Pulmonary-specific expression of tumor necrosis factor-alpha alters surfactant lipid metabolism.
Tumor necrosis factor (TNF)-alpha is a major cytokine implicated in inducing acute and chronic lung injury, conditions associated with surfactant phosphatidylcholine (PtdCho) deficiency. Acutely, TNF-alpha decreases PtdCho synthesis but stimulates surfactant secretion. To investigate chronic effects of TNF-alpha, we investigated PtdCho metabolism in a murine transgenic model exhibiting lung-specific TNF-alpha overexpression. Compared with controls, TNF-alpha transgenic mice exhibited a discordant pattern of PtdCho metabolism, with a decrease in PtdCho and disaturated PtdCho (DSPtdCho) content in the lung, but increased levels in alveolar lavage. Transgenics had lower activities and increased immunoreactive levels of cytidylyltransferase (CCT), a key PtdCho biosynthetic enzyme. Ceramide, a CCT inhibitor, was elevated, and linoleic acid, a CCT activator, was decreased in transgenics. Radiolabeling studies revealed that alveolar reuptake of DSPtdCho was significantly decreased in transgenic mice. These observations suggest that chronic expression of TNF-alpha results in a complex pattern of PtdCho metabolism where elevated lavage PtdCho may originate from alveolar inflammatory cells, decreased surfactant reuptake, or altered surfactant secretion. Reduced parenchymal PtdCho synthesis appears to be attributed to CCT enzyme that is physiologically inactivated by ceramide or by diminished availability of activating lipids.
Carroll
James L
JL
Department of Internal Medicine, The University of Iowa College of Medicine, Iowa City, IA 52242, USA.
McCoy
Diann M
DM
McGowan
Stephen E
SE
Salome
Ronald G
RG
Ryan
Alan J
AJ
Mallampalli
Rama K
RK
D000818:Animals; D015153:Blotting, Western; D002794:Choline / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D002797:Choline Kinase / Q000378:metabolism; D002798:Diacylglycerol Cholinephosphotransferase / Q000378:metabolism; D005227:Fatty Acids / Q000378:metabolism; D015870:Gene Expression / Q000502:physiology; D008168:Lung / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010713:Phosphatidylcholines / Q000493:pharmacokinetics*; D010743:Phospholipids / Q000378:metabolism; D011663:Pulmonary Surfactants / Q000493:pharmacokinetics*; D012333:RNA, Messenger / Q000032:analysis; D013107:Sphingolipids / Q000378:metabolism; D014316:Tritium; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics*
D005227:Fatty Acids; D010713:Phosphatidylcholines; D010743:Phospholipids; D011663:Pulmonary Surfactants; D012333:RNA, Messenger; D013107:Sphingolipids; D014409:Tumor Necrosis Factor-alpha; C017463:lecithins, disaturated; C017506:methylcholine; D014316:Tritium; D002797:Choline Kinase; D002798:Diacylglycerol Cholinephosphotransferase; D002794:Choline