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

Authors
Ray-NB; Durairaj-L; Chen-BB; McVerry-BJ; Ryan-AJ; Donahoe-M; Waltenbaugh-AK; O'Donnell-CP; Henderson-FC; Etscheidt-CA; McCoy-DM; Agassandian-M; Hayes-Rowan-EC; Coon-TA; Butler-PL; Gakhar-L; Mathur-SN; Sieren-JC; Tyurina-YY; Kagan-VE; McLennan-G; Mallampalli-RK
Source
Nat Med 2010 Oct; 16(10):1120-1127
NIOSHTIC No.
20037902
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.
Keywords
Pulmonary-system-disorders; Lung-disorders; Lung-function; Respiratory-infections; Respiratory-system-disorders; Mortality-data; Mortality-rates; Pathogenesis; Bacterial-infections; Phospholipids; Surfactants; Cell-function; Cytology; Cellular-transport-mechanism; Molecular-biology; Gene-mutation; Peptides; Animals; Humans; Therapeutic-agents
CODEN
NAMEFI
Publication Date
20101001
Document Type
Journal Article
Email Address
mallampallirk@upmc.edu
Funding Type
Grant
Fiscal Year
2011
NTIS Accession No.
NTIS Price
Identifying No.
Grant-Number-R01-OH-008282
Issue of Publication
10
ISSN
1078-8956
Source Name
Nature Medicine
State
IA; PA
Performing Organization
University of Pittsburgh at Pittsburgh
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