THE NEUROPEPTIDE CORTISTATIN REGULATES DERMAL AND PULMONARY FIBROSIS IN AN EXPERIMENTAL MODEL OF SYSTEMIC SCLEROSIS

2021 ◽  
Author(s):  
Margarita Barriga ◽  
Raquel Benitez ◽  
Gema Robledo ◽  
Marta Caro ◽  
Francisco O’Valle ◽  
...  
Keyword(s):  
Systemic Sclerosis ◽  
Connective Tissue ◽  
Inverse Correlation ◽  
Skin Lesions ◽  
Tissue Growth ◽  
Dermal Fibroblasts ◽  
Preclinical Model ◽  
Wild Type ◽  
Inflammatory Infiltration ◽  
Oncologic Patients

Introduction: Scleroderma, or systemic sclerosis, is a complex connective tissue disorder characterized by autoimmunity, vasculopathy and progressive fibrosis of skin and internal organs. Because its aetiology is unknown, the identification of genes/factors involved in disease severity, differential clinical forms and associated-complications is critical for understanding its pathogenesis and designing novel treatments. Neuroendocrine mediators in skin emerge as potential candidates. We investigated the role played by the neuropeptide cortistatin in a preclinical model of scleroderma. Methods: Dermal fibrosis was induced by repetitive intradermal injections of bleomycin in wild-type and cortistatin-deficient mice. The histopathological signs and expression of fibrotic markers were evaluated in skin and lungs. Results: An inverse correlation between cortistatin levels and fibrogenic activation exists in damaged skin and dermal fibroblasts. Bleomycin-challenged skin lesions of mice that are partially- and totally-deficient in cortistatin showed exacerbated histopathological signs of scleroderma, characterized by thicker and more fibrotic dermal layer, enlarged epidermis and increased inflammatory infiltration in comparison to those of wild-type mice. Cortistatin-deficiency enhanced dermal collagen deposits, connective tissue growth factor expression and loss of microvessels, and predisposed to suffer severe complications that co-occur with dermal exposition to bleomycin, including pulmonary fibrotic disease and increased mortality. Treatment with cortistatin mitigated these pathological processes. Discussion/Conclusion: We identify cortistatin as an endogenous break of skin inflammation and fibrosis. Deficiency in cortistatin could be a marker of poor-prognosis of scleroderma and associated-complications. Cortistatin-based therapies emerge as attractive candidates to treat severe forms of systemic sclerosis, and to manage fibrosis-related side effects of bleomycin-chemotherapy in oncologic patients.

Increased and prolonged inflammation and angiogenesis in delayed-type hypersensitivity reactions elicited in the skin of thrombospondin-2–deficient mice

Blood ◽  
2002 ◽  
Vol 99 (2) ◽  
pp. 538-545 ◽  
Author(s):  
Bernhard Lange-Asschenfeldt ◽  
Wolfgang Weninger ◽  
Paula Velasco ◽  
Themis R. Kyriakides ◽  
Ulrich H. von Andrian ◽  
...  
Keyword(s):  
Inflammatory Diseases ◽  
Angiogenesis Inhibitor ◽  
Dermal Fibroblasts ◽  
Delayed Type Hypersensitivity ◽  
Hypersensitivity Reactions ◽  
Wild Type ◽  
Edema Formation ◽  
Inflammatory Infiltration ◽  
Deficient Mice

Abstract Angiogenesis and enhanced microvascular permeability are hallmarks of a large number of inflammatory diseases. Although up-regulation of proangiogenic factors such as vascular endothelial growth factor and interleukin-8 have been previously reported in inflamed tissue, the biologic role of endogenous inhibitors of angiogenesis in inflammation has remained unclear. To investigate the biologic role of the potent angiogenesis inhibitor thrombospondin-2 (TSP-2) in the control of cutaneous inflammation, delayed-type hypersensitivity reactions were elicited in the ear skin of wild-type and TSP-2–deficient mice by topical sensitization and challenge with oxazolone. Cutaneous TSP-2 expression was up-regulated in the inflamed skin of wild-type mice, predominantly in dermal fibroblasts and microvessels. Lack of TSP-2 resulted in a significantly enhanced inflammatory response with increased angiogenesis, edema formation, and inflammatory infiltration. Ear swelling and inflammation persisted for more than 2 weeks in TSP-2–deficient mice, as compared with 1 week in wild-type mice. Although baseline vascular permeability was unchanged, significantly enhanced microvascular leakage was found in the inflamed skin of TSP-2–deficient mice. Moreover, the fraction of rolling leukocytes was significantly increased in the untreated skin of TSP-2–deficient mice. These results reveal an important role of TSP-2 in limiting the extent and the duration of edema formation, angiogenesis, and inflammatory cell infiltration during acute and chronic inflammation.

Clinical Manifestations of Scleroderma

1995 ◽  
Vol 16 (2) ◽  
pp. 49-49
Author(s):  
Patricia L. Haber
Keyword(s):  
Systemic Sclerosis ◽  
Connective Tissue ◽  
Clinical Manifestations ◽  
Skin Lesions ◽  
Localized Scleroderma ◽  
Unknown Etiology ◽  
Collagen Deposition ◽  
Muscle Fibrosis ◽  
Favorable Prognosis ◽  
Organ Systems

Scleroderma is a connective tissue disease of unknown etiology. Its most characteristic feature is thickening of the skin due to increased collagen deposition. However, the disease may involve multiple other organ systems. Two broad categories of scleroderma have been defined: localized and systemic. Although all forms of scleroderma are rare, localized scleroderma occurs more frequently than systemic sclerosis and has a more favorable prognosis. Several types of localized scleroderma exist. Morphea is characterized by the presence of one or more patches of hard, ivory-colored skin lesions. They begin with erythema and progress to nonpitting edema before becoming sclerotic. The margins of active lesions often have a violaceous hue. Underlying muscle fibrosis and atrophy may occur.

scholarly journals Differential Regulation of Angiotensin II-induced Expression of Connective Tissue Growth Factor by Protein Kinase C Isoforms in the Myocardium

2005 ◽  
Vol 280 (16) ◽  
pp. 15719-15726 ◽  
Author(s):  
Zhiheng He ◽  
Kerrie J. Way ◽  
Emi Arikawa ◽  
Eva Chou ◽  
Darren M. Opland ◽  
...  
Keyword(s):  
Protein Kinase C ◽  
Angiotensin Ii ◽  
Growth Factor ◽  
Protein Kinase ◽  
Connective Tissue ◽  
Mrna Expression ◽  
Tissue Growth ◽  
Dominant Negative ◽  
Wild Type ◽  
Kinase C

Protein kinase C (PKC) and angiotensin II (AngII) can regulate cardiac function in pathological conditions such as in diabetes or ischemic heart disease. We have reported that expression of connective tissue growth factor (CTGF) is increased in the myocardium of diabetic mice. Now we showed that the increase in CTGF expression in cardiac tissues of streptozotocin-induced diabetic rats was reversed by captopril and islet cell transplantation. Infusion of AngII in rats increased CTGF mRNA expression by 15-fold, which was completely inhibited by co-infusion with AT1 receptor antagonist, candesartan. Similarly, incubation of cultured cardiomyocytes with AngII increased CTGF mRNA expression by 2-fold, which was blocked by candesartan and a general PKC inhibitor, GF109203X. The role of PKC isoform-dependent action was further studied using adenoviral vector-mediated gene transfer of dominant negative (dn) PKC or wild type PKC isoforms. Expression of dnPKCα, -ϵ, and -ζ isoforms suppressed AngII-induced CTGF expression in cardiomyocytes. In contrast, expression of dominant negative PKCδ significantly increased AngII-induced CTGF expression, whereas expression of wild type PKCδ inhibited this induction. This inhibitory effect was further confirmed in the myocardium of transgenic mice with cardiomyocyte-specific overexpression of PKCδ (δTg mice). Thus, AngII can regulate CTGF expression in cardiomyocytes through a PKC activation-mediated pathway in an isoform-selective manner both in physiological and diabetic states and may contribute to the development of cardiac fibrosis in diabetic cardiomyopathy.

scholarly journals CLINICAL AND SEROLOGICAL PARAMETERS OF PROGRESSION AND PROGNOSIS IN PATIENTS WITH SYSTEMIC SCLEROSIS – A STATE OF THE ART REVIEW

2020 ◽  
Vol 73 (7) ◽  
pp. 1528-1532
Author(s):  
Ewa Wielosz ◽  
Maria Majdan
Keyword(s):  
Systemic Sclerosis ◽  
Connective Tissue ◽  
Rna Polymerase ◽  
Connective Tissue Disease ◽  
State Of The Art ◽  
Rna Polymerase Iii ◽  
Vascular Complications ◽  
Skin Lesions ◽  
Tendon Ruptures ◽  
Generalized Type

Systemic sclerosis (SSc) is a multi-organ connective tissue disease that leads to the dysfunction and the impaired morphology of blood vessels due to non-specific inflammation and progressive fibrosis. Due to the diversity of SSc and even though the factors predisposing to the severe course of SSc are known, it is not always possible to predict the disease progression and to determine the prognosis. Ideally, the group of patients with faster progression of organ lesions and a worse course of the disease should be identified and the early intensive treatment should be instituted. The aim of the article, is an attempt to identify the factors that worsen the prognosis in the course of SSc. The analysis of numerous studies demonstrated that patients with short-lasting SSc, with the presence of anti-RNA polymerase III antibodies, with a generalized type of SSc with quickly progressing skin lesions and males should be most strictly monitored. Moreover, vascular complications, tendon ruptures and fast capillaries loss observed in nailfold capillaroscopy are the factors deteriorating the prognosis in SSc. In conclusion, despite the known, the factors that worsen the prognosis, it is difficult to predict the course of systemic sclerosis. Due to its incompletely elucidated etiopathology as well as the diverse and unpredictable nature of the disease, reliable markers to determine the prognosis in SSc have not been found.

Sign in / Sign up

Export Citation Format

Share Document