Necrotic Cell Death in Response to Oxidant Stress Involves the Activation of the Apoptogenic Caspase-8/Bid Pathway
Copyright policy )Necrotic Cell Death in Response to Oxidant Stress Involves the Activation of the Apoptogenic Caspase-8/Bid Pathway
Human epithelial (A549) cells exposed to hyperoxia die by cellular necrosis. In the current study, we demonstrated the involvement of apoptogenic factors in epithelial cell necrosis in response to hyperoxia, including the formation of the Fas-related death-inducing signaling complex and initiation of mitochondria-dependent apoptotic pathways. We showed increased activation of both Bid and Bax in A549 cells subjected to hyperoxia. Bax activation involved a Bid-assisted conformational change. We discovered that the response to hyperoxia in vivo predominantly involved the activation of the Bid/caspase-8 pathway without apparent increases in Bax expression. Disruption of the Bid pathway by gene deletion protected against cell death in vivo and in vitro. Likewise, inhibition of caspase-8 by Flip also protected against cell death. Taken together, we have demonstrated the involvement of apoptogenic factors in epithelial cell responses to hyperoxia, despite a final outcome of cellular necrosis. We have, for the first time, identified a predominant role for the caspase-8/Bid pathway in signaling associated with hyperoxic lung injury and cell death in vivo and in vitro.
- University of Pittsburgh United States
Male, Caspase 8, Fas Ligand Protein, Lung Neoplasms, CASP8 and FADD-Like Apoptosis Regulating Protein, Intracellular Signaling Peptides and Proteins, Apoptosis, Adenocarcinoma, Fibroblasts, Caspase Inhibitors, Caspase 9, Caspases, Animals, Humans, Enzyme Inhibitors, Carrier Proteins, Lung, Cells, Cultured, Gene Deletion, BH3 Interacting Domain Death Agonist Protein
Male, Caspase 8, Fas Ligand Protein, Lung Neoplasms, CASP8 and FADD-Like Apoptosis Regulating Protein, Intracellular Signaling Peptides and Proteins, Apoptosis, Adenocarcinoma, Fibroblasts, Caspase Inhibitors, Caspase 9, Caspases, Animals, Humans, Enzyme Inhibitors, Carrier Proteins, Lung, Cells, Cultured, Gene Deletion, BH3 Interacting Domain Death Agonist Protein
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