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

Abstract

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.