and Fabio Mori
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Male ,Clinical tests ,medicine.medical_specialty ,Supine position ,Hypertension, Pulmonary ,Pulmonary Artery ,Doppler echocardiography ,Asymptomatic ,General Biochemistry, Genetics and Molecular Biology ,History and Philosophy of Science ,medicine.artery ,Internal medicine ,medicine ,Humans ,Subclinical infection ,Scleroderma, Systemic ,Lung ,medicine.diagnostic_test ,business.industry ,General Neuroscience ,Middle Aged ,medicine.disease ,Pulmonary hypertension ,Echocardiography, Doppler ,medicine.anatomical_structure ,Pulmonary artery ,Exercise Test ,Cardiology ,Female ,medicine.symptom ,business - Abstract
In systemic sclerosis (SSc), the involvement of the interstitium or vascular system of the lung may lead to pulmonary arterial hypertension (PAH). PAH is often asymptomatic or oligosymptomatic in early SSc and, when it becomes symptomatic, pulmonary vascular system is already damaged. Exercise echocardiography (ex-echo), measuring pulmonary artery pressure (PAP) during exercise and allowing to differentiate physiologic from altered PAP responses, may identify subclinical PAH. Our aims were (a) to evaluate by ex-echo the change of PAP in patients with SSc without lung involvement; and (b) to correlate PAP during exercise (ex-PAP) values to clinical and biohumoral parameters of PAH. Twenty-seven patients with limited SSc (ISSc) without interstitial lung involvement were studied. Patients underwent rest and exercise two-dimensional and Doppler echocardiography by supine cycloergometer. Systolic PAP was calculated using the maximum systolic velocity of the tricuspid regurgitant jet at rest and during exercise values of systolic PAP exceeding 40 mmHg at ex-echo were considered as abnormal, and biohumoral markers potentially related to PAH were assessed. Eighteen of 27 SSc patients presented an ex-PAP > 40 mmHg, while in 9 of 27 patients ex-PAP values remained < 40 mmHg (48.8 +/- 4.5 mmHg versus 36.2 +/- 3.1 mmHg; P < 0.001). Other echocardiographic and ergometric parameters, clinical tests, and biohumoral markers were not different in the two groups. Ex-PAP significantly correlated with D-dimer (P = 0.0125; r2 = 0.2029). Ex-echo identifies a cluster of SSc patients with subclinical PAH that may develop PAH. This group should be followed up and may be considered for specific therapies to prevent disease evolution.
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- 2007
10. Flow-Mediated Vasodilation and Carotid Intima-Media Thickness in Systemic Sclerosis
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Federico Perfetto, Ginevra Fiori, Maria Letizia Conforti, Francesca Bartoli, Angela Del Rosso, Jelena Blagojevic, Marco Matucci Cerinic, I. Miniati, Alberto Moggi Pignone, Alessio Tempestini, Mauro Di Chicco, Serena Guiducci, Marzia Bacci, and Sergio Castellani
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Male ,medicine.medical_specialty ,Brachial Artery ,Vasodilation ,Disease ,General Biochemistry, Genetics and Molecular Biology ,History and Philosophy of Science ,medicine.artery ,Internal medicine ,medicine ,Humans ,Vascular Diseases ,cardiovascular diseases ,Brachial artery ,Prospective cohort study ,Ultrasonography ,Macrovascular disease ,Scleroderma, Systemic ,business.industry ,General Neuroscience ,Middle Aged ,medicine.disease ,Carotid Arteries ,Endocrinology ,Intima-media thickness ,cardiovascular system ,Cardiology ,Female ,Tunica Intima ,Tunica Media ,business ,Dyslipidemia ,Flow-Mediated Vasodilation - Abstract
Increased evidence suggests an accelerated macrovascular disease in systemic sclerosis (SSc). Brachial artery flow-mediated vasodilation (FMD) and carotid intima-media thickness (IMT) are two indicators of subclinic cardiovascular disease and are frequently used as surrogate measures of subclinic atherosclerosis. The aim of this study was to evaluate macrovascular involvement in SSc. We studied 35 SSc patients (6 males and 29 females; 11 with diffuse and 24 with limited disease) and 20 healthy controls. Brachial artery FMD was assessed by method described by Celermajer in all patients and 13 control subjects. IMT was measured using high-resolution B-mode ultrasonography in patients and controls. Traditional risk factors for atherosclerosis (hypertension, dyslipidemia, and smoke) were also assessed. FMD was significantly impaired (3.41% +/- 4.56% versus 7.66% +/- 4.24%; P < 0.037) and IMT was significantly elevated compared with healthy controls (0.93 +/- 0.29 mm versus 0.77 +/- 0.13 mm; P < 0.005). FMD was not significantly different in SSc with increased IMT compared with those with normal IMT). No correlation was found between risk factors for atherosclerosis and the impairment of FMD or IMT in SSc patients. The impairment of endothelial function and structural changes of large vessels are evident in SSc, but do not seem associated with traditional risk factors for atherosclerosis. Prospective studies including also clinical outcomes are needed to assess the features and significance of macrovacular involvement in SSc.
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- 2007
11. Angiotensin-Converting Enzyme in Systemic Sclerosis: From Endothelial Injury to a Genetic Polymorphism
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Rosanna Abbate, Cinzia Fatini, Marco Matucci Cerinic, M Cinelli, Veronica Rogai, Elena Sticchi, and Serena Guiducci
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medicine.medical_specialty ,Angiotensins ,Bradykinin ,Angiotensin-Converting Enzyme Inhibitors ,Peptidyl-Dipeptidase A ,General Biochemistry, Genetics and Molecular Biology ,chemistry.chemical_compound ,History and Philosophy of Science ,Internal medicine ,Renin ,Renin–angiotensin system ,medicine ,Animals ,Humans ,Endothelium ,Endothelial dysfunction ,Allele frequency ,Macrovascular disease ,Polymorphism, Genetic ,Scleroderma, Systemic ,biology ,Vascular disease ,General Neuroscience ,Angiotensin-converting enzyme ,medicine.disease ,Angiotensin II ,Endocrinology ,chemistry ,biology.protein - Abstract
The main pathologic hallmark of systemic sclerosis (SSc) is endothelial derangement; the pathologic alterations of the vessel wall in SSc are strikingly similar to the modification detected in the atherosclerotic lesions, and it is now evident that SSc is also characterized by accelerated macrovascular disease. Peptides related to angiotensin II, the final product of the renin-angiotensin system (RAS), play a role as regulators of endothelial cell function. Angiotensin-converting enzyme (ACE), the key enzyme in the RAS, is the predominant pathway of angiotensin II formation in blood and tissues. In intron 16 of the gene encoding for ACE an insertion/deletion (I/D) polymorphism, consisting of the presence or absence of a 287-base pair Alu sequence, has been identified. This polymorphism has been related to ACE enzyme levels, and data from experimental studies reported a functional role for this polymorphism in modulating the angiotensin II levels. We previously documented a high ACE D allele frequency in SSc patients and its role in increasing the risk of SSc, thus suggesting that the I/D polymorphism might be a useful genetic marker to identify SSc patients at risk to develop a severe vascular disease, frequently leading to gangrene. Moreover, our preliminary data, besides supporting the role of ACE I/D polymorphism as a predisposing factor to SSc, demonstrated its involvement in accelerated macrovascular disease by increasing the intima media thickness. Therefore, in SSc, not only endothelial dysfunction, but also vascular damage, linked to ACE I/D polymorphism, may significantly contribute to accelerated macrovascular disease, as the ACE D allele, by regulating both the production of angiotensin II and the degradation of bradykinin, contributes to mechanisms involved in the induction and maintenance of vessel wall modification.
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- 2006
12. The antiangiogenic tissue kallikrein pattern of endothelial cells in systemic sclerosis
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Francesca Margheri, Bashar Kahaleh, Serena Guiducci, Luciana Rossi, Marco Matucci-Cerinic, Betti Giusti, Mario Del Rosso, M Cinelli, Filippo Poggi, Gabriella Fibbi, Angela Del Rosso, Laura Papucci, Rosanna Abbate, Alberto Magi, and Simona Serratì
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Male ,Pathology ,medicine.medical_specialty ,Angiogenesis ,Blotting, Western ,Immunology ,Tissue kallikrein ,Cell Count ,Biology ,Rheumatology ,medicine ,Humans ,Immunology and Allergy ,Pharmacology (medical) ,RNA, Messenger ,Phosphorylation ,Antibodies, Blocking ,Extracellular Signal-Regulated MAP Kinases ,Cells, Cultured ,Cell Proliferation ,Oligonucleotide Array Sequence Analysis ,Skin ,Matrigel ,Scleroderma, Systemic ,Neovascularization, Pathologic ,Reverse Transcriptase Polymerase Chain Reaction ,Cell growth ,Gene Expression Profiling ,Microcirculation ,Endothelial Cells ,Kallikrein ,Blot ,Endothelial stem cell ,Gene Expression Regulation ,Cancer research ,Tissue Kallikreins ,Female ,Nucleotides, Cyclic ,circulatory and respiratory physiology - Abstract
Objective Postnatal angiogenesis relies on a proper response of endothelial cells to angiogenic stimuli. In systemic sclerosis (SSc), endothelial cells are unresponsive to angiogenic factors. Since circumstantial and experimental evidence points to tissue kallikreins as powerful effectors of the angiogenic response, we undertook this study to investigate the kallikrein pattern of normal and SSc endothelial cells in order to identify differences that can account for defective angiogenesis. Methods Expression of 14 tissue kallikreins was studied by a microarray approach, by reverse transcription–polymerase chain reaction, and by Western blotting in endothelial cells isolated from the skin of clinically healthy subjects and SSc patients. Cell proliferation was quantified by direct cell counting. Invasion and capillary morphogenesis were evaluated in a Boyden chamber and in culture flasks layered with Matrigel. Cyclic nucleotide production was measured by enzyme immunoassay. MAP kinase and ERK activation were measured by Western blotting. Results Endothelial cells from SSc patients showed poor expression of kallikreins 9, 11, and 12 compared with endothelial cells from normal subjects. Antibodies against the relevant kallikreins on normal endothelial cells revealed that while kallikreins 9, 11, and 12 induced cell growth, only kallikrein 12 regulated invasion and capillary morphogenesis. Buffering of kallikrein 12 with antibodies resulted in the acquisition of an SSc-like pattern by normal cells in in vitro angiogenesis. Reduction of cAMP and cGMP production and of ERK phosphorylation upon administration of antikallikrein antibodies revealed that the activity of kallikreins 9, 11, and 12 was mediated by kinins. Conclusion Reduction of tissue kallikreins 9, 11, and 12 may be relevant to reduced angiogenesis in SSc patients.
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- 2005
13. Matrix metalloproteinase 12-dependent cleavage of urokinase receptor in systemic sclerosis microvascular endothelial cells results in impaired angiogenesis
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Lorenzo Cosmi, Bashar Kahaleh, Mario Del Rosso, Marco Pucci, M Cinelli, Simona Serratì, Francesco Liotta, Marco Matucci-Cerinic, Serena Guiducci, Francesco Annunziato, Gabriella Fibbi, Pan-Sheng Fan, Francesca Margheri, Angela Del Rosso, and Silvia D'Alessio
- Subjects
endocrine system ,Pathology ,medicine.medical_specialty ,integumentary system ,Angiogenesis ,Immunology ,Biology ,Matrix metalloproteinase ,Endothelial stem cell ,Neovascularization ,Urokinase receptor ,Blot ,medicine.anatomical_structure ,Rheumatology ,Dermis ,cardiovascular system ,medicine ,Cancer research ,Immunology and Allergy ,Pharmacology (medical) ,medicine.symptom ,skin and connective tissue diseases ,Receptor - Abstract
Objective Defective angiogenesis, resulting in tissue ischemia, is particularly prominent in the diffuse form of systemic sclerosis (SSc). The present study was undertaken to identify possible differences between normal and SSc microvascular endothelial cells (MVECs) in the expression of the cell-associated urokinase-type plasminogen activator (uPA)/uPA receptor (uPAR) system, which is critical in the angiogenic process. Methods MVECs were isolated from the dermis of healthy individuals and from the dermis of patients with diffuse SSc. The uPA/uPAR system was examined at the protein and messenger RNA levels. Angiogenesis was assayed on Matrigel-coated porous filters and plates to evaluate cell proliferation, invasion, and capillary morphogenesis. Cleavage of uPAR and the activity of matrix metalloproteinase 12 (MMP-12) were evaluated by Western blotting. Results Compared with MVECs from healthy skin, MVECs from SSc patients showed higher expression of uPAR. However, in SSc MVECs, uPAR undergoes truncation between domain 1 and domain 2, as shown by flow cytometry, enzyme-linked immunosorbent assay, and Western blotting, a cleavage that is known to impair uPAR functions. These properties of SSc MVECs were associated with poor spontaneous and uPA-dependent invasion, proliferation, and capillary morphogenesis. The uPAR cleavage occurring in SSc MVECs was associated with overexpression of MMP-12. SSc MVEC–conditioned medium impaired uPA-dependent proliferation and invasion as well as capillary morphogenesis in normal MVECs in vitro. Both a general hydroxamate inhibitor of MMP activity and anti–MMP-12 antibodies restored this SSc MVEC–induced impaired functioning. Conclusion Overproduction of MMP-12 by SSc MVECs accounts for the cleavage of uPAR and the impairment of angiogenesis in vitro and may contribute to reduced angiogenesis in SSc patients.
- Published
- 2004
14. Overexpression of monocyte chemoattractant protein 1 in systemic sclerosis: Role of platelet-derived growth factor and effects on monocyte chemotaxis and collagen synthesis
- Author
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Oliver Distler, Thomas Pap, Otylia Kowal-Bielecka, Rotraud Meyringer, Serena Guiducci, Michael Landthaler, J�rgen Sch�lmerich, Beat A. Michel, Renate E. Gay, Marco Matucci-Cerinic, Steffen Gay, and Ulf M�ller-Ladner
- Subjects
Pathology ,medicine.medical_specialty ,Platelet-derived growth factor ,Monocyte chemotaxis ,medicine.medical_treatment ,Immunology ,Becaplermin ,Biology ,Polymerase Chain Reaction ,Monocytes ,Immunoenzyme Techniques ,Extracellular matrix ,chemistry.chemical_compound ,Rheumatology ,Dermis ,medicine ,Humans ,Immunology and Allergy ,Pharmacology (medical) ,RNA, Messenger ,skin and connective tissue diseases ,Fibroblast ,Cells, Cultured ,Chemokine CCL2 ,In Situ Hybridization ,DNA Primers ,Skin ,Platelet-Derived Growth Factor ,Scleroderma, Systemic ,Dose-Response Relationship, Drug ,integumentary system ,Growth factor ,Proto-Oncogene Proteins c-sis ,Fibroblasts ,Chemotaxis, Leukocyte ,Procollagen peptidase ,medicine.anatomical_structure ,chemistry ,Collagen ,Type I collagen - Abstract
Objective In addition to its chemotactic properties, recent evidence suggests that monocyte chemoattractant protein 1 (MCP-1) might participate in the fibrotic process by inducing the secretion of extracellular matrix (ECM) components. Since the factors that initiate the accumulation of inflammatory infiltrates and ECM deposits in systemic sclerosis (SSc) skin lesions are still unknown, this study was undertaken to examine the role of MCP-1 in SSc. Methods In situ hybridization and immunohistochemistry studies for MCP-1 were performed on skin biopsy specimens from patients with SSc and healthy controls. To identify possible stimulators of MCP-1 overexpression in SSc lesions, cultured dermal fibroblasts were incubated with recombinant platelet-derived growth factor (PDGF) and analyzed by real-time polymerase chain reaction (PCR) and enzyme-linked immunosorbent assay. The chemotactic effects of SSc fibroblasts were examined using a modified Boyden chamber assay. To analyze the fibrotic potential of MCP-1, cultured dermal fibroblasts were incubated with recombinant MCP-1, and type I procollagen was measured by radioimmunoassay and real-time PCR. Results MCP-1 was expressed by fibroblasts, keratinocytes, and perivascular infiltrates throughout the skin, in involved as well as uninvolved skin areas, from 10 of 11 SSc patients, whereas no expression of MCP-1 was found in healthy controls. Stimulation with PDGF resulted in a significant increase in MCP-1 messenger RNA and protein, with differences between healthy control fibroblasts and fibroblasts from SSc patients. The chemotactic activity for peripheral blood mononuclear cells of SSc fibroblast supernatants increased in a time-dependent manner. Antibodies blocking MCP-1 decreased the chemotactic activity of SSc fibroblasts by a mean ± SD of 37 ± 12%. Despite an increase in type I collagen levels over time, no effect of recombinant MCP-1 on the synthesis of type I collagen was observed. Conclusion These data indicate that MCP-1 might contribute to the initiation of inflammatory infiltrates in SSc. Possible stimuli of MCP-1 in dermal SSc lesions include PDGF, which is known to be expressed in SSc. In contrast to previous findings in fibrotic lung diseases, no effect of MCP-1 on collagen synthesis was observed in SSc dermal fibroblasts in vitro.
- Published
- 2001
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