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  • Margarita Barriga,
  • Raquel Benitez,
  • Viviane Ferraz-de-Paula,
  • Marta Caro,
  • Gema Robledo,
  • Francisco O'Valle,
  • Jenny Campos-Salinas,
  • Mario Delgado
Margarita Barriga
Instituto de Parasitologia y Biomedicina Lopez-Neyra

Corresponding Author:[email protected]

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Raquel Benitez
Instituto de Parasitologia y Biomedicina Lopez-Neyra
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Viviane Ferraz-de-Paula
School of Veterinary Medicine, University of São Paulo
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Marta Caro
Instituto de Parasitologia y Biomedicina Lopez-Neyra
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Gema Robledo
Institute of Parasitology and Biomedicine López-Neyra
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Francisco O'Valle
University ofGranada
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Jenny Campos-Salinas
Instituto de Parasitologia y Biomedicina Lopez-Neyra
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Mario Delgado
Institute of Parasitology and Biomedicine López-Neyra
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Background and Purpose: Acute lung injury (ALI), acute respiratory distress syndrome (ARDS) and pulmonary fibrosis remain major causes of morbidity, mortality and healthcare burden in the critically ill patient. There is an urgent medical need for identifying factors of susceptibility and prognosis and for designing new therapeutic tools for treating these disorders. Here, we evaluate the capacity 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-exposition to both injury agents. Moreover, cortistatin-deficient pulmonary macrophages and fibroblasts showed exaggerated ex vivo inflammatory and fibrotic responses. The anti-fibrotic protective effect of cortistatin was also observed in experimental scleroderma, in which lack of cortistatin predisposes to develop more severe dermal lesions and associated pulmonary fibrosis. Conclusion and Implications: We identify to cortistatin as an endogenous break of pulmonary inflammation and fibrosis. Deficiency in cortistatin could be a marker of poor-prognosis in inflammatory/fibrotic pulmonary disorders. Cortistatin-based therapies emerge as attractive candidates to treat severe ALI/ARDS, including SARS-Cov-2-associated ARDS.
12 Feb 2021Submitted to British Journal of Pharmacology
17 Feb 2021Submission Checks Completed
17 Feb 2021Assigned to Editor
19 Feb 2021Reviewer(s) Assigned
05 May 2021Review(s) Completed, Editorial Evaluation Pending
05 May 2021Editorial Decision: Revise Minor
02 Jun 20211st Revision Received
03 Jun 2021Submission Checks Completed
03 Jun 2021Assigned to Editor
03 Jun 2021Reviewer(s) Assigned
23 Jun 2021Review(s) Completed, Editorial Evaluation Pending
24 Jun 2021Editorial Decision: Accept
Nov 2021Published in British Journal of Pharmacology volume 178 issue 21 on pages 4368-4388. 10.1111/bph.15615