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Article ; Online: Multiple subregions within the caveolin-1 scaffolding domain inhibit fibrosis, microvascular leakage, and monocyte migration.

Reese, Charles F / Chinnakkannu, Panneerselvam / Tourkina, Elena / Hoffman, Stanley / Kuppuswamy, Dhandapani

2022 Volume 17, Issue 2, Page(s) e0264413

Abstract: The caveolin-1 scaffolding domain (CSD, amino acids 82-101 of caveolin-1) has been shown to suppress bleomycin-induced lung and skin fibrosis and angiotensin II (AngII)-induced myocardial fibrosis. To identify active subregions within CSD, we split its ... ...

Abstract	The caveolin-1 scaffolding domain (CSD, amino acids 82-101 of caveolin-1) has been shown to suppress bleomycin-induced lung and skin fibrosis and angiotensin II (AngII)-induced myocardial fibrosis. To identify active subregions within CSD, we split its sequence into three slightly overlapping 8-amino acid subregions (82-89, 88-95, and 94-101). Interestingly, all three peptides showed activity. In bleomycin-treated mice, all three subregions suppressed the pathological effects on lung and skin tissue morphology. In addition, while bone marrow monocytes isolated from bleomycin-treated mice showed greatly enhanced migration in vitro toward CXCL12, treatment in vivo with CSD and its subregions almost completely suppressed this enhanced migration. In AngII-induced heart failure, both 82-89 and 88-95 significantly suppressed fibrosis (both Col I and HSP47 levels), microvascular leakage, and heart weight/ body weight ratio (HW/BW) while improving ventricular function. In contrast, while 94-101 suppressed the increase in Col I, it did not improve the other parameters. The idea that all three subregions can be active depending on the assay was further supported by experiments studying the in vitro migration of human monocytes in which all three subregions were extremely active. These studies are very novel in that it has been suggested that there is only one active region within CSD that is centered on amino acids 90-92. In contrast, we demonstrate here the presence of other active regions within CSD.
MeSH term(s)	Animals ; Bleomycin/adverse effects ; Bleomycin/pharmacology ; Caveolin 1/metabolism ; Cell Movement ; Mice ; Monocytes/metabolism ; Pulmonary Fibrosis/chemically induced ; Pulmonary Fibrosis/metabolism ; Skin Diseases/chemically induced ; Skin Diseases/metabolism
Chemical Substances	Cav1 protein, mouse ; Caveolin 1 ; Bleomycin (11056-06-7)
Language	English
Publishing date	2022-02-25
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2267670-3
ISSN	1932-6203 ; 1932-6203
ISSN (online)	1932-6203
ISSN	1932-6203
DOI	10.1371/journal.pone.0264413
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Article ; Online: Multiple subregions within the caveolin-1 scaffolding domain inhibit fibrosis, microvascular leakage, and monocyte migration.

Charles F Reese / Panneerselvam Chinnakkannu / Elena Tourkina / Stanley Hoffman / Dhandapani Kuppuswamy

PLoS ONE, Vol 17, Iss 2, p e

2022 Volume 0264413

Abstract	The caveolin-1 scaffolding domain (CSD, amino acids 82-101 of caveolin-1) has been shown to suppress bleomycin-induced lung and skin fibrosis and angiotensin II (AngII)-induced myocardial fibrosis. To identify active subregions within CSD, we split its sequence into three slightly overlapping 8-amino acid subregions (82-89, 88-95, and 94-101). Interestingly, all three peptides showed activity. In bleomycin-treated mice, all three subregions suppressed the pathological effects on lung and skin tissue morphology. In addition, while bone marrow monocytes isolated from bleomycin-treated mice showed greatly enhanced migration in vitro toward CXCL12, treatment in vivo with CSD and its subregions almost completely suppressed this enhanced migration. In AngII-induced heart failure, both 82-89 and 88-95 significantly suppressed fibrosis (both Col I and HSP47 levels), microvascular leakage, and heart weight/ body weight ratio (HW/BW) while improving ventricular function. In contrast, while 94-101 suppressed the increase in Col I, it did not improve the other parameters. The idea that all three subregions can be active depending on the assay was further supported by experiments studying the in vitro migration of human monocytes in which all three subregions were extremely active. These studies are very novel in that it has been suggested that there is only one active region within CSD that is centered on amino acids 90-92. In contrast, we demonstrate here the presence of other active regions within CSD.
Keywords	Medicine ; R ; Science ; Q
Subject code	500
Language	English
Publishing date	2022-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
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Article ; Online: Caveolin-1 signaling in lung fibrosis.

Tourkina, Elena / Hoffman, Stanley

The open rheumatology journal

2012 Volume 6, Page(s) 116–122

Abstract: Caveolin-1 is a master regulator of several signaling cascades because it is able to bind to and thereby inhibit members of a variety of kinase families. While associated with caveolae and involved in their generation, caveolin-1 is also present at other ...

Abstract	Caveolin-1 is a master regulator of several signaling cascades because it is able to bind to and thereby inhibit members of a variety of kinase families. While associated with caveolae and involved in their generation, caveolin-1 is also present at other sites. A variety of studies have suggested that caveolin-1 may be a useful therapeutic target in fibrotic diseases of the lung and other tissues because in these diseases a low level of caveolin-1 expression is associated with a high level of collagen expression and fibrosis. Reduced caveolin-1 expression is observed not only in the fibroblasts that secrete collagen, but also in epithelial cells and monocytes. This is intriguing because both epithelial cells and monocytes have been suggested to be precursors of fibroblasts. Likely downstream effects of loss of caveolin-1 in fibrosis include activation of TGF-β signaling and upregulation of CXCR4 in monocytes resulting in their enhanced migration into damaged tissue where its ligand CXCL12 is produced. Finally, it may be possible to target caveolin-1 in fibrotic diseases without the use of gene therapy. A caveolin-1 peptide (caveolin-1 scaffolding domain) has been identified that retains the function of the full-length molecule to inhibit kinases and that can be modified by addition of the Antennapedia internalization sequence to allow it to enter cells both in vitro and in vivo.
Language	English
Publishing date	2012-06-15
Publishing country	United Arab Emirates
Document type	Journal Article
ZDB-ID	2395999-X
ISSN	1874-3129 ; 1874-3129
ISSN (online)	1874-3129
ISSN	1874-3129
DOI	10.2174/1874312901206010116
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Article ; Online: Fibrocytes in the Fibrotic Lung

StanleyHoffman / ElenaTourkina

Frontiers in Pharmacology, Vol

Altered Phenotype Detected by Flow Cytometry

2014 Volume 5

Abstract: Fibrocytes are bone marrow hematopoietic-derived cells that also express a mesenchymal cell marker (commonly collagen I) and participate in fibrotic diseases of multiple organs. Given their origin, they or their precursors must be circulating cells ... ...

Abstract	Fibrocytes are bone marrow hematopoietic-derived cells that also express a mesenchymal cell marker (commonly collagen I) and participate in fibrotic diseases of multiple organs. Given their origin, they or their precursors must be circulating cells before recruitment into target tissues. While most previous studies focused on circulating fibrocytes, here we focus on the fibrocyte phenotype in fibrotic tissue. The study’s relevance to human disease is heightened by use of a model in which bleomycin is delivered systemically, recapitulating several features of human scleroderma including multi-organ fibrosis not observed when bleomycin is delivered directly into the lungs. Using flow cytometry, we find in the fibrotic lung a large population of CD45high fibrocytes (called Region I) rarely found in vehicle-treated control mice. A second population of CD45+ fibrocytes (called Region II) is observed in both control and fibrotic lung. The level of CD45 in circulating fibrocytes is far lower than in either Region I or II lung fibrocytes. The chemokine receptors CXCR4 and CCR5 are expressed at higher levels in Region I than in Region II and are present at very low levels in all other lung cells including CD45+/collagen I- leucocytes. The collagen chaperone HSP47 is present at similar high levels in both Regions I and II, but at a higher level in fibrotic lung than in control lung. There is also a major population of HSP47high/CD45- cells in fibrotic lung not present in control lung. CD44 is present at higher levels in Region I than in Region II and at much lower levels in all other cells including CD45+/collagen I- leucocytes. When lung fibrosis is inhibited by restoring caveolin-1 activity using a caveolin-1 scaffolding domain peptide (CSD), a strong correlation is observed between fibrocyte number and fibrosis score. In summary, the distinctive phenotype of fibrotic lung fibrocytes suggests that fibrocyte differentiation occurs primarily within the target organ.
Keywords	Bone Marrow ; Collagen ; CXCR4 ; caveolin-1 ; CD44 ; scleroderma ; CD45. CCR5 ; HSP47 ; monocyte recruitment ; Therapeutics. Pharmacology ; RM1-950 ; Medicine ; R
Subject code	610
Language	English
Publishing date	2014-06-01T00:00:00Z
Publisher	Frontiers
Document type	Article ; Online
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Article ; Online: Caveolin-1 Regulates Chemokine Receptor 5-Mediated Contribution of Bone Marrow-Derived Cells to Dermal Fibrosis

ElenaTourkina / RichardPVisconti

Frontiers in Pharmacology, Vol

2014 Volume 5

Abstract: In fibrotic diseases caveolin-1 underexpression in fibroblasts results in collagen overexpression and in monocytes leads to hypermigration. These profibrotic behaviors are blocked by the caveolin-1 scaffolding domain peptide (CSD) which compensates for ... ...

Abstract	In fibrotic diseases caveolin-1 underexpression in fibroblasts results in collagen overexpression and in monocytes leads to hypermigration. These profibrotic behaviors are blocked by the caveolin-1 scaffolding domain peptide (CSD) which compensates for caveolin-1 deficiency. Monocytes and fibroblasts are related in that monocytes are the progenitors of fibrocytes (CD45+/Collagen I+ cells) that, in turn, are the progenitors of many fibroblasts in fibrotic tissues. In an additional anti-fibrotic activity, CSD blocks monocyte differentiation into fibrocytes. We studied a mouse fibrosis model (Pump Model) involving systemic bleomycin delivery that closely models scleroderma (SSc) in several ways, the most important of which for this study is that fibrosis is observed in the lungs, skin, and internal organs. We show here that dermal thickness is increased 2-fold in the Pump Model and that this effect is almost completely blocked by CSD (p < 0.001). Concomitantly, the subcutaneous fat layer becomes > 80 % thinner. This effect is also blocked by CSD (p < 0.001). Even in mice receiving vehicle instead of bleomycin, CSD increases the thickness of the fat layer. To study the mechanisms of action of bleomycin and CSD, we examined the accumulation of the chemokine receptor CCR5 and its ligands MIP1α and MIP1β in fibrotic tissue and their roles in monocyte migration. Fibrocytes and other leukocytes expressing CCR5 and its ligands were present at high levels in the fibrotic dermis of SSc patients and Pump Model mice while CSD blocked their accumulation in mouse dermis. Migration toward CCR5 ligands of SSc monocytes and Pump Model bone marrow cells was 3-fold greater than cells from control subjects. This enhanced migration was almost completely blocked by CSD. These results suggest that low monocyte caveolin-1 promotes fibrosis by enhancing the recruitment of fibrocytes and their progenitors into affected tissue.
Keywords	Bleomycin ; Lipodystrophy ; Migration ; Adipocyte ; monocyte ; scleroderma ; fibrocyte ; Therapeutics. Pharmacology ; RM1-950 ; Medicine ; R
Language	English
Publishing date	2014-06-01T00:00:00Z
Publisher	Frontiers Media S.A.
Document type	Article ; Online
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Article ; Online: Reversal of maladaptive fibrosis and compromised ventricular function in the pressure overloaded heart by a caveolin-1 surrogate peptide.

Pleasant-Jenkins, Dorea / Reese, Charles / Chinnakkannu, Panneerselvem / Kasiganesan, Harinath / Tourkina, Elena / Hoffman, Stanley / Kuppuswamy, Dhandapani

Laboratory investigation; a journal of technical methods and pathology

2017 Volume 97, Issue 4, Page(s) 370–382

Abstract: Chronic ventricular pressure overload (PO) results in congestive heart failure (CHF) in which myocardial fibrosis develops in concert with ventricular dysfunction. Caveolin-1 is important in fibrosis in various tissues due to its decreased expression in ... ...

Abstract	Chronic ventricular pressure overload (PO) results in congestive heart failure (CHF) in which myocardial fibrosis develops in concert with ventricular dysfunction. Caveolin-1 is important in fibrosis in various tissues due to its decreased expression in fibroblasts and monocytes. The profibrotic effects of low caveolin-1 can be blocked with the caveolin-1 scaffolding domain peptide (CSD, a caveolin-1 surrogate) using both mouse models and human cells. We have studied the beneficial effects of CSD on mice in which PO was induced by trans-aortic constriction (TAC). Beneficial effects observed in TAC mice receiving CSD injections daily included: improved ventricular function (increased ejection fraction, stroke volume, and cardiac output; reduced wall thickness); decreased collagen I, collagen chaperone HSP47, fibronectin, and CTGF levels; decreased activation of non-receptor tyrosine kinases Pyk2 and Src; and decreased activation of eNOS. To determine the source of cells that contribute to fibrosis in CHF, flow cytometric studies were performed that suggested that myofibroblasts in the heart are in large part bone marrow-derived. Two CD45+ cell populations were observed. One (Zone 1) contained CD45+/HSP47-/macrophage marker+ cells (macrophages). The second (Zone 2) contained CD45
MeSH term(s)	Animals ; Aorta/pathology ; Aorta/physiopathology ; Blotting, Western ; Caveolin 1/pharmacology ; Collagen Type I/genetics ; Collagen Type I/metabolism ; Constriction, Pathologic/physiopathology ; Fibrosis/prevention & control ; Flow Cytometry ; Focal Adhesion Kinase 2/metabolism ; Gene Expression/drug effects ; HSP47 Heat-Shock Proteins/genetics ; HSP47 Heat-Shock Proteins/metabolism ; Heart/drug effects ; Heart/physiopathology ; Humans ; Integrin beta3/metabolism ; Leukocyte Common Antigens/metabolism ; Male ; Mice, Inbred C57BL ; Myocardium/metabolism ; Myocardium/pathology ; Nitric Oxide Synthase Type III/metabolism ; Peptide Fragments/pharmacology ; Pressure ; Reverse Transcriptase Polymerase Chain Reaction ; Ventricular Function/drug effects ; src-Family Kinases/metabolism
Chemical Substances	Caveolin 1 ; Collagen Type I ; HSP47 Heat-Shock Proteins ; Integrin beta3 ; Peptide Fragments ; caveolin-1 (82-101) ; Nitric Oxide Synthase Type III (EC 1.14.13.39) ; Focal Adhesion Kinase 2 (EC 2.7.10.2) ; Ptk2b protein, mouse (EC 2.7.10.2) ; src-Family Kinases (EC 2.7.10.2) ; Leukocyte Common Antigens (EC 3.1.3.48)
Language	English
Publishing date	2017-01-23
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	80178-1
ISSN	1530-0307 ; 0023-6837
ISSN (online)	1530-0307
ISSN	0023-6837
DOI	10.1038/labinvest.2016.153
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Article ; Online: Adipose-derived mesenchymal stromal/stem cells in systemic sclerosis: Alterations in function and beneficial effect on lung fibrosis are regulated by caveolin-1.

Lee, Rebecca / Del Papa, Nicoletta / Introna, Martin / Reese, Charles F / Zemskova, Marina / Bonner, Michael / Carmen-Lopez, Gustavo / Helke, Kristi / Hoffman, Stanley / Tourkina, Elena

Journal of scleroderma and related disorders

2019 Volume 4, Issue 2, Page(s) 127–136

Abstract: The potential value of mesenchymal stromal/stem cell therapy in treating skin fibrosis in scleroderma (systemic sclerosis) and of the caveolin-1 scaffolding domain peptide in treating lung, skin, and heart fibrosis is known. To understand how these ... ...

Abstract	The potential value of mesenchymal stromal/stem cell therapy in treating skin fibrosis in scleroderma (systemic sclerosis) and of the caveolin-1 scaffolding domain peptide in treating lung, skin, and heart fibrosis is known. To understand how these observations may relate to differences between mesenchymal stromal/stem cells from healthy subjects and subjects with fibrosis, we have characterized the fibrogenic and adipogenic potential of adipose-derived mesenchymal stromal/stem cells from systemic sclerosis patients, from mice with fibrotic lung and skin disease induced by systemic bleomycin treatment, and from healthy controls. Early passage systemic sclerosis adipose-derived mesenchymal stromal/stem cells have a profibrotic/anti-adipogenic phenotype compared to healthy adipose-derived mesenchymal stromal/stem cells (low caveolin-1, high α-smooth muscle actin, high HSP47, low pAKT, low capacity for adipogenic differentiation). This phenotype is mimicked by treating healthy adipose-derived mesenchymal stromal/stem cells with transforming growth factor beta or caveolin-1 small interfering RNA and is reversed in systemic sclerosis adipose-derived mesenchymal stromal/stem cells by treatment with caveolin-1 scaffolding domain peptide, but not scrambled caveolin-1 scaffolding domain peptide. Similar results were obtained with adipose-derived mesenchymal stromal/stem cells from systemic sclerosis patients and from bleomycin-treated mice, indicating the central role of caveolin-1 in mesenchymal stromal/stem cell differentiation in fibrotic disease.
Language	English
Publishing date	2019-01-25
Publishing country	England
Document type	Journal Article
ISSN	2397-1991
ISSN (online)	2397-1991
DOI	10.1177/2397198318821510
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Article ; Online: Suppression of angiotensin II-induced pathological changes in heart and kidney by the caveolin-1 scaffolding domain peptide.

Chinnakkannu, Panneerselvam / Reese, Charles / Gaspar, John Antony / Panneerselvam, Saraswathi / Pleasant-Jenkins, Dorea / Mukherjee, Rupak / Baicu, Catalin / Tourkina, Elena / Hoffman, Stanley / Kuppuswamy, Dhandapani

PloS one

2018 Volume 13, Issue 12, Page(s) e0207844

Abstract: Dysregulation of the renin-angiotensin system leads to systemic hypertension and maladaptive fibrosis in various organs. We showed recently that myocardial fibrosis and the loss of cardiac function in mice with transverse aortic constriction (TAC) could ... ...

Abstract	Dysregulation of the renin-angiotensin system leads to systemic hypertension and maladaptive fibrosis in various organs. We showed recently that myocardial fibrosis and the loss of cardiac function in mice with transverse aortic constriction (TAC) could be averted by treatment with the caveolin-1 scaffolding domain (CSD) peptide. Here, we used angiotensin II (AngII) infusion (2.1 mg/kg/day for 2 wk) in mice as a second model to confirm and extend our observations on the beneficial effects of CSD on heart and kidney disease. AngII caused cardiac hypertrophy (increased heart weight to body weight ratio (HW/BW) and cardiomyocyte cross-sectional area); fibrosis in heart and kidney (increased levels of collagen I and heat shock protein-47 (HSP47)); and vascular leakage (increased levels of IgG in heart and kidney). Echocardiograms of AngII-infused mice showed increased left ventricular posterior wall thickness (pWTh) and isovolumic relaxation time (IVRT), and decreased ejection fraction (EF), stroke volume (SV), and cardiac output (CO). CSD treatment (i.p. injections, 50 μg/mouse/day) of AngII-infused mice significantly suppressed all of these pathological changes in fibrosis, hypertrophy, vascular leakage, and ventricular function. AngII infusion increased β1 and β3 integrin levels and activated Pyk2 in both heart and kidney. These changes were also suppressed by CSD. Finally, bone marrow cell (BMC) isolated from AngII-infused mice showed hyper-migration toward SDF1. When AngII-infused mice were treated with CSD, BMC migration was reduced to the basal level observed in cells from control mice. Importantly, CSD did not affect the AngII-induced increase in blood pressure (BP), indicating that the beneficial effects of CSD were not mediated via normalization of BP. These results strongly indicate that CSD suppresses AngII-induced pathological changes in mice, suggesting that CSD can be developed as a treatment for patients with hypertension and pressure overload-induced heart failure.
MeSH term(s)	Angiotensin II/administration & dosage ; Angiotensin II/physiology ; Angiotensins/antagonists & inhibitors ; Animals ; Bone Marrow Cells/drug effects ; Bone Marrow Cells/physiology ; Capillary Permeability/drug effects ; Caveolin 1/administration & dosage ; Cell Movement/drug effects ; Fibrosis/etiology ; Fibrosis/pathology ; Fibrosis/prevention & control ; Heart/drug effects ; Hypertrophy, Left Ventricular/etiology ; Hypertrophy, Left Ventricular/pathology ; Hypertrophy, Left Ventricular/prevention & control ; Kidney/drug effects ; Kidney/pathology ; Male ; Mice ; Mice, Inbred C57BL ; Myocardium/pathology ; Peptide Fragments/administration & dosage ; Renin-Angiotensin System/drug effects ; Renin-Angiotensin System/physiology ; Signal Transduction/drug effects
Chemical Substances	Angiotensins ; Caveolin 1 ; Peptide Fragments ; caveolin-1 (82-101) ; Angiotensin II (11128-99-7)
Language	English
Publishing date	2018-12-21
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2267670-3
ISSN	1932-6203 ; 1932-6203
ISSN (online)	1932-6203
ISSN	1932-6203
DOI	10.1371/journal.pone.0207844
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Article: Enhanced chemokine-receptor expression, function, and signaling in healthy African American and scleroderma-patient monocytes are regulated by caveolin-1.

Lee, Rebecca / Reese, Charles / Perry, Beth / Heywood, Jonathan / Bonner, Michael / Zemskova, Marina / Silver, Richard M / Hoffman, Stanley / Tourkina, Elena

Fibrogenesis & tissue repair

2015 Volume 8, Page(s) 11

Abstract: Background: A major health disparity suffered by African Americans (AA) is a predisposition toward fibrotic diseases of the skin, lung, and other organs. We previously showed that healthy AA and scleroderma (systemic sclerosis (SSc)) patient monocytes ... ...

Abstract	Background: A major health disparity suffered by African Americans (AA) is a predisposition toward fibrotic diseases of the skin, lung, and other organs. We previously showed that healthy AA and scleroderma (systemic sclerosis (SSc)) patient monocytes share biochemical and functional differences from control Caucasian (C) monocytes that may predispose AA to SSc. The central difference is a decrease in caveolin-1. Low caveolin-1 levels promote monocyte migration, their differentiation into fibrocytes, and fibrocyte recruitment into fibrotic tissues. Here we have greatly expanded our studies on the mechanism of action in fibrosis of caveolin-1 in AA and SSc monocytes. Results: Expression of chemokine receptors (CCR1, CCR2, CCR3) is enhanced in healthy AA monocytes compared to healthy C monocytes and further increased in SSc monocytes. A parallel increase in function occurs assessed by migration toward chemokines MCP-1 and MCP-3. Chemokine-receptor expression and function are inhibited by the caveolin-1 scaffolding domain peptide (CSD) via its action as a surrogate for caveolin-1. Cells bearing chemokine receptors accumulate to high levels in fibrotic lung and skin tissue from SSc patients and from mice treated with bleomycin. This accumulation is almost completely blocked in mice treated with CSD. In signaling studies, Src activation is enhanced in AA monocytes compared to C monocytes and further increased in SSc monocytes. Lyn is also highly activated in SSc monocytes. Src and Lyn activation are inhibited by CSD. Src and Lyn's roles in monocyte migration were demonstrated using specific inhibitors. Conclusions: To the best of our knowledge, this is the first report that the expression and function of CCR1, CCR2, and CCR3 are upregulated in monocytes from healthy AA and from SSc patients via molecular mechanisms involving caveolin-1, Src/Lyn, and MEK/ERK. The results suggest that the migration/recruitment of monocytes and fibrocytes into fibrotic tissues, mediated at least in part by CCR1, CCR2, and CCR3, plays a major role in the progression of lung and skin fibrosis and in the predisposition of AA to fibrotic diseases. Our findings further suggest that chemokine receptors and signaling molecules, particularly caveolin-1, that control their expression/function are promising targets for treating fibrotic diseases.
Language	English
Publishing date	2015-06-20
Publishing country	England
Document type	Journal Article
ZDB-ID	2460211-5
ISSN	1755-1536
ISSN	1755-1536
DOI	10.1186/s13069-015-0028-7
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Article ; Online: Racial differences between blacks and whites with systemic sclerosis.

Silver, Richard M / Bogatkevich, Galina / Tourkina, Elena / Nietert, Paul J / Hoffman, Stanley

Current opinion in rheumatology

2012 Volume 24, Issue 6, Page(s) 642–648

Abstract: Purpose of review: Racial disparities appear to exist in the susceptibility and severity of systemic sclerosis (SSc, scleroderma) and are responsible for a greater health burden in blacks as compared with whites. Disparities in socioeconomic status and ... ...

Abstract	Purpose of review: Racial disparities appear to exist in the susceptibility and severity of systemic sclerosis (SSc, scleroderma) and are responsible for a greater health burden in blacks as compared with whites. Disparities in socioeconomic status and access to healthcare do not sufficiently explain the observed differences in prevalence and mortality. It is important to determine whether there might be a biologic basis for the racial disparities observed in SSc. Recent findings: We present data to suggest that the increased susceptibility and severity of SSc in blacks may result in part from an imbalance of profibrotic and antifibrotic factors. Racial differences in the expression of transforming growth factor-β1 (TGF-β1) and caveolin-1, as well as differences in the expression of hepatocyte growth factor and PPAR-γ, have been demonstrated in blacks with SSc, as well as in normal black individuals. A genetic predisposition to fibrosis may account for much of the racial disparities between black and white patients with SSc. Summary: A better understanding of the biologic basis for the racial disparities observed in SSc may lead to improved therapies, along with the recognition that different therapies may need to be adapted for different groups of patients.
MeSH term(s)	African Americans/ethnology ; African Americans/genetics ; Caveolin 1/genetics ; Disease Susceptibility/ethnology ; European Continental Ancestry Group/ethnology ; European Continental Ancestry Group/genetics ; Genetic Predisposition to Disease/ethnology ; Genetic Predisposition to Disease/genetics ; Health Status Disparities ; Hepatocyte Growth Factor/genetics ; Humans ; PPAR gamma/genetics ; Scleroderma, Systemic/ethnology ; Scleroderma, Systemic/genetics ; Scleroderma, Systemic/therapy ; Transforming Growth Factor beta1/genetics
Chemical Substances	Caveolin 1 ; PPAR gamma ; Transforming Growth Factor beta1 ; Hepatocyte Growth Factor (67256-21-7)
Language	English
Publishing date	2012-09-06
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S. ; Review
ZDB-ID	1045317-9
ISSN	1531-6963 ; 1040-8711
ISSN (online)	1531-6963
ISSN	1040-8711
DOI	10.1097/BOR.0b013e328356d9dc
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