Targeting antioxidant gene expression to prevent and treat pulmonary redox imbalance in a murine model of ventilator-induced lung injury

在这个建议中，我们介绍了我们以前的工作，研究实验策略，以减轻呼吸机引起的肺损伤的氧化应激。这些策略包括硫化物物质的潜在抗炎作用，如硫化钠溶液（Na 2S）和气态硫化氢（H2S）。我们以前在VILI小鼠模型中的工作已经证明，连续吸入H2S气体增强肺中白细胞粘附和趋化因子分子的表达，加速肺水肿形成，并在高潮气量机械通气期间以高浓度（60 ppm）吸入时促进肺损伤。相反，我们已经证明，全身血管内治疗与Na 2S代表一种新的治疗策略，以减轻氧化应激和预防VILI通过抗氧化基因表达在这个实验模型。我们的工作已经证实了H2S和Na 2S处理的有益和有害影响。因此，在当前提案中，我们的目标是通过以下方式对这些研究进行随访：a）尝试确定介导全身性Na 2S治疗保护作用的潜在肺和肺外机制，以及B）基于吸入H2S的已知毒理学，将测试针对类似抗氧化途径但毒性较低的替代方法。作为补充，我们建议调查肺-脑相互作用的各个方面，以描述和支持与新发现的称为呼吸机诱导的神经认知障碍（VINI）的实体相关的新的、创新的假设。然后，该提案产生的初步结果（原则证明）将为独立的关于自愿网络信息倡议的后续提案奠定基础。

In this proposal, we introduce our previous work studying experimental strategies to attenuate oxidative stress in ventilator-induced lung injury.. These strategies include the potential anti-inflammatory effects of sulfide species, such as sodium sulfide solution (Na2S) and gaseous hydrogen sulfide (H2S). Our previous work in a mouse model of VILI has demonstrated that continuous inhalation of H2S gas enhances the expression of leukocyte adhesion and chemoattractant molecules in the lung, accelerates pulmonary edema formation, and promotes lung injury when it is inhaled at high concentrations (60 ppm) during mechanical ventilation with a high tidal volume. In contrast, we have demonstrated that systemic intravascular treatment with Na2S represent a novel therapeutic strategy to attenuate oxidative stress and to prevent VILI via antioxidative gene expression in this experimental model. Our work has substantiated both beneficial as well as detrimental effects of H2S and Na2S treatment. Therefore, in the current proposal, we aim to follow up on these studies by a) attempting to identify the underlying pulmonary and extrapulmonary mechanisms that mediate the protective effect of systemic Na2S treatment, and b) based on the know toxicology of inhaled H2S, will test alternative approaches which target similar antioxidative pathways, but with less toxicity. As a supplement, we propose to investigate aspects of lung-brain interaction to delineate and support new, innovative hypotheses related to the newly identified entity called ventilator-induced neurocognitive impairment (VINI). Preliminary results generated in this proposal (proof-of-principle) shall then set the stage for an independent follow-up proposal on VINI.