Abstract
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.
Highlights
Despite major treatment efforts made over the past decades, acute lung injury (ALI) and its most severe form, acute respiratory distress syndrome (ARDS), characterized by refractory hypoxia, severe inflammation, increased vascular permeability and diffuse alveolar damage, remains a major cause of morbidity and mortality in critically ill patients (Matthay et al, 2017)
Cortistatin-14 (CST-14) is a cyclic neuropeptide belonging to the somatostatin family that has emerged as a potent immunomodulatory agent (Gonzalez-Rey & Delgado, 2008) with capacity to protect against exacerbated inflammatory and autoimmune responses in various experimental models of sepsis, rheumatoid arthritis, colitis, myocarditis and multiple sclerosis (Delgado-Maroto et al, 2017; Gonzalez-Rey, Chorny, Del Moral, et al, 2007; Gonzalez-Rey, Chorny, Robledo, & Delgado, 2006; Gonzalez-Rey, Varela, Sheibanie, et al, 2006; Souza-Moreira et al, 2013)
We further investigated the role played by cortistatin in a wellcharacterized model of pulmonary fibrosis induced by intratracheal injection of bleomycin, which shares significant similarities with human idiopathic pulmonary fibrosis (IPF) and has been widely used for studying pulmonary fibrogenesis and evaluating the effect of therapeutic antifibrotic strategies (Kolb et al, 2020)
Summary
Despite major treatment efforts made over the past decades, acute lung injury (ALI) and its most severe form, acute respiratory distress syndrome (ARDS), characterized by refractory hypoxia, severe inflammation, increased vascular permeability and diffuse alveolar damage, remains a major cause of morbidity and mortality in critically ill patients (Matthay et al, 2017). Cortistatin-14 (CST-14) is a cyclic neuropeptide belonging to the somatostatin family that has emerged as a potent immunomodulatory agent (Gonzalez-Rey & Delgado, 2008) with capacity to protect against exacerbated inflammatory and autoimmune responses in various experimental models of sepsis, rheumatoid arthritis, colitis, myocarditis and multiple sclerosis (Delgado-Maroto et al, 2017; Gonzalez-Rey, Chorny, Del Moral, et al, 2007; Gonzalez-Rey, Chorny, Robledo, & Delgado, 2006; Gonzalez-Rey, Varela, Sheibanie, et al, 2006; Souza-Moreira et al, 2013) These effects are exerted through the regulation of a plethora of inflammatory cytokines and chemokines, and by deactivating macrophages and lymphocytes, indicating that it is a multitargeted and safe modulator of the cytokine storm in various tissues. We will investigate the role of cortistatin as a potential endogenous protective factor in the progression to severe ALI and pulmonary fibrosis in mice that are partially or totally deficient in this neuropeptide
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