Aging susceptibility to lung injury ^ tissue remodeling and oxidative stress

描述(由申请人提供)：在美国，每年有超过20万名受试者发生急性肺损伤，超过40%的患者死于这种疾病。老年患者代表了不成比例的急性肺损伤患者数量，但导致这种易感性增加的因素尚不清楚。我们现在有证据表明，衰老通过建立一种只有在接触有害物质后才会释放的促纤维化状态，使肺容易失修。当比较2个月和24个月龄的小鼠时，我们发现，在基线水平，衰老小鼠的肺部显示出促纤维化生长因子转化生长因子β及其受体转化生长因子β1及其主要细胞内转导因子Smad3；纤维连接蛋白剪接变异体EDA，一种与肺纤维化有关的基质糖蛋白；以及蛋白酶MMP2和MMP9的表达增加。我们还发现，从衰老小鼠肺中获取的成纤维细胞显示Thy-1的表达减少；Thy-1阴性的成纤维细胞促进了纤维化反应。重要的是，当接触博莱霉素时，老年动物表现出更大的纤维化，正如组织学和羟脯氨酸定量所证明的那样。鉴于上述发现的重要性，我们将注意力转向促进这些事件的因素。这项研究让我们研究了氧化应激的作用。已有研究表明，老年动物(和人类)的血浆半胱氨酸/半胱氨酸氧化还原电位发生氧化。我们证明了这种类型的氧化应激在体外促进了肺成纤维细胞的增殖、肌成纤维细胞的转分化以及转化生长因子-β和纤维连接蛋白的表达。在此基础上，我们假设衰老通过半胱氨酸/半胱氨酸氧化还原电位的氧化，导致“促纤维化”状态，使宿主在受到侮辱后容易失修并发展为急性肺损伤。通过研究细胞外半胱氨酸/半胱氨酸氧化还原电位的氧化如何促进衰老小鼠肺部的促纤维化状态，通过确定营养干预作为预防策略的影响，以及测试在其他方面健康的年轻人和老年人的支气管肺泡灌洗液中这种促纤维化状态的证据，将对这一假说进行研究。 公共卫生相关性：急性肺损伤的发病率和死亡率在老年患者中更为常见。许多报告表明，损伤后衰老的肺会变得年久失修，但导致这一现象的机制仍不完全清楚。我们认为，一种特殊的氧化应激(半胱氨酸/半胱氨酸氧化还原电位的氧化)会在衰老的肺中诱导“促纤维化”状态，从而增加对急性肺损伤的易感性。该项目试图探索这一可能性，希望确定可以作为预防性治疗的饮食干预措施。

DESCRIPTION (provided by applicant): Acute lung injury occurs in over 200,000 subjects in the U.S. each year and over 40% of affected individuals succumb to this disease. Elderly patients represent a disproportionate number of afflicted individuals with acute lung injury, but the factors responsible for this increased susceptibility remain unclear. We now have evidence suggesting that aging renders the lung susceptible to disrepair through the establishment of a 'pro-fibrotic' state that is unleashed only after exposure to an injurious agent. When comparing mice at 2 months and 24 months of age, we found that, at baseline, the lungs of senescent mice show increased expression of the pro-fibrotic growth factor transforming growth factor beta, its receptor TGF-¿RI, and its main intracellular transducer, Smad3; the fibronectin splicing variant EDA, a matrix glycoprotein linked to lung fibrogenesis; and the proteases MMP2 and MMP9. We also found that fibroblasts harvested from the lungs of senescent mice show decreased expression of Thy-1; Thy-1 negative fibroblasts promote fibrogenic responses. Importantly, when exposed to bleomycin, elderly animals show greater fibrosis as demonstrated histologically and by quantification of hydroxyproline. In view of the importance of the above findings, we turned our attention to the factors promoting these events. That search led us to investigate the role of oxidant stress. It has been shown that elderly animals (and humans) manifest oxidation of their plasma cysteine/cystine redox potential. We demonstrated that this type of oxidant stress promotes lung fibroblast proliferation, myofibroblast transdifferentiation, and expression of TGF-¿ and fibronectin in vitro. Based on the above, we hypothesize that aging, through oxidation of the cysteine/cystine redox potential, results in a 'pro- fibrotic' state that renders the host susceptible to disrepair and the development of acute lung injury after an insult. The hypothesis will be investigated by examining how oxidation of the extracellullar cysteine/cystine redox potential promotes a pro-fibrotic state in senescent murine lungs, by determining the impact of nutritional interventions as preventive strategies, and by testing for evidence of this pro-fibrotic state in the bronchoalveolar lavage fluid of young versus elderly humans who are otherwise healthy. PUBLIC HEALTH RELEVANCE: The incidence and mortality from acute lung injury are more common in elderly patients. Many reports suggest that senescent lungs are proned to disrepair after injury, but the mechanisms responsible for this remain incompletely understood. We believe that a special kind of oxidant stress (oxidation of the cysteine/cystine redox potential) induce a 'pro-fibrotic' state in senescent lungs thereby increasing susceptibility to acute lung injury. This project seeks to explore this possibility with the hope of identifying dietary interventions that could serve as preventive therapy.