The importance of gamma‐glutamyl transferase in lung glutathione homeostasis and antioxidant defense

An extensive literature now supports a fundamental role for glutathione in the antioxidant protection of the lung and its gas exchange surface [1]. However, the physiological significance of lung glutathione turnover by the extracellular catabolic enzyme gamma-glutamyl transferase (GGT) has remained controversial. The function of GGT in the lung has been a major research focus in my laboratory. Our studies initially focused on normal rat lung both at different stages of development [2–4] and in different conditions of oxidant stress [5]. More recently, these studies have been complemented by experiments with a newly defined model of GGT deficiency, the GGTenu1 mutant mouse [6,7]. The cumulative information we have generated from this work in rat and mouse, that correlates the cellular sites of GGT gene expression with that of GGT protein and enzyme activity, supports a critical biological role for GGT in lung glutathione homeostasis and epithelial cell antioxidant defense. Our initial studies in rat lung revealed key insights into epithelial cell biology, surfactant function, intercellular glutathione transport, the role of GGT in the lung response to oxidant stress, and the role of oxygen as a regulator of gene expression in the lung. The GGT enu1 mutant mouse provided a model in which to test some of these observations and to more specifically define the role of GGT in the lung. In particular, we find that the absence of GGT expression in the mutant mouse lung severely limits glutathione availability and induces oxidant stress in normal oxygen conditions in both a subset of epithelial cells and in the surfactant that bathes cells at epithelial surfaces. Injury in these GGT-deficient lung epithelial cells is accelerated in the presence of hyperoxia with GGTenu1 mutants dying more rapidly compared to normal mice [8]. Our study of the GGTenu1 mouse also led us to identify novel truncated GGT protein isoforms that are generated by alternative splicing of GGT mRNA. While the intact GGT protein is expressed on the plasma membrane, these truncated isoforms are retained in the endoplasmic reticulum (ER). Surprisingly, both the native GGT and one of its ER isoforms can mediate