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      Cell-free hemoglobin: a novel mediator of acute lung injury

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          Abstract

          Patients with the acute respiratory distress syndrome (ARDS) have elevated levels of cell-free hemoglobin (CFH) in the air space, but the contribution of CFH to the pathogenesis of acute lung injury is unknown. In the present study, we demonstrate that levels of CFH in the air space correlate with measures of alveolar-capillary barrier dysfunction in humans with ARDS ( r = 0.89, P < 0.001) and in mice with ventilator-induced acute lung injury ( r = 0.89, P < 0.001). To investigate the specific contribution of CFH to ARDS, we studied the impact of purified CFH in the mouse lung and on cultured mouse lung epithelial (MLE-12) cells. Intratracheal delivery of CFH in mice causes acute lung injury with air space inflammation and alveolar-capillary barrier disruption. Similarly, in MLE-12 cells, CFH increases proinflammatory cytokine expression and increases paracellular permeability as measured by electrical cell-substrate impedance sensing. Next, to determine whether these effects are mediated by the iron-containing heme moiety of CFH, we treated mice with intratracheal hemin, the chloride salt of heme, and found that hemin was sufficient to increase alveolar permeability but failed to induce proinflammatory cytokine expression or epithelial cell injury. Together, these data identify CFH in the air space as a previously unrecognized driver of lung epithelial injury in human and experimental ARDS and suggest that CFH and hemin may contribute to ARDS through different mechanisms. Interventions targeting CFH and heme in the air space could provide a new therapeutic approach for ARDS.

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          Author and article information

          Journal
          Am J Physiol Lung Cell Mol Physiol
          Am. J. Physiol. Lung Cell Mol. Physiol
          ajplung
          ajplung
          AJPLUNG
          American Journal of Physiology - Lung Cellular and Molecular Physiology
          American Physiological Society (Bethesda, MD )
          1040-0605
          1522-1504
          15 January 2016
          15 March 2016
          15 March 2017
          : 310
          : 6
          : L532-L541
          Affiliations
          1Division of Allergy, Pulmonary, and Critical Care Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee;
          2Section of Pulmonary and Critical Care Medicine, Louisiana State University School of Medicine, New Orleans, Louisiana;
          3Division of Clinical Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee; and
          4Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee
          Author notes
          Address for reprint requests and other correspondence: J. Bastarache, Division of Allergy, Pulmonary, and Critical Care Medicine, Vanderbilt Univ. School of Medicine, T-1218 MCN, Nashville, TN 37232-2650 (e-mail: julie.bastarache@ 123456vanderbilt.edu ).
          Article
          PMC4796260 PMC4796260 4796260 L-00155-2015
          10.1152/ajplung.00155.2015
          4796260
          26773065
          Copyright © 2016 the American Physiological Society
          Funding
          Funded by: 100000002 HHS | National Institutes of Health (NIH)
          Award ID: HL087738
          Award ID: HL126671
          Award ID: HL103836
          Award ID: HL090785
          Award ID: HL117676
          Award ID: HL103836
          Award ID: HL090785
          Funded by: 100000968 American Heart Association (AHA)
          Award ID: Established Investigator Award
          Award ID: Mentored Clinical Research Award
          Funded by: 100007206 Vanderbilt Institute for Clinical and Translational Research (VICTR)
          Award ID: RR024975
          Funded by: 100006108 HHS | NIH | National Center for Advancing Translational Sciences (NCATS)
          Award ID: UL1TR000445
          Funded by: Vanderbilt Faculty Research Scholars
          Categories
          Call for Papers
          Translational Research in Acute Lung Injury and Pulmonary Fibrosis

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