Dynamic regulation of cardiolipin by the lipid pump Atp8b1 determines the severity of lung injury in experimental pneumonia

Details

• Personal Author:
  Agassandian M ; Butler PL ; Chen BB ; Coon TA ; Donahoe M ; Durairaj L ; Etscheidt CA ; Gakhar L ; Hayes-Rowan EC ; Henderson FC ; Kagan VE ; Mallampalli RK ; Mathur SN ; McCoy DM ; McLennan G ; McVerry BJ ; O'Donnell CP ; Ray NB ; Ryan AJ ; Sieren JC ; Tyurina YY ; Waltenbaugh AK
• Description:
  Pneumonia remains the leading cause of death from infection in the US, yet fundamentally new conceptual models underlying its pathogenesis have not emerged. We show that humans and mice with bacterial pneumonia have markedly elevated amounts of cardiolipin, a rare, mitochondrial-specific phospholipid, in lung fluid and find that it potently disrupts surfactant function. Intratracheal cardiolipin administration in mice recapitulates the clinical phenotype of pneumonia, including impaired lung mechanics, modulation of cell survival and cytokine networks and lung consolidation. We have identified and characterized the activity of a unique cardiolipin transporter, the P-type ATPase transmembrane lipid pump Atp8b1, a mutant version of which is associated with severe pneumonia in humans and mice. Atp8b1 bound and internalized cardiolipin from extracellular fluid via a basic residue-enriched motif. Administration of a peptide encompassing the cardiolipin binding motif or Atp8b1 gene transfer in mice lessened bacteria-induced lung injury and improved survival. The results unveil a new paradigm whereby Atp8b1 is a cardiolipin importer whose capacity to remove cardiolipin from lung fluid is exceeded during inflammation or when Atp8b1 is defective. This discovery opens the door for new therapeutic strategies directed at modulating the abundance or molecular interactions of cardiolipin in pneumonia. [Description provided by NIOSH]
• Subjects:
  Animals Bacterial Infections Cytology Lipids Lung Lung Diseases Mortality Occupational Health Respiratory System Respiratory Tract Diseases Safety Surface-Active Agents

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• Keywords:
  Bacterial-infections Cell-function Cellular-transport-mechanism Gene-mutation Humans Lung-disorders Lung-function Molecular-biology Mortality-data Mortality-rates Pathogenesis Peptides Phospholipids Pulmonary-system-disorders Respiratory-infections Respiratory-system-disorders Surfactants Therapeutic-agents

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• ISSN:
  1078-8956
• Document Type:
  Text
• Funding:
  Grant
• Genre:
  Journal Article
• Place as Subject:
  Iowa ; OSHA Region 3 ; OSHA Region 7 ; Pennsylvania
• CIO:
  National Institute for Occupational Safety and Health (NIOSH)
• Topic:
  Workplace Safety & Health
• Location:
  North America
• Volume:
  16
• Issue:
  10
• NIOSHTIC Number:
  nn:20037902
• Citation:
  Nat Med 2010 Oct; 16(10):1120-1127
• Contact Point Address:
  Rama K Mallampalli, Department of Internal Medicine, Acute Lung Injury Center of Excellence, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
• Email:
  mallampallirk@upmc.edu
• Federal Fiscal Year:
  2011
• NORA Priority Area:
  Manufacturing
• Performing Organization:
  University of Pittsburgh at Pittsburgh
• Peer Reviewed:
  True
• Start Date:
  20050701
• Source Full Name:
  Nature Medicine
• End Date:
  20160630
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:7acb8d445cf59fb358c1f47c30fbd7d6f0f40ad8c453d2b56e880e6436ec0904a9d12a645264f452f92961f6a7b73fe03758e53c2e6b4d0715ea83f396b2573b
• Download URL:
  https://stacks.cdc.gov/view/cdc/191823/cdc_191823_DS1.pdf
• File Type:
  [PDF - 954.57 KB ]