Journal article
Dynamic regulation of cardiolipin by the lipid pump Atp8b1 determines the severity of lung injury in experimental pneumonia
Nature medicine, Vol.16(10), pp.1120-1127
10/2010
DOI: 10.1038/nm.2213
PMCID: PMC4500192
PMID: 20852622
Abstract
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.
Details
- Title: Subtitle
- Dynamic regulation of cardiolipin by the lipid pump Atp8b1 determines the severity of lung injury in experimental pneumonia
- Creators
- Nancy B Ray - Departments of Internal Medicine, University of Iowa, Iowa City, IA 52242Lakshmi Durairaj - Departments of Internal Medicine, University of Iowa, Iowa City, IA 52242Bill B Chen - Departments of Internal Medicine, Acute Lung Injury Center of Excellence, University of Pittsburgh, Pittsburgh, PA 15213Bryan J McVerry - Departments of Internal Medicine, Acute Lung Injury Center of Excellence, University of Pittsburgh, Pittsburgh, PA 15213Alan J Ryan - Departments of Internal Medicine, University of Iowa, Iowa City, IA 52242Michael Donahoe - Departments of Internal Medicine, Acute Lung Injury Center of Excellence, University of Pittsburgh, Pittsburgh, PA 15213Alisa K Waltenbaugh - Departments of Internal Medicine, Acute Lung Injury Center of Excellence, University of Pittsburgh, Pittsburgh, PA 15213Christopher P O'Donnell - Departments of Internal Medicine, Acute Lung Injury Center of Excellence, University of Pittsburgh, Pittsburgh, PA 15213Florita C Henderson - Departments of Internal Medicine, University of Iowa, Iowa City, IA 52242Christopher A Etscheidt - Departments of Internal Medicine, University of Iowa, Iowa City, IA 52242Diann M McCoy - Departments of Internal Medicine, University of Iowa, Iowa City, IA 52242Marianna Agassandian - Departments of Internal Medicine, University of Iowa, Iowa City, IA 52242Emily C Hayes-Rowan - Departments of Internal Medicine, Acute Lung Injury Center of Excellence, University of Pittsburgh, Pittsburgh, PA 15213Tiffany A Coon - Departments of Internal Medicine, Acute Lung Injury Center of Excellence, University of Pittsburgh, Pittsburgh, PA 15213Phillip L Butler - Departments of Biochemistry, University of Iowa, Iowa City, IA 52242Lokesh Gakhar - Departments of Biochemistry, University of Iowa, Iowa City, IA 52242Satya N Mathur - Departments of Internal Medicine, University of Iowa, Iowa City, IA 52242Jessica C Sieren - Departments of Internal Medicine, University of Iowa, Iowa City, IA 52242Yulia Y Tyurina - Center for Free Radical and Antioxidant Health, Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, PA 15219Valerian E Kagan - Center for Free Radical and Antioxidant Health, Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, PA 15219Geoffrey McLennan - Department of Biomedical Engineering, University of Iowa, Iowa City, IA 52242Rama K Mallampalli - Veteran's Affairs Pittsburgh Healthcare System, Pittsburgh, PA 15206
- Resource Type
- Journal article
- Publication Details
- Nature medicine, Vol.16(10), pp.1120-1127
- DOI
- 10.1038/nm.2213
- PMID
- 20852622
- PMCID
- PMC4500192
- NLM abbreviation
- Nat Med
- ISSN
- 1078-8956
- eISSN
- 1546-170X
- Publisher
- United States
- Grant note
- HL098174 / NHLBI NIH HHS HL097376 / NHLBI NIH HHS R01 HL097376 / NHLBI NIH HHS HL096376 / NHLBI NIH HHS R01 HL096376 / NHLBI NIH HHS K23 HL075402 / NHLBI NIH HHS U01 HL102288 / NHLBI NIH HHS R01 HL098174 / NHLBI NIH HHS HL70755 / NHLBI NIH HHS R01 HL068135 / NHLBI NIH HHS HL068135 / NHLBI NIH HHS R01 HL080229 / NHLBI NIH HHS HL094488 / NHLBI NIH HHS T32 HL007344 / NHLBI NIH HHS HL080229 / NHLBI NIH HHS R01 HL081784 / NHLBI NIH HHS HL081784 / NHLBI NIH HHS OH008282 / NIOSH CDC HHS K08 HL083101 / NHLBI NIH HHS
- Language
- English
- Date published
- 10/2010
- Academic Unit
- Roy J. Carver Department of Biomedical Engineering; Radiology; Pulmonary, Critical Care, and Occupational Medicine; Microbiology and Immunology; Stead Family Department of Pediatrics; Biochemistry and Molecular Biology; Medicine Administration; Internal Medicine
- Record Identifier
- 9984051556002771
Metrics
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