Dynamic regulation of cardiolipin by the lipid pump Atp8b1 determines the severity of lung injury in experimental pneumonia.
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.
Ray
Nancy B
NB
Departments of Internal Medicine, University of Iowa, Iowa City, IA 52242.
Durairaj
Lakshmi
L
Departments of Internal Medicine, University of Iowa, Iowa City, IA 52242.
Chen
Bill B
BB
Departments of Internal Medicine, Acute Lung Injury Center of Excellence, University of Pittsburgh, Pittsburgh, PA 15213.
McVerry
Bryan J
BJ
Departments of Internal Medicine, Acute Lung Injury Center of Excellence, University of Pittsburgh, Pittsburgh, PA 15213.
Ryan
Alan J
AJ
Departments of Internal Medicine, University of Iowa, Iowa City, IA 52242.
Donahoe
Michael
M
Departments of Internal Medicine, Acute Lung Injury Center of Excellence, University of Pittsburgh, Pittsburgh, PA 15213.
Waltenbaugh
Alisa K
AK
Departments of Internal Medicine, Acute Lung Injury Center of Excellence, University of Pittsburgh, Pittsburgh, PA 15213.
O'Donnell
Christopher P
CP
Departments of Internal Medicine, Acute Lung Injury Center of Excellence, University of Pittsburgh, Pittsburgh, PA 15213.
Henderson
Florita C
FC
Departments of Internal Medicine, University of Iowa, Iowa City, IA 52242.
Etscheidt
Christopher A
CA
Departments of Internal Medicine, University of Iowa, Iowa City, IA 52242.
McCoy
Diann M
DM
Departments of Internal Medicine, University of Iowa, Iowa City, IA 52242.
Agassandian
Marianna
M
Departments of Internal Medicine, University of Iowa, Iowa City, IA 52242.
Hayes-Rowan
Emily C
EC
Departments of Internal Medicine, Acute Lung Injury Center of Excellence, University of Pittsburgh, Pittsburgh, PA 15213.
Coon
Tiffany A
TA
Departments of Internal Medicine, Acute Lung Injury Center of Excellence, University of Pittsburgh, Pittsburgh, PA 15213.
Butler
Phillip L
PL
Departments of Biochemistry, University of Iowa, Iowa City, IA 52242.
Gakhar
Lokesh
L
Departments of Biochemistry, University of Iowa, Iowa City, IA 52242.
Mathur
Satya N
SN
Departments of Internal Medicine, University of Iowa, Iowa City, IA 52242.
Sieren
Jessica C
JC
Departments of Internal Medicine, University of Iowa, Iowa City, IA 52242.
Tyurina
Yulia Y
YY
Center for Free Radical and Antioxidant Health, Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, PA 15219.
Kagan
Valerian E
VE
Center for Free Radical and Antioxidant Health, Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, PA 15219.
McLennan
Geoffrey
G
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.
Mallampalli
Rama K
RK
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.
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
D002308:Cardiolipins; D049294:Phospholipid Transfer Proteins; D011663:Pulmonary Surfactants; D000251:Adenosine Triphosphatases; C111067:ATP8B1 protein, human; C491742:Atp8b1 protein, mouse