title: Dynamic regulation of cardiolipin by the lipid pump Atp8b1 determines the severity of lung injury in experimental pneumonia.
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.
authors.affiliation: Departments of Internal Medicine, University of Iowa, Iowa City, IA 52242.
authors.forename: Nancy B
authors.initials: NB
authors.lastname: Ray
authors.affiliation: Departments of Internal Medicine, University of Iowa, Iowa City, IA 52242.
authors.forename: Lakshmi
authors.initials: L
authors.lastname: Durairaj
authors.affiliation: Departments of Internal Medicine, Acute Lung Injury Center of Excellence, University of Pittsburgh, Pittsburgh, PA 15213.
authors.forename: Bill B
authors.initials: BB
authors.lastname: Chen
authors.affiliation: Departments of Internal Medicine, Acute Lung Injury Center of Excellence, University of Pittsburgh, Pittsburgh, PA 15213.
authors.forename: Bryan J
authors.initials: BJ
authors.lastname: McVerry
authors.affiliation: Departments of Internal Medicine, University of Iowa, Iowa City, IA 52242.
authors.forename: Alan J
authors.initials: AJ
authors.lastname: Ryan
authors.affiliation: Departments of Internal Medicine, Acute Lung Injury Center of Excellence, University of Pittsburgh, Pittsburgh, PA 15213.
authors.forename: Michael
authors.initials: M
authors.lastname: Donahoe
authors.affiliation: Departments of Internal Medicine, Acute Lung Injury Center of Excellence, University of Pittsburgh, Pittsburgh, PA 15213.
authors.forename: Alisa K
authors.initials: AK
authors.lastname: Waltenbaugh
authors.affiliation: Departments of Internal Medicine, Acute Lung Injury Center of Excellence, University of Pittsburgh, Pittsburgh, PA 15213.
authors.forename: Christopher P
authors.initials: CP
authors.lastname: O'Donnell
authors.affiliation: Departments of Internal Medicine, University of Iowa, Iowa City, IA 52242.
authors.forename: Florita C
authors.initials: FC
authors.lastname: Henderson
authors.affiliation: Departments of Internal Medicine, University of Iowa, Iowa City, IA 52242.
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Etscheidt
authors.affiliation: Departments of Internal Medicine, University of Iowa, Iowa City, IA 52242.
authors.forename: Diann M
authors.initials: DM
authors.lastname: McCoy
authors.affiliation: Departments of Internal Medicine, University of Iowa, Iowa City, IA 52242.
authors.forename: Marianna
authors.initials: M
authors.lastname: Agassandian
authors.affiliation: Departments of Internal Medicine, Acute Lung Injury Center of Excellence, University of Pittsburgh, Pittsburgh, PA 15213.
authors.forename: Emily C
authors.initials: EC
authors.lastname: Hayes-Rowan
authors.affiliation: Departments of Internal Medicine, Acute Lung Injury Center of Excellence, University of Pittsburgh, Pittsburgh, PA 15213.
authors.forename: Tiffany A
authors.initials: TA
authors.lastname: Coon
authors.affiliation: Departments of Biochemistry, University of Iowa, Iowa City, IA 52242.
authors.forename: Phillip L
authors.initials: PL
authors.lastname: Butler
authors.affiliation: Departments of Biochemistry, University of Iowa, Iowa City, IA 52242.
authors.forename: Lokesh
authors.initials: L
authors.lastname: Gakhar
authors.affiliation: Departments of Internal Medicine, University of Iowa, Iowa City, IA 52242.
authors.forename: Satya N
authors.initials: SN
authors.lastname: Mathur
authors.affiliation: Departments of Internal Medicine, University of Iowa, Iowa City, IA 52242.
authors.forename: Jessica C
authors.initials: JC
authors.lastname: Sieren
authors.affiliation: Center for Free Radical and Antioxidant Health, Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, PA 15219.
authors.forename: Yulia Y
authors.initials: YY
authors.lastname: Tyurina
authors.affiliation: Center for Free Radical and Antioxidant Health, Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, PA 15219.
authors.forename: Valerian E
authors.initials: VE
authors.lastname: Kagan
authors.affiliation: Departments of Internal Medicine, University of Iowa, Iowa City, IA 52242.|Department of Radiology, University of Iowa, Iowa City, IA 52242.|Department of Biomedical Engineering, University of Iowa, Iowa City, IA 52242.
authors.forename: Geoffrey
authors.initials: G
authors.lastname: McLennan
authors.affiliation: Departments of Internal Medicine, Acute Lung Injury Center of Excellence, University of Pittsburgh, Pittsburgh, PA 15213.|Veteran's Affairs Pittsburgh Healthcare System, Pittsburgh, PA 15206.
authors.forename: Rama K
authors.initials: RK
authors.lastname: Mallampalli
mesh_terms: D000251:Adenosine Triphosphatases / Q000502:physiology*; D000818:Animals; D001665:Binding Sites; D002308:Cardiolipins / Q000502:physiology*; D002470:Cell Survival; D002478:Cells, Cultured; D004195:Disease Models, Animal; D006801:Humans; D008168:Lung / Q000378:metabolism / Q000502:physiology; D055370:Lung Injury / Q000209:etiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D049294:Phospholipid Transfer Proteins; D018410:Pneumonia, Bacterial / Q000150:complications* / Q000378:metabolism; D011663:Pulmonary Surfactants / Q000378:metabolism
chemical_list: D002308:Cardiolipins; D049294:Phospholipid Transfer Proteins; D011663:Pulmonary Surfactants; D000251:Adenosine Triphosphatases; C111067:ATP8B1 protein, human; C491742:Atp8b1 protein, mouse