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Long-term risks of medications that cause profound and sustained suppression of acid secretion are an increasing source of concern. Because of concerns over a potentially increased incidence of gastric malignancies in patients with pernicious anemia, clinicians have become increasingly aware of changes in gastric flora, and levels of carcinogen, as well as changes in hormonal milieu, which can accompany profound suppression of acid secretion. The risks of gastric epithelial and endocrine cell neoplasia in patients receiving powerful antisecretory agents are not yet known, but cannot be dismissed until long-term follow-up studies are available. The relationship between proliferation of epithelial and endocrine elements and sustained suppression of acid secretion may provide new insight into processes that regulate replication and growth of cells in the gastric mucosa. [ABSTRACT FROM AUTHOR]

Mammary gland involution is the most dramatic example of physiological cell death. It occurs through an initial phase of lysosomal-mediated cell death (LCD) followed by mitochondrial-mediated apoptosis. Zinc (Zn) activates both LCD and apoptosis in vitro. The Zn transporter ZnT2 imports Zn into vesicles and mitochondria and ZnT2-overexpression activates cell death in mammary epithelial cells (MECs). We tested the hypothesis that ZnT2-mediated Zn transport is critical for mammary gland involution in mice. Following weaning, ZnT2 abundance increased in lysosomes and mitochondria, which paralleled Zn accumulation in each of these organelles. Adenoviral expression of ZnT2 in lactating mouse mammary glands in vivo increased Zn in lysosomes and mitochondria and activated LCD and apoptosis, promoting a profound reduction in MECs and alveoli. Injection of TNFα, a potent activator of early involution, into the mammary gland fat pads of lactating mice increased ZnT2 and Zn in lysosomes and activated premature involution. Exposure of cultured MECs to TNFα redistributed ZnT2 to lysosomes and increased lysosomal Zn, which activated lysosomal swelling, cathepsin B release, and LCD. Our data implicate ZnT2 as a critical mediator of cell death during involution and importantly, that as an initial involution signal, TNFα redistributes ZnT2 to lysosomes to activate LCD. [ABSTRACT FROM AUTHOR]