Protective role of cortistatin in pulmonary inflammation and fibrosis

Autor(es)

Barriga, Margarita ^[1] ; Benitez, Raquel ^[1] ; Ferraz-de-Paula, Viviane ^{[2, 1]} ; Garcia-Frutos, Marina ^[1] ; Caro, Marta ^[1] ; Robledo, Gema ^[1] ; O'Valle, Francisco ^{[3, 4]} ; Campos-Salinas, Jenny ^[1] ; Delgado, Mario ^[1]

Afiliação do(s) autor(es)

^[1] Inst Parasitol & Biomed Lopez Neyra IPBLN CSIC, Dept Immunol & Cell Biol, Granada - Spain

^[2] Univ Sao Paulo, Sch Pharmaceut Sci, Dept Clin & Toxicol Anal, Sao Paulo - Brazil

^[3] Univ Granada, Sch Med, Pathol Dept, IBIMER, CIBM, Granada - Spain

^[4] Biosanit Res Inst IBS Granada, Granada - Spain

• Tipo de documento: Artigo Científico
• Fonte: British Journal of Pharmacology; v. 178, n. 21 AUG 2021.
• Citações Web of Science: 0

Resumo

Background and Purpose 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. Experimental Approach 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. Key Results 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. Conclusion and Implications 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. (AU)

• Processo FAPESP: 12/21767-5 - Avaliação dos mecanismos neuroimunes envolvidos na diminuição da atividade e da migração de neutrófilos induzida por estresse num modelo murino de inflamação intestinal
• Beneficiário: Viviane Ferraz de Paula
• Modalidade de apoio: Bolsas no Exterior - Estágio de Pesquisa - Pós-Doutorado