Aging related susceptibility to lung injury - remodeling and oxidative stress

描述（由申请人提供）：在美国，每年有超过20万受试者发生急性肺损伤，超过40%的患者死于这种疾病。老年患者在急性肺损伤患者中占不成比例的比例，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，衰老使肺部容易年久失修，通过建立“促纤维化”状态，只有在接触有害物质后才会释放出来。在比较2月龄和24月龄小鼠时，我们发现，在基线时，衰老小鼠的肺部促纤维化生长因子转化生长因子β、其受体TGF-¿RI及其主要细胞内传感器Smad3的表达增加；纤维连接蛋白剪接变体EDA，一种与肺纤维化相关的基质糖蛋白；以及蛋白酶MMP2和MMP9。我们还发现，从衰老小鼠的肺中获取的成纤维细胞显示Thy-1的表达减少；Thy-1阴性成纤维细胞促进成纤维反应。重要的是，当暴露于博来霉素时，老年动物表现出更大的纤维化，这是通过组织学和羟脯氨酸定量证明的。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。这项研究使我们开始研究氧化应激的作用。研究表明，老年动物（和人类）的血浆半胱氨酸/胱氨酸氧化还原电位出现氧化。我们证明了这种类型的氧化应激促进肺成纤维细胞增殖、肌成纤维细胞转分化和TGF-¿和纤维连接蛋白的表达。基于以上，我们假设衰老，通过半胱氨酸/胱氨酸氧化还原电位的氧化，导致“前纤维化”状态，使宿主在损伤后容易失修和急性肺损伤的发展。该假说将通过检查细胞外半胱氨酸/胱氨酸氧化还原电位的氧化如何促进衰老小鼠肺的促纤维化状态，通过确定营养干预作为预防策略的影响，以及通过检测年轻人与健康老年人的支气管肺泡灌洗液中促纤维化状态的证据来进行研究。

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.