The accelerated loss of 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 whether 
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, 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. Activation of extrinsic apoptosis 
in addition to zinc depletion resulted in an abrupt decrease in transepithelial 
resistance, a substantial increase in apoptosis, and an increased paracellular 
leak. Cultures were rescued by supplementation with zinc sulfate. Further 
analysis revealed that exogenous zinc facilitates cell survival through 
activation of the phosphatidylinositol 3-kinase/Akt signaling pathway. We 
conclude that intracellular zinc is a vital factor in lung epithelium that 
protects cells from death receptor-mediated apoptosis and barrier dysfunction.