Zinc, a major soluble component of particulate matter, may be a critical toxic agent in the cardiorespiratory pathophysiologic effects of exposure to atmospheric dusts. Nonetheless, the molecular targets that underlie zinc toxicity within lung remain unknown. We recently reported that extracellular zinc (1-100 ?M) increased amiloride-sensitive sodium currents of heterologously expressed murine epithelial Na+ channel (ENaC) subunits. Since a) ENaC-dependent sodium reabsorption across airway epithelia has a significant role in regulating the volume of airway surface liquids (and hence mucociliary transport);and b) activation of ENaC is essential in the pathogenesis of chronic airway disorders such as cystic fibrosis, we hypothesize that activation of ENaC by zinc is an important molecular determinant of the toxicity of inhaled particulate matter. Accordingly, the specific aims of this proposal are (i) to determine the effects of zinc on ENaC activity and its impact on periciliary liquid (PCL) height, mucociliary transport (MCT) and ciliary beat frequency (CBF) in primary cultures of human bronchial epithelium (HBE);(ii) to determine the effects of zinc on ENaC activity in a heterologous expression system;and (iii) to identify the molecular mechanism by which zinc activates ENaC. Our proposed studies regarding the effects of extracellular zinc on ENaC activity in primary cultures of airway epithelium and in heterologous expression systems will provide fundamental biophysical and molecular information towards our understanding of the pulmonary response to inhaled particulate matter. Our proposed study will examine the link between excess zinc, a suspected major player in human lung injury due to inhaled particulates, and the activity of lung sodium channels that are critical regulators of mucus clearance, the primary lung defense mechanism. This study will enhance our understanding of mechanisms by which atmospheric dusts result in lung damage, and will provide basic information that may lead to the development of intervention measures.

National Institute of Health (NIH)
National Institute of Environmental Health Sciences (NIEHS)
Research Project (R01)
Project #
Application #
Study Section
Xenobiotic and Nutrient Disposition and Action Study Section (XNDA)
Program Officer
Nadadur, Srikanth
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Pittsburgh
Internal Medicine/Medicine
Schools of Medicine
United States
Zip Code
Chen, Jingxin; Kleyman, Thomas R; Sheng, Shaohu (2014) Deletion of ?-subunit exon 11 of the epithelial Na+ channel reveals a regulatory module. Am J Physiol Renal Physiol 306:F561-7
Chen, Jingxin; Kleyman, Thomas R; Sheng, Shaohu (2013) Gain-of-function variant of the human epithelial sodium channel. Am J Physiol Renal Physiol 304:F207-13
Chen, Jingxin; Myerburg, Mike M; Passero, Christopher J et al. (2011) External Cu2+ inhibits human epithelial Na+ channels by binding at a subunit interface of extracellular domains. J Biol Chem 286:27436-46
Shi, Shujie; Ghosh, D Dipon; Okumura, Sora et al. (2011) Base of the thumb domain modulates epithelial sodium channel gating. J Biol Chem 286:14753-61
Winarski, Katie L; Sheng, Nan; Chen, Jingxin et al. (2010) Extracellular allosteric regulatory subdomain within the gamma subunit of the epithelial Na+ channel. J Biol Chem 285:26088-96
Maarouf, Ahmad B; Sheng, Nan; Chen, Jingxin et al. (2009) Novel determinants of epithelial sodium channel gating within extracellular thumb domains. J Biol Chem 284:7756-65