Zinc modulates cytokine-induced lung epithelial cell barrier permeability

Abstract

Apoptosis plays a causative role in acute lung injury in part due to epithelial cell loss. We recently reported that zinc protects the lung epithelium during inflammatory stress whereas depletion of intracellular zinc enhances extrinsic apoptosis. In this investigation, we evaluated the relationship between zinc, caspase-3, and cell-to-cell contact via proteins that form the adherens junction complex. Cell adhesion proteins are directly responsible for formation of the mechanical barrier of the lung epithelium. We hypothesized that exposure to inflammatory cytokines, in conjunction with zinc deprivation, would induce caspase-3, leading to degradation of junction proteins, loss of cell-to-cell contact, and compromised barrier function. Primary human upper airway and type I/II alveolar epithelial cultures were obtained from multiple donors and exposed to inflammatory stimuli that provoke extrinsic apoptosis in addition to depletion of intracellular zinc. We observed that zinc deprivation combined with tumor necrosis factor-α, interferon-γ, and Fas receptor ligation accelerates caspase-3 activation, proteolysis of E-cadherin and β-catenin, and cellular apoptosis, leading to increased paracellular leak across monolayers of both upper airway and alveolar lung epithelial cultures. Zinc supplementation inhibited apoptosis and paracellular leak, whereas caspase inhibition was less effective. We conclude that zinc is a vital factor in the lung epithelium that protects against death receptor-mediated apoptosis and barrier dysfunction. Furthermore, our findings suggest that although caspase-3 inhibition reduces lung epithelial apoptosis it does not prevent mechanical dysfunction. These findings facilitate future studies aimed at developing therapeutic strategies to prevent acute lung injury.

The zinc sensing receptor, ZnR/GPR39, triggers metabotropic calcium signalling in colonocytes and regulates occludin recovery in experimental colitis

“…Indeed, zinc supplementation to Crohn's disease patients during clinical remission reduced intestinal permeability [12]. A similar role on epithelial barrier, and thereby permeability, was described for Zn 2þ in lung bacterial infection [43]. Importantly, a direct effect of ZnR/GPR39 on the epithelial barrier is also supported by the faster renewal of the epithelial surface layer along the mucosa with crypt reorganization and increased proliferation rate of epithelial cells in WT compared with ZnR/GPR39 KO mice.…”

Rikkunshito ameliorates bleomycin-induced acute lung injury in a ghrelin-independent manner

“…The blockage of the nuclear translocation of NF-B, as well as the suppression of IL-1␤ expression, might reduce the induction of inflammatory cytokines and neutrophil alveolar infiltration in BLM-treated, RKT-administered mice. The numbers of apoptotic AECs have been positively correlated with the levels of alveolar capillary barrier dysfunction, enhanced lung permeability, and subsequent lung scarring (3,30). We showed here that the administration of RKT reduced the apoptosis of AECs in BLM-treated mice.…”

Zinc Deficiency Mediates Alcohol-Induced Alveolar Epithelial and Macrophage Dysfunction in Rats

“…They observed that zinc deprivation combined with proinflammatory cytokines accelerated caspase-3 activation, leading to increased paracellular leak across monolayers of lung epithelial cultures. Zinc also plays a role in the regulation of cellular glutathione (29) and protects cell membranes from oxidative damage (30). This is particularly intriguing, as we have published extensively on the role of oxidant stress and glutathione depletion in experimental models of chronic alcohol ingestion and in human subjects with alcohol abuse (5,7,(31)(32)(33)(34).…”