The mechanisms by which H2S attenuates PHT, aside from increasing lung angiogenesis, remain unclear. To our knowledge, there are no data available on H2S interactions with the signaling pathways contributing to PHT in the hyperoxia model. Interestingly, H2S SCH772984 protects against ballon injury induced neointima hyperplasia of the carotid artery and decreases vascular smooth muscle cell proliferation in this model. Likewise, we found that GYY4137 attenuated PDGFinduced PASMC proliferation. Interestingly, we showed that the expression of activated Akt in vivo decreased in the lungs of animals exposed to hyperoxia, while the expression of total caspase-3, a marker of apoptosis, significantly increased. This observation indicates a potential role of the prosurvival PI3K/Akt pathway in determining the ability of AECs to resist to hyperoxic injury. H2S attenuates particulate matter– induced human lung endothelial barrier disruption via combined ROS scavenging and Akt activation. Moreover, we have shown recently that activation of Akt protects alveoli from experimental oxygen-induced lung injury in newborn rats. Accordingly, previous studies report that the H2S donor sodium hydrosulfide induces a dose and time-dependent increase in Akt phosphorylation in endothelial cells, which can be inhibited by the PI3K inhibitors LY 294002 and wortmannin. This suggests that H2S stimulates the activation of pro-survival Akt. Activation of Akt by various extracellular signals increases endothelial cell proliferation, migration, and tube formation in vitro, and mediates protective cytoskeletal rearrangement. However, the mechanism by which H2S activates Akt is poorly understood and remains to be investigated. We also found that sirtuin1 gene expression was higher in H2Streated groups compared to untreated hyperoxia-exposed animals. Sirtuins are nuclear nicotinamide adenine dinucleotide-dependent histone deacetylases. In mammalian cells, sirtuin1 appears to control the cellular response to stress by regulating the FOXO family of forkhead transcription factors. Because FOXO transcription factors transactivate a series of target genes that have critical roles in the cellular response to stress stimuli, endogenous sirtuin1 may potentiate FOXO’s ability to detoxify ROS and to repair damaged DNA. It has been reported that sirtuin1 levels were reduced in macrophages and lungs of smokers and patients with chronic obstructive pulmonary disease due to its post-translational modifications by cigarette smoke-derived reactive components. Lung cells exposed to hyperoxia can generate free radicals such as superoxide anion, hydroxyl, and alkyl radicals via mitochondrial electron transport. Mitochondrial DNA, metabolism, and function are highly susceptible to ROS-induced injury. Such mitochondrial injury can contribute to the pathogenesis of necrotic and apoptotic cell death. Whether enhancement of cell survival in this study is related to energy homeostasis and protection of mitochondrial function was investigated by measuring the DYm of hyperoxia-exposed H2S treated and untreated cells.