Protective role of cortistatin in pulmonary inflammation and fibrosis Barriga, Margarita Benítez, Raquel Ferraz de Paula, Viviane García Frutos, Marina Caro, Marta Robledo, Gema O'Valle Ravassa, Francisco Javier Campos Salinas, Jenny Karina Delgado, Mario Acute lung injury Fibroblasts Macrophages Neuropeptide Pulmonary inflammation Fundacao de Amparo a Pesquisa do Estado de Sao Paulo, Grant/Award Number: 12/21767-5; Ministerio de Ciencia e Innovacion, Grant/Award Number: SAF2015-67787-R 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. 2021-10-01T11:28:40Z 2021-10-01T11:28:40Z 2021-07-08 journal article Barriga, M... [et al.] (2021). Protective role of cortistatin in pulmonary inflammation and fibrosis. British Journal of Pharmacology, 1– 21. [https://doi.org/10.1111/bph.15615] http://hdl.handle.net/10481/70575 10.1111/bph.15615 eng http://creativecommons.org/licenses/by/3.0/es/ open access Atribución 3.0 España John Wiley & Sons