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: Nancy B Ray, Lakshmi Durairaj, Bill B Chen, Bryan J McVerry, Alan J Ryan, Michael Donahoe, Alisa K Waltenbaugh, Christopher P O'Donnell, Florita C Henderson, Christopher A Etscheidt, Diann M McCoy, Marianna Agassandian, Emily C Hayes-Rowan, Tiffany A Coon, Phillip L Butler, Lokesh Gakhar, Satya N Mathur, Jessica C Sieren, Yulia Y Tyurina, Valerian E Kagan, Geoffrey McLennan, Rama K Mallampalli
• Journal: Nature medicine (Nat Med) Vol. 16 Issue 10 Pg. 1120-1127 (Oct 2010) ISSN: 1546-170X [Electronic] United States
• PMID: 20852622 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S., Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Cardiolipins
• Phospholipid Transfer Proteins
• Pulmonary Surfactants
• Adenosine Triphosphatases
• ATP8B1 protein, human
• Atp8b1 protein, mouse

Topics

• Adenosine Triphosphatases (physiology)
• Animals
• Binding Sites
• Cardiolipins (physiology)
• Cell Survival
• Cells, Cultured
• Disease Models, Animal
• Humans
• Lung (metabolism, physiology)
• Lung Injury (etiology)
• Mice
• Mice, Inbred C57BL
• Phospholipid Transfer Proteins
• Pneumonia, Bacterial (complications, metabolism)
• Pulmonary Surfactants (metabolism)