cortistatin-14 and Fibrosis

Scleroderma, or systemic sclerosis, is a complex connective tissue disorder characterized by autoimmunity, vasculopathy, and progressive fibrosis of the 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 the skin emerge as potential candidates. We investigated the role played by the neuropeptide cortistatin in a preclinical model of scleroderma.. 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 the skin and lungs.. An inverse correlation between cortistatin levels and fibrogenic activation exists in the 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, loss of microvessels, and predisposition 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.. 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.

Topics: Animals; Bleomycin; Disease Models, Animal; Fibrosis; Mice; Neuropeptides; Pulmonary Fibrosis; Scleroderma, Systemic

Liver fibrosis induced by chronic hepatic injury remains a major cause of morbidity and mortality worldwide. Identification of susceptibility/prognosis factors and new therapeutic tools for treating hepatic fibrotic disorders are urgent medical needs. Cortistatin is a neuropeptide with potent anti-inflammatory and anti-fibrotic activities in lung that binds to receptors that are expressed in liver fibroblasts and hepatic stellate cells. We evaluated the capacity of cortistatin to regulate liver fibrosis.. We experimentally induced liver fibrosis in mice by chronic CCl. Hepatic expression of cortistatin inversely correlated with liver fibrosis grade in mice and humans with hepatic disorders. Cortistatin-deficient mice showed exacerbated signs of liver damage and fibrosis and increased mortality rates when challenged by hepatotoxic and cholestatic injury. Compared with wild-type mice, non-parenchymal liver cells isolated from cortistatin-deficient mice showed increased presence of cells with activated myofibroblast phenotypes and a differential genetic signature that is indicative of activated hepatic stellate cells and periportal fibroblasts and of myofibroblasts with active contractile apparatus. Cortistatin treatment reversed in vivo and in vitro these exaggerated fibrogenic phenotypes and protected from progression to severe liver fibrosis in response to hepatic injury.. We identify cortistatin as an endogenous molecular brake on liver fibrosis and its deficiency as a potential poor-prognosis marker for chronic hepatic disorders that link with fibrosis. Cortistatin-based therapies emerge as attractive strategies for ameliorating severe hepatic fibrosis of various aetiologies.

Topics: Animals; Chemical and Drug Induced Liver Injury, Chronic; Fibrosis; Hepatic Stellate Cells; Liver; Liver Cirrhosis; Mice; Myofibroblasts; Neuropeptides

Acute lung injury (ALI), acute respiratory distress syndrome (ARDS) and pulmonary fibrosis remain major causes of morbidity, mortality and a healthcare burden in critically ill patient. There is an urgent need to identify factors causing susceptibility and for the design of new therapeutic agents. Here, we evaluate the effectiveness of the immunomodulatory neuropeptide cortistatin to regulate pulmonary inflammation and fibrosis in vivo.. ALI/ARDS and pulmonary fibrosis were induced experimentally in wild-type and cortistatin-deficient mice by pulmonary infusion of the bacterial endotoxin LPS or the chemotherapeutic drug bleomycin, and the histopathological signs, pulmonary leukocyte infiltration and cytokines, and fibrotic markers were evaluated.. Partially deficient mice in cortistatin showed exacerbated pulmonary damage, pulmonary inflammation, alveolar oedema and fibrosis, and subsequent increased respiratory failure and mortality when challenged to LPS or bleomycin, even at low doses. Treatment with cortistatin reversed these aggravated phenotypes and protected from progression to severe ARDS and fibrosis, after high exposure to both injury agents. Moreover, cortistatin-deficient pulmonary macrophages and fibroblasts showed exaggerated ex vivo inflammatory and fibrotic responses, and treatment with cortistatin impaired their activation. Finally, the protective effects of cortistatin in ALI and pulmonary fibrosis were partially inhibited by specific antagonists for somatostatin and ghrelin receptors.. We identified cortistatin as an endogenous inhibitor of pulmonary inflammation and fibrosis. Deficiency in cortistatin could be a marker of poor prognosis in inflammatory/fibrotic pulmonary disorders. Cortistatin-based therapies could emerge as attractive candidates to treat severe ALI/ARDS, including SARS-CoV-2-associated ARDS.

Topics: Animals; Disease Models, Animal; Fibrosis; Inflammation; Lipopolysaccharides; Lung; Mice; Neuropeptides; Pneumonia