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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 <jats:italic>in vivo<\/jats:italic>.<\/jats:p><\/jats:sec><jats:sec><jats:title>Experimental Approach<\/jats:title><jats:p>ALI\/ARDS and pulmonary fibrosis were induced experimentally in wild\u2010type and cortistatin\u2010deficient 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.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key Results<\/jats:title><jats:p>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\u2010deficient pulmonary macrophages and fibroblasts showed exaggerated <jats:italic>ex vivo<\/jats:italic> 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.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion and Implications<\/jats:title><jats:p>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\u2010based therapies could emerge as attractive candidates to treat severe ALI\/ARDS, including SARS\u2010CoV\u20102\u2010associated ARDS.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.15615","type":"journal-article","created":{"date-parts":[[2021,7,8]],"date-time":"2021-07-08T19:23:07Z","timestamp":1625772187000},"page":"4368-4388","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Protective role of cortistatin in pulmonary inflammation and fibrosis"],"prefix":"10.1111","volume":"178","author":[{"given":"Margarita","family":"Barriga","sequence":"first","affiliation":[{"name":"Department of Immunology and Cell Biology Institute of Parasitology and Biomedicine Lopez\u2010Neyra IPBLN\u2010CSIC  Granada Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raquel","family":"Benitez","sequence":"additional","affiliation":[{"name":"Department of Immunology and Cell Biology Institute of 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