Zinc modulates airway epithelium susceptibility to death receptor-mediated apoptosis

Shenying Bao, Daren L. Knoell

Research output: Contribution to journalArticle

56 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)L433-L441
JournalAmerican Journal of Physiology - Lung Cellular and Molecular Physiology
Volume290
Issue number3
DOIs
StatePublished - Mar 1 2006

Fingerprint

Death Domain Receptors
Zinc
Epithelium
Apoptosis
Lung
Cell Survival
Phosphatidylinositol 3-Kinase
Zinc Sulfate
Caspase 8
Chelating Agents
Caspases
Caspase 3
Cell Death
Epithelial Cells

Keywords

  • Airway epithelium
  • Barrier dysfunction
  • Caspase
  • Programmed cell death

ASJC Scopus subject areas

  • Physiology
  • Pulmonary and Respiratory Medicine
  • Physiology (medical)
  • Cell Biology

Cite this

Zinc modulates airway epithelium susceptibility to death receptor-mediated apoptosis. / Bao, Shenying; Knoell, Daren L.

In: American Journal of Physiology - Lung Cellular and Molecular Physiology, Vol. 290, No. 3, 01.03.2006, p. L433-L441.

Research output: Contribution to journalArticle

@article{0277d7de18f54e9c9fd726a0c72e44b7,
title = "Zinc modulates airway epithelium susceptibility to death receptor-mediated apoptosis",
abstract = "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.",
keywords = "Airway epithelium, Barrier dysfunction, Caspase, Programmed cell death",
author = "Shenying Bao and Knoell, {Daren L.}",
year = "2006",
month = "3",
day = "1",
doi = "10.1152/ajplung.00341.2005",
language = "English (US)",
volume = "290",
pages = "L433--L441",
journal = "American Journal of Physiology - Renal Physiology",
issn = "0363-6127",
publisher = "American Physiological Society",
number = "3",

}

TY - JOUR

T1 - Zinc modulates airway epithelium susceptibility to death receptor-mediated apoptosis

AU - Bao, Shenying

AU - Knoell, Daren L.

PY - 2006/3/1

Y1 - 2006/3/1

N2 - 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.

AB - 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.

KW - Airway epithelium

KW - Barrier dysfunction

KW - Caspase

KW - Programmed cell death

UR - http://www.scopus.com/inward/record.url?scp=33644950641&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=33644950641&partnerID=8YFLogxK

U2 - 10.1152/ajplung.00341.2005

DO - 10.1152/ajplung.00341.2005

M3 - Article

C2 - 16284213

AN - SCOPUS:33644950641

VL - 290

SP - L433-L441

JO - American Journal of Physiology - Renal Physiology

JF - American Journal of Physiology - Renal Physiology

SN - 0363-6127

IS - 3

ER -