Surfactant, comprised mainly of the phospholipid, phosphatidylcholine (PC), and key hydrophobic proteins, is deficient in ARDS. Recent studies suggest that surfactant replacement therapy might be useful in ARDS. The cytokine, tumor necrosis factor (TNF), plays a key role in the pathogenesis of acute lung injury, and has been shown to decrease the levels of surfactant PC. The major question addressed in this proposal is how TNF decreased lung PC content. Previous studies have shown that TNF decreases PC by increasing PC degradation. This proposal will address a complementary paradigm that TNF decreases PC synthesis. The biosynthesis of PC is regulated tightly in cells by the rate regulatory enzyme cytidylyltransferase (CT). The regulation of CT is largely-post translational, since CT is activated by fatty acids and inhibited by sphingolipids and enzyme phosphorylation. One effect of TNF is the generation of a novel class of bioactive lipid second messengers derived from sphingomyelin (SM) hydrolysis. These sphingolipid products include ceramide and sphingosine. TNF also activates multiple mitogen-activated protein (MAP) kinase pathways, including the p42/44 MAP pathway. Both p42/44 MAP kinase and sphingosine inhibit CT activity. Sphingosine can also stimulate p42/44 MAP kinase activity. Thus, the generation of sphingosine, in response to TNF activation of the SM hydrolysis pathway, might represent a novel effector mechanism for the inhibitory effects of TNF on surfactant PC synthesis. These observations led to the overall hypothesis that TNF decreases surfactant lipids, in part, by decreasing PC synthesis. In this project, we will determine if the negative effects of tumor necrosis factor (TNF) on CT activity are due to induction of the lipid inhibitor, sphingosine and/or activation of the p42/44 MAP kinase (AIM 1). We will also determine if activation of CT by glucocorticoids is mediated by altering specific fatty acids or sphingolipids and if these effects of glucocorticoid pre-treatment oppose inhibition of CT by TNF (AIM 2). These basic studies are especially relevant in view of ongoing clinical studies; for example, these studies might impact the development of newer treatment strategies directed at increasing surfactant synthesis such as modulation of sphingolipid generation. In addition, results that emerge from these studies could lead to modification of existing surfactant preparations used to treat ARDS.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Specialized Center (P50)
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University of Iowa
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Nyunoya, Toru; Monick, Martha M; Klingelhutz, Aloysius L et al. (2009) Cigarette smoke induces cellular senescence via Werner's syndrome protein down-regulation. Am J Respir Crit Care Med 179:279-87
Monick, Martha M; Powers, Linda S; Barrett, Christopher W et al. (2008) Constitutive ERK MAPK activity regulates macrophage ATP production and mitochondrial integrity. J Immunol 180:7485-96
Hansdottir, Sif; Monick, Martha M; Hinde, Sara L et al. (2008) Respiratory epithelial cells convert inactive vitamin D to its active form: potential effects on host defense. J Immunol 181:7090-9
Groskreutz, Dayna J; Monick, Martha M; Yarovinsky, Timur O et al. (2007) Respiratory syncytial virus decreases p53 protein to prolong survival of airway epithelial cells. J Immunol 179:2741-7
Monick, Martha M; Powers, Linda S; Hassan, Ihab et al. (2007) Respiratory syncytial virus synergizes with Th2 cytokines to induce optimal levels of TARC/CCL17. J Immunol 179:1648-58
Ashare, Alix; Monick, Martha M; Nymon, Amanda B et al. (2007) Pseudomonas aeruginosa delays Kupffer cell death via stabilization of the X-chromosome-linked inhibitor of apoptosis protein. J Immunol 179:505-13
Monick, Martha M; Powers, Linda S; Gross, Thomas J et al. (2006) Active ERK contributes to protein translation by preventing JNK-dependent inhibition of protein phosphatase 1. J Immunol 177:1636-45
Flaherty, Dawn M; Monick, Martha M; Hinde, Sara L (2006) Human alveolar macrophages are deficient in PTEN. The role of endogenous oxidants. J Biol Chem 281:5058-64
Groskreutz, Dayna J; Monick, Martha M; Powers, Linda S et al. (2006) Respiratory syncytial virus induces TLR3 protein and protein kinase R, leading to increased double-stranded RNA responsiveness in airway epithelial cells. J Immunol 176:1733-40
Nyunoya, Toru; Monick, Martha M; Klingelhutz, Aloysius et al. (2006) Cigarette smoke induces cellular senescence. Am J Respir Cell Mol Biol 35:681-8

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