Normal alveolar epithelial lining fluid contains high levels of glutathione

Abstract

The epithelial cells on the alveolar surface of the human lower respiratory tract are vulnerable to toxic oxidants derived from inhaled pollutants or inflammatory cells. Although these lung cells have intracellular antioxidants, these defenses may be insufficient to protect the epithelial surface against oxidants present at the alveolar surface. This study demonstrates that the epithelial lining fluid (ELF) of the lower respiratory tract contains large amounts of the sulfhydryl-containing antioxidant glutathione (GSH). The total glutathione (the reduced form GSH and the disulfide GSSG) concentration of normal ELF was 140-fold higher than that in plasma of the same individuals, and 96% of the glutathione in ELF was in the reduced form. Compared with nonsmokers, cigarette smokers had 80% higher levels of ELF total glutathione, 98% of which was in the reduced form. Studies of cultured lung epithelial cells and fibroblasts demonstrated that these concentrations of reduced glutathione were sufficient to protect these cells against the burden of H2O2 in the range released by alveolar macrophages removed from the lower respiratory tract of nonsmokers and smokers, respectively, suggesting that the glutathione present in the alveolar ELF of normal individuals likely contributes to the protective screen against oxidants in the extracellular milieu of the lower respiratory tract.

Induction of γ‐glutamylcysteine synthetase by cigarette smoke is associated with AP‐1 in human alveolar epithelial cells

“…3A,B). GSH levels have been shown to be twofold higher in the ELF [5,6] and erythrocytes [21] of chronic cigarette smokers so induction of ~(3CS-HS mRNA by CSC in epithelial cells is a possible mechanism for this elevation of GSH since intracellular GSH is exported from alveolar epithelial cells [22,23]. CSC also induces DNA-binding of the redox sensitive transcription factors AP-1 (fos/jun heterodimeric complex) and hARE in A549 cells (Fig.…”

“…Reiuced glutathione (GSH), a ubiquitous cellular non-protein • ulphydryl, functions to maintain cellular redox balance and J~ also involved in the detoxification of xenobiotics, electroi~hiles, organic peroxides and heavy metals, either through ~firect thiol conjugation or in enzyme-catalysed reactions [4]. We and others have demonstrated increased levels of GSH in ,~ssociation with an increased oxidant burden in the epithelial Lining fluid (ELF) of healthy chronic smokers [5,6]. The mech-,nism of this increase in GSH is currently unknown.…”

“…We hypothesised that GSH synthesis may be induced in alveolar epithelial cells as an adaptive response to CSC exposure by upregulation of ~SCS-HS gene expression. These findings may be relevant to the enhanced GSH levels which are present in the ELF of chronic smokers [5,6].…”

Antioxidants in cystic fibrosis☆Conclusions from the CF Antioxidant Workshop, Bethesda, Maryland, November 11-12, 2003

“…In healthy subjects, ELF contains much higher levels of GSH (100-400 μM) than plasma (3 μM) [51]. In fact, GSH is the only antioxidant which is selectively elevated in ELF compared to plasma [40].…”

“…In fact, GSH is the only antioxidant which is selectively elevated in ELF compared to plasma [40]. Chronic oxidative stress such as that caused by smoking can adaptively induce enzymes that result in a doubling of GSH levels in BALF over those in healthy nonsmokers [51]. The great majority of this is in the reduced state: 96% of the GSH in ELF of nonsmokers and 98% of that in smokers are reduced.…”