Lysosomal and mitochondrial pathways in H2O2-induced apoptosis of alveolar type II cells

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 remainpoorlydefined. Herewe investigatedthe role oflysosomes asmodulators ofoxidant-mediatedAT II cellapoptosis using an in vitro model of H2O2-stress. H2O2 stress led to time-dependent increases in intracellular oxidants, mitochondrial membrane polarization, cytochrome c release, lysosomal rupture, and AT II cells apoptosis. Increased apoptosiswaspreventedbyspecificinhibitionofthecaspasecascadeusingthebroad-spectrumcaspaseinhibitorz-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. J. Cell. Biochem. 94: 433-445, 2005. 2004 Wiley-Liss, Inc.