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      Consequences of hypoxia for the pulmonary alveolar epithelial cell innate immune response 1

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          Abstract

          Pulmonary innate immune responses involve a highly regulated multicellular network to defend the enormous surface area of the lung. Disruption of these responses renders the host susceptible to pneumonia. Alveolar epithelial cells (AEC) are a critical source of innate immune molecules such as granulocyte-macrophage colony stimulating factor (GM-CSF), that determine the functional maturation of alveolar macrophages. In many pulmonary diseases, heterogeneous ventilation leads to regional hypoxia in the lung. The effect of hypoxia on AEC innate immune function is unknown. We now report that exposure of primary murine AEC to hypoxia (1% oxygen) for 24h results in significant suppression of key innate immune molecules, including GM-CSF, CCL2, and IL-6. This exposure did not cause toxicity but did induce stabilization of hypoxia inducible factor 1α protein (HIF-1α) and shift to glycolytic metabolism. Focusing on GM-CSF, we found that hypoxia greatly decreased the rate of GM-CSF transcription. Hypoxic both decreased NF-kB signaling in AEC and induced chromosomal changes resulting in decreased accessibility in the GM-CSF proximal promoter of target sequences for NF-kB binding. In mice exposed to hypoxia in vivo (12% oxygen for 2 days), lung GM-CSF protein expression was reduced. In vivo phagocytosis of fluorescent beads by alveolar macrophages was also suppressed, but this effect was reversed by treatment with GM-CSF. These studies suggest that in critically ill patients, local hypoxia may contribute to the susceptibility of poorly ventilated lung units to infection through complementary effects on several pathways reducing AEC expression of GM-CSF and other key innate immune molecules.

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          Author and article information

          Journal
          2985117R
          4816
          J Immunol
          J. Immunol.
          Journal of immunology (Baltimore, Md. : 1950)
          0022-1767
          1550-6606
          19 October 2018
          31 October 2018
          01 December 2018
          01 December 2019
          : 201
          : 11
          : 3411-3420
          Affiliations
          [* ] Department of Veterans Affairs Medicine Center, Salt Lake City, Utah and the Division of Respiratory, Critical Care and Occupational Pulmonary Medicine, Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, Utah
          Author notes
          Address correspondence to: Robert Paine III, M.D., Division of Respiratory, Critical Care and, Occupational Pulmonary Medicine, University of Utah School of Medicine, 26 North 1900 East; Room 701, Salt Lake City, Utah 84132, Phone: 801-581-7671; Fax: 801-585-3355, robert.paine@ 123456hsc.utah.edu
          Article
          PMC6246786 PMC6246786 6246786 nihpa1509078
          10.4049/jimmunol.1701387
          6246786
          30381478
          e212e274-e7f2-4108-b9e1-208a17a68ba6
          History
          Categories
          Article

          gene transcription,NF-kB,hypoxia,innate immunity,lung
          gene transcription, NF-kB, hypoxia, innate immunity, lung

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