title: Lysosomal and mitochondrial pathways in H2O2-induced apoptosis of alveolar type II cells.
abstract: Increasing evidence suggests a role for apoptosis in the maintenance of the alveolar epithelium under normal and pathological conditions. However, the signaling pathways modulating alveolar type II (AT II) cell apoptosis remain poorly defined. Here we investigated the role of lysosomes as modulators of oxidant-mediated AT II cell apoptosis using an in vitro model of H(2)O(2)-stress. H(2)O(2) stress led to time-dependent increases in intracellular oxidants, mitochondrial membrane polarization, cytochrome c release, lysosomal rupture, and AT II cells apoptosis. Increased apoptosis was prevented by specific inhibition of the caspase cascade using the broad-spectrum caspase inhibitor z-VAD-fmk or a caspase 3 inhibitor, or by using functional inhibitors for cathepsin D (pepstatin A) or cathepsin B. Inhibition of cathepsin D also prevented mitochondrial permeabilization and cythocrome c release suggesting that lysosomal rupture precedes and is necessary for the activation of the mitochondrial pathway of cell death.
authors.affiliation: Physiology Program, Department of Environmental Health, Harvard School of Public Health, 665 Huntington Ave., Boston, MA 02115, USA.
authors.forename: Lei
authors.initials: L
authors.lastname: Yin
authors.forename: Rebecca
authors.initials: R
authors.lastname: Stearns
authors.forename: Beatriz
authors.initials: B
authors.lastname: González-Flecha
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D002460:Cell Line; D006861:Hydrogen Peroxide / Q000494:pharmacology*; D066298:In Vitro Techniques; D008247:Lysosomes / Q000201:enzymology / Q000378:metabolism* / Q000648:ultrastructure; D018613:Microscopy, Confocal; D008854:Microscopy, Electron; D008928:Mitochondria / Q000201:enzymology / Q000378:metabolism* / Q000648:ultrastructure; D011650:Pulmonary Alveoli / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology
chemical_list: D006861:Hydrogen Peroxide