Epithelial cell apoptosis is a hallmark of acute lung injury in inflammatory lung disease yet little is known about the cause of cell death. To study this we have focused our attention on zinc, a known cytoprotectant essential to mammalian cells. Our laboratory reported remarkable differences in cell viability following modulation of intracellular zinc concentration during inflammatory stress. We discovered that zinc initiates intracellular signaling events that promote cell survival and barrier function during inflammatory stress whereas zinc depletion promotes cell death and tissue dysfunction. To extend these studies we turned our attention to zinc transporter proteins. Zinc regulation is highly evolved in metazoa and is comprised of two major families of zinc transporter proteins. The SLC39A family functions as zinc importers to shuttle dietary zinc into the cell and the SLC30A family acts as a counterbalance by exporting excess zinc outside of the cell. Both families are believed to be indispensable for normal cell function as they maintain cellular zinc content with great precision yet little is known regarding their role during conditions of stress. Since we know that zinc is an indispensable component of the lung epithelium during inflammatory stress we predict that zinc transporters also have an essential role. In prelminary studies we made the striking observation that only the zinc importer SLC39A8 was consistently and highly up-regulated, establishing it as a lead candidate responsible for intracellular zinc mobilization into the lung epithelium during inflammatory stress. In this investigation we will test the central hypothesis that modulation of zinc transporter expression and function during inflammatory stress is required for zinc transport sufficient for cell protection against death-inducing stimuli. To do this we will address four specific aims:
Specific Aim 1 : The role of zinc transporters in human lung epithelium during acute inflammatory stress.
Specific Aim 2 : SLC39A8 directs zinc into the lung epithelium in response to inflammation leading to cytoprotection.
Specific Aim 3 : The physiologic consequences of zinc in lung epithelium, and Specific Aim 4: Inter-individual polymorphic variation of zinc transporters as a factor in lung epithelial cell dysfunction and disease. The relevance of this proposal is that it will evaluate an important gap in our current understanding of zinc metabolism, reveal new insight into lung disease susceptibility, and potentially generate innovative strategies to prevent acute lung injury.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL086981-03
Application #
7588768
Study Section
Lung Injury, Repair, and Remodeling Study Section (LIRR)
Program Officer
Harabin, Andrea L
Project Start
2007-04-05
Project End
2012-03-31
Budget Start
2009-04-01
Budget End
2010-03-31
Support Year
3
Fiscal Year
2009
Total Cost
$375,000
Indirect Cost
Name
Ohio State University
Department
Other Health Professions
Type
Schools of Pharmacy
DUNS #
832127323
City
Columbus
State
OH
Country
United States
Zip Code
43210
Liu, Ming-Jie; Bao, Shengying; Napolitano, Jessica R et al. (2014) Zinc regulates the acute phase response and serum amyloid A production in response to sepsis through JAK-STAT3 signaling. PLoS One 9:e94934
Liu, Ming-Jie; Bao, Shengying; Gálvez-Peralta, Marina et al. (2013) ZIP8 regulates host defense through zinc-mediated inhibition of NF-?B. Cell Rep 3:386-400
Leikauf, George D; Concel, Vincent J; Bein, Kiflai et al. (2013) Functional genomic assessment of phosgene-induced acute lung injury in mice. Am J Respir Cell Mol Biol 49:368-83
Liu, Ming-Jie; Bao, Shengying; Bolin, Eric R et al. (2013) Zinc deficiency augments leptin production and exacerbates macrophage infiltration into adipose tissue in mice fed a high-fat diet. J Nutr 143:1036-45
Mihai, Cosmin; Bao, Shengying; Lai, Ju-Ping et al. (2012) PTEN inhibition improves wound healing in lung epithelia through changes in cellular mechanics that enhance migration. Am J Physiol Lung Cell Mol Physiol 302:L287-99
Leikauf, George D; Pope-Varsalona, Hannah; Concel, Vincent J et al. (2012) Integrative assessment of chlorine-induced acute lung injury in mice. Am J Respir Cell Mol Biol 47:234-44
Julian, Mark W; Shao, Guohong; Bao, Shengying et al. (2012) Mitochondrial transcription factor A serves as a danger signal by augmenting plasmacytoid dendritic cell responses to DNA. J Immunol 189:433-43
Julian, Mark W; Bao, Shengying; Knoell, Daren L et al. (2011) Intestinal epithelium is more susceptible to cytopathic injury and altered permeability than the lung epithelium in the context of acute sepsis. Int J Exp Pathol 92:366-76
Besecker, Beth Y; Exline, Matthew C; Hollyfield, Jennifer et al. (2011) A comparison of zinc metabolism, inflammation, and disease severity in critically ill infected and noninfected adults early after intensive care unit admission. Am J Clin Nutr 93:1356-64
Jang, An Soo; Concel, Vincent J; Bein, Kiflai et al. (2011) Endothelial dysfunction and claudin 5 regulation during acrolein-induced lung injury. Am J Respir Cell Mol Biol 44:483-90

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