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.

The role of signalling molecules on actin glutathionylation and protein carbonylation induced by cadmium in haemocytes of musselMytilus galloprovincialis(Lmk)

“…Our results show that PI 3-kinase, NADPH oxidase and NO synthase seemed to be involved both in actin glutathionylation and protein carbonylation in haemocytes exposed to Cd. Activation of PI 3-kinase by Cd has also been reported in previous studies (Kim et al, 2000;Eom et al, 2001;Ostrakhovitch et al, 2002;Bao and Knoell, 2006). Since, PI 3-kinase has been proposed as a survival signal in mild oxidative stress (Konishi et al, 1999;Sonoda et al, 1999;Shimamura et al, 2003), we could hypothesize that NADPH oxidase and NO synthase activation may be a result of PKC and PI 3-kinase activation after Cd exposure in haemocytes of mussels.…”

Zinc chloride stimulates DNA synthesis of mouse embryonic stem cells: Involvement of PI3K/Akt, MAPKs, and mTOR

“…The reversal of cell proliferation at various Zn 2þ concentrations might be influenced by differences in cell types, marker indices, or experimental conditions (serum-free media; in vivo vs. in vitro), but it might also result from different mechanisms being activated by different concentrations of Zn 2þ . Extracellular zinc activates the PI3K/Akt pathway in many cell types (Bao and Knoell, 2006;Walter et al, 2006;Min et al, 2007), and in our previous study, this activation increased CDK protein levels and […”

Role of zinc supplementation in acute respiratory tract infections in children aged 2 to 60 months

“…In a prospective study, preventive zinc supplementations to all age groups (infants, pre-schoolers and older prepubertal children) showed a 6% non-significant reduction in mortality due to all causes. 21 Prospective studies specifically on risk of incidence of ARIs in young children in developing countries have shown that routine zinc supplementation reduced them. 22,23 These studies were done to assess the association between respiratory morbidity and zinc in children.…”