In mammalian cells, H2S is produced from L-cysteine, catalyzed by one of two pyridoxal-59-phosphate-dependent enzymes, cystathionine b-synthase and/or cystathionine c-lyase. H2S is considered a toxic gas. Its smell of rotten eggs can be perceived at concentrations as low as 0.0047 ppm. In serious cases, it causes cough, headache, pulmonary edema, or even coma. However, recent reports show that H2S is endogenously generated in the mammalian body and plays important physiological roles. Growing evidence implicates H2S in the pathogenesis of pulmonary diseases. In the present study we show, both in vitro and in vivo, that H2S treatment displays lung-protective properties in the developing lung. Because angiogenesis contributes to alveolar growth, we examined the protective effect of H2S on HPAECs. In vitro, H2S preserved HPAECs viability and maintained HPAECs network formation in hyperoxia. Furthermore, H2S reduced HPAEC ROS levels in hyperoxia. This is consistent with reports showing that H2S protects cells and proteins from oxidative stress induced by peroxynitrite and hypochlorous acid. In endothelial cells, hydrogen peroxide and organic hydroperoxides such as lipid hydroperoxides are responsible for the activation of heme oxygenase-1, one of the ROS responders that trigger extensive oxidative damage in endothelial cells. H2S is capable of destroying hydrogen peroxide and LOOHs. Consistent with these in vitro data, we show through vWF staining and CD31 lung protein expression that H2S preserved lung vascular growth in rats pups exposed to chronic hyperoxia. Inhaled NO is a potent pulmonary vasodilator and promotes distal lung growth. Inhaled NO shows promise as a prophylactic therapy to decrease the incidence of BPD in experimental models, while results in preterm infants remain inconclusive. Thus, we hypothesized that H2S would have similar beneficial effects on distal lung growth and PHT. In vivo, H2S indeed ONX-0914 attenuated the arrested alveolar growth in the chronic oxygen induced arrested alveolar growth in rat model. While we demonstrate for the first time the protective effect of H2S on the developing lung, recent reports indicated a therapeutic potential of H2S in various acute adult lung injury models. Inhalation of 80 ppm H2S ameliorates lung pathology in LPS and in ventilator induced lung injury. Interestingly, Francis et al observed that 1 or 5 ppm H2S did not alter ventilation-induced lung injury, while 60 ppm H2S worsened ventilator-induced lung injury. In contrast, intravenous pretreatment with sodium sulfide attenuated reduced pulmonary edema, enhanced the pulmonary expression of Nrf2-dependent antioxidant genes and prevented oxidative stress-induced depletion of glutathione in lung tissue. This is consistent with the protective effect observed in the neonatal chronic hyperoxia-induced lung injury model, in which Nrf2 preserves alveolar growth while Nrf2 deficiency worsens lung injury,. PHT often complicates chronic lung diseases including BPD and significantly worsens the prognosis. H2S induces vasodilatation and inhibits vascular smooth muscle cell proliferation.