Reports have also suggested that nSMase2 plays a role in stress-induced bronchial and lung injury in pulmonary diseases. For example, in HAE cells, H2O2 induced activation of nSMase2, ceramide generation, and apoptosis and this was inhibited by GSH. Oxidant exposure was also suggested to affect nSMase2 localization with oxidant exposure causing preferential trafficking to the PM whereas in contrast, exposure to GSH resulted in nSMase2 trafficking to the nucleus (Levy et al., 2006). A subsequent study also found that nSMase2 was required for cigarette smoke-mediated ceramide generation and apoptosis in human bronchial epithelial cells (Levy et al., 2009). As with H2O2, GSH also inhibited the cigarette smoke-induced effects on nSMase2 activity and apoptosis. Finally, the nSMase2 inhibitor GW4869 was shown to inhibit hypoxia-induced pulmonary vasoconstriction in vivo (Cogolludo et al., 2009). In isolated rat pulmonary artery smooth muscle cells, hypoxia increased ceramide content which was abrogated by GW4869. These data suggest that nSMase2 plays roles in vasoconstrictor response to hypoxia.
