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Peptide Activation of Epithelial Adgrf5 (Gpr116) Regulates Pulmonary Alveolar Homeostasis

Ludwig, Marie-Gabrielle and Seuwen, Klaus and Vidal, Solange (2017) Peptide Activation of Epithelial Adgrf5 (Gpr116) Regulates Pulmonary Alveolar Homeostasis. JCI Insight.

Abstract

Pulmonary alveolar homeostasis is dependent upon balanced airway and tissue surfactant pools. Quantitative and qualitative alterations in alveolar surfactant pools are associated with inflammation and tissue destruction in severe lung diseases including infant respiratory distress syndrome, acute lung injury and pulmonary alveolar proteinosis. Identification of a physiologically-dominant molecular pathway within alveolar epithelial cells that senses and regulates endogenous alveolar surfactant pools, coupled with the ability to pharmacologically modulate it both positively and negatively, would be a major therapeutic advance for patients with lung diseases associated with pulmonary surfactant disorders. We and others have previously shown that Gpr116 is a critical regulator of surfactant homeostasis in mice. Here we extend this work to show that human and mouse Gpr116 proteins are highly conserved at the amino acid level, are expressed on the plasma membrane of alveolar type II cells and functionally couple to intracellular G proteins when activated. Further, we have identified a synthetic peptide, GAP16, that is capable of activating mouse and human Gpr116 in vitro, resulting in increased Gq/11-dependent inositol phosphate conversion and calcium mobilization, cortical F-actin stabilization, and increased impedance of cell monolayers. Administration of GAP16 suppressed surfactant secretion from primary type II cells in vitro and nebulization of GAP16 to wild type mice was sufficient to suppress surfactant secretion from alveolar type II cells in vivo. These data provide proof-of-concept that Gpr116 is a plausible therapeutic target to modulate endogenous alveolar surfactant pools in humans to pulmonary diseases associated with surfactant dysfunction.

Item Type: Article
Date Deposited: 06 Jun 2017 00:45
Last Modified: 06 Jun 2017 00:45
URI: https://oak.novartis.com/id/eprint/31790

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