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1 Department of Medicine, Davis Heart and Lung Research Institute, Columbus, OH, USA; Division of Pulmonary, Critical Care, and Sleep Medicine, The Ohio State University, Columbus, OH, USA
2 Department of Pharmacy, The Ohio State University, Columbus, OH, USA; Department of Medicine, Davis Heart and Lung Research Institute, Columbus, OH, USA; Division of Pulmonary, Critical Care, and Sleep Medicine, The Ohio State University, Columbus, OH, USA
* To whom correspondence should be addressed. E-mail: knoell-2{at}medctr.osu.edu.
The accelerated loss of the lung epithelium through activation of extrinsic apoptosis is believed to play a causative role in lung pathogenesis. Previous investigations have shown that zinc is required to sustain lung epithelial cell viability under stress conditions and that depletion of intracellular zinc predisposes cells to apoptosis. In this investigation we determined if intracellular zinc deficiency enhanced the susceptibility of primary, differentiated cultures of human lung epithelium to death receptor-mediated apoptosis leading to barrier dysfunction. Cultures obtained from multiple donors were exposed to stimuli that provoke death receptor-mediated apoptosis and depleted of intracellular zinc with a zinc-specific chelating agent. Transepithelial resistance (Rt), paracellular transport, caspase-8 and caspase-3 activity, and apoptosis were measured. Activation of extrinsic apoptosis or zinc chelation alone resulted in a nominal increase in caspase function and apoptosis without major evidence of barrier disruption. In contrast, activation of extrinsic apoptosis in addition to zinc depletion resulted in an abrupt decrease in Rt, substantial increase in apoptosis, and increased paracellular leak. Cultures were rescued by supplementation with zinc sulphate. Further analysis revealed that exogenous zinc facilitates cell survival through activation of the PI 3 kinase/Akt signaling pathway. From our findings we conclude that intracellular zinc is a vital factor in the lung epithelium that protects cells from death receptor-mediated apoptosis and barrier dysfunction.
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