Macrophage Polarization Favors Epithelial Repair During Acute Respiratory Distress Syndrome

Objectives: Alveolar macrophage polarization and role on alveolar repair during human acute respiratory distress syndrome remain unclear. This study aimed to determine during human acute respiratory distress syndrome: the alveolar macrophage polarization, the effect of alveolar environment on macrophage polarization, and the role of polarized macrophages on epithelial repair. Design: Experimental ex vivo and in vitro investigations. Setting: Four ICUs in three teaching hospitals. Patients: Thirty-three patients with early moderate-to-severe acute respiratory distress syndrome were enrolled for assessment of the polarization of alveolar macrophages. Interventions: Polarization of acute respiratory distress syndrome macrophages was studied by flow cytometry and quantitative polymerase chain reaction. Modulation of macrophage polarization was studied in vitro using phenotypic and functional readouts. Macrophage effect on repair was studied using alveolar epithelial cells in wound healing models. Measurements and Main Results: Ex vivo, alveolar macrophages from early acute respiratory distress syndrome patients exhibited anti-inflammatory characteristics with high CD163 expression and interleukin-10 production. Accordingly, early acute respiratory distress syndrome-bronchoalveolar lavage fluid drives an acute respiratory distress syndrome–specific anti-inflammatory macrophage polarization in vitro, close to that induced by recombinant interleukin-10. Culture supernatants from macrophages polarized in vitro with acute respiratory distress syndrome-bronchoalveolar lavage fluid or interleukin-10 and ex vivo acute respiratory distress syndrome alveolar macrophages specifically promoted lung epithelial repair. Inhibition of the hepatocyte growth factor pathway in epithelial cells and hepatocyte growth factor production in macrophages both reversed this effect. Finally, hepatocyte growth factor and soluble form of CD163 concentrations expressed relatively to macrophage count were higher in bronchoalveolar lavage fluid from acute respiratory distress syndrome survivors. Conclusions: Early acute respiratory distress syndrome alveolar environment drives an anti-inflammatory macrophage polarization favoring epithelial repair through activation of the hepatocyte growth factor pathway. These results suggest that macrophage polarization may be an important step for epithelial repair and acute respiratory distress syndrome recovery. Dr. Garnier conceived and performed the experiments, analyzed the data, and drafted the article. Dr. Gibelin developed the in vitro models and revised the article. Dr. Mailleux contributed to experiments and revised the article. Ms. Leçon, Drs. Hurtado-Nedelec, and Laschet contributed to ex vivo and in vitro experiments. Drs. Trebbia, Neuville, and Tanaka provided patients’ bronchoalveolar lavage samples and revised the article. Drs. Crestani, Dehoux, and Quesnel conceived the experiments, analyzed the data, and revised the article. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (https://ift.tt/29S62lw). Supported, in part, by research grants from the “Fondation pour la Recherche Médicale (FDM20150633109), the Société de Réanimation de Langue Française and Société de Pneumologie de Langue Française (SRLF/SPLF 2014 research grant), the Société Française d’Anesthésie et Réanimation (SFAR 2016 research grant),” and the French “Programme Hospitalier de Recherche Clinique (MIN00-05).” Dr. Garnier’s institution received funding from Fondation pour la recherche médicale, Société de Réanimation de Langue Française & Société de Pneumologie de Langue Française, Société Française d’Anesthésie et Réanimation, and French Ministry Program “Programme Hospitalier de Recherche Clinique.” Drs. Hurtado-Nedelec and Laschet disclosed government work. Dr. Crestani received funding from Astra Zeneca, Boehringer Ingelheim, and Roche. The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: marcgarnier@gmail.com Copyright © by 2018 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

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