Airway　epithelial　mitochondrial　injury　plays　a　critical　role　in　the　pathogenesis　of　chronic　obstructive　pulmonary　disease　(COPD).　The　p66Shc　adaptor　protein　is　a　newly　recognized　mediator　of　mitochondrial　dysfunction.　However,　little　is　known　about　the　effect　of　p66Shc　on　airway　epithelial　damage　in　the　development　of　COPD.　The　aim　of　the　present　study　is　to　investigate　the　roles　of　p66Shc　and　its　upstream　regulators　in　the　mitochondrial　injury　of　airway　epithelial　cells　(Beas-2b)　induced　by　cigarette　smoke　extract　(CSE).　Our　present　study　revealed　that　CSE　increased　p66Shc　expression　and　its　mitochondrial　translocation　in　concentration　and　time-dependent　manners　in　airway　epithelial　cells.　And　p66Shc　siRNA　significantly　attenuated　mitochondrial　dysfunction　and　cell　injury　when　airway　epithelial　cells　were　stimulated　with　7.5%　CSE.　The　total　and　phosphorylated　expression　of　PKC　beta　and　PKC　delta　was　significantly　increased　associated　with　mitochondrial　dysfunction　and　cell　injury　when　airway　epithelial　cells　were　exposed　to　7.5%　CSE.　The　pretreatments　with　pharmacological　inhibitors　of　PKC　beta　and　PKC　delta　could　notably　suppress　p66Shc　phosphorylation　and　its　mitochondrial　translocation　and　protect　the　mitochondria　and　cells　against　oxidative　damage　when　airway　epithelial　cells　were　incubated　with　7.5%　CSE.　These　data　suggest　that　a　novel　PKC　beta/delta-p66Shc　signaling　pathway　may　be　involved　in　the　pathogenesis　of　COPD　and　other　oxidative　stress-associated　pulmonary　diseases　and　provide　a　potential　therapeutic　target　for　these　diseases.