Effects of intratracheal instillation of TNF-alpha on surfactant metabolism.
Tumor necrosis factor-alpha (TNF-alpha) has been shown to play an integral role in the pathogenesis of the acute respiratory distress syndrome. This disorder is characterized by a deficiency of alveolar surfactant, a surface-active material that is composed of key hydrophobic proteins and the major lipid disaturated phosphatidylcholine (DSPC). We investigated how TNF-alpha might alter DSPC content in rat lungs by instilling the cytokine (2.5 microg) intratracheally for 10 min and then assaying parameters of DSPC synthesis and degradation in alveolar type II epithelial cells, which produce surfactant. Cells isolated from rats given TNF-alpha had 26% lower levels of phosphatidylcholine compared with control. TNF-alpha treatment also decreased the ability of these cells to incorporate [(3)H]choline into DSPC by 45% compared with control isolates. There were no significant differences in the levels of choline substrate or choline transport between the groups. However, TNF-alpha produced a 64% decrease in the activity of cytidylyltransferase, the rate-regulatory enzyme required for DSPC synthesis. TNF-alpha administration in vivo also tended to stimulate phospholipase A(2) activity, but it did not alter other parameters for DSPC degradation such as activities for phosphatidylcholine-specific phospholipase C or phospholipase D. These observations indicate that TNF-alpha decreases the levels of surfactant lipid by decreasing the activity of a key enzyme involved in surfactant lipid synthesis. The results do not exclude stimulatory effects of the cytokine on phosphatidylcholine breakdown.
Salome
R G
RG
Department of Internal Medicine and the Department of Veterans Affairs Medical Center, University of Iowa College of Medicine, Iowa City, Iowa 52242, USA.
McCoy
D M
DM
Ryan
A J
AJ
Mallampalli
R K
RK
D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000166:cytology; D002470:Cell Survival / Q000187:drug effects; D002794:Choline / Q000378:metabolism; D019916:Choline-Phosphate Cytidylyltransferase / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D008297:Male; D009929:Organ Size / Q000187:drug effects; D010713:Phosphatidylcholines / Q000096:biosynthesis / Q000378:metabolism; D010741:Phospholipases A / Q000378:metabolism; D011650:Pulmonary Alveoli / Q000737:chemistry / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D011663:Pulmonary Surfactants / Q000737:chemistry / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020545:Respiratory Mucosa / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D014132:Trachea; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage / Q000494:pharmacology*
D010713:Phosphatidylcholines; D011663:Pulmonary Surfactants; D014409:Tumor Necrosis Factor-alpha; C017463:lecithins, disaturated; D019916:Choline-Phosphate Cytidylyltransferase; D010741:Phospholipases A; D002794:Choline