Aging susceptibility to lung injury ^ tissue remodeling and oxidative stress

衰老对肺损伤的易感性^组织重塑和氧化应激

• 批准号: 8189673
• 负责人: JESSE ROMAN
• 金额: $ 18.34万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8189673
• 关键词: Acute Lung Injury; Acute respiratory failure; Adult Respiratory Distress Syndrome; Affect; Age; Age-Months; Aging; Alcohols; Animals; Antioxidants; Attention; Bleomycin; Bronchoalveolar Lavage Fluid; Collagen; Critical Care; Critical Illness; Cysteine; Cystine; Data; Development; Dietary Intervention; Disease; Elderly; Endotoxemia; Endotoxins; Event; Exposure to; Extracellular Matrix; Fibroblasts; Fibronectins; Fibrosis; Funding; Glycoproteins; Growth Factor; Harvest; Histologic; Histology; Human; Hydroxyproline; In Vitro; Incidence; Individual; Inflammatory; Inflammatory Response; Injury; Integration Host Factors; Investigation; Laboratories; Lead; Link; Lung; MMP2 gene; MMP9 gene; Mus; Myofibroblast; Nicotine; Nutritional; Organ; Outcome; Oxidation-Reduction; Oxidative Stress; Pathway interactions; Peptide Hydrolases; Plasma; Predisposition; Prevention strategy; Preventive; Preventive Intervention; Process; Production; RNA Splicing; Reporting; Research; Role; Signal Transduction; Sirolimus; Surface; Testing; Tissues; Transducers; Transforming Growth Factor beta; Transforming Growth Factors; Variant; Virus; Work; age related; base; collagenase; design; dietary supplements; fibrogenesis; human FRAP1 protein; improved; injured; lung injury; mortality; novel; older patient; oxidant stress; oxidation; prevent; receptor; repaired; response; senescence; therapy design; transcription factor; transdifferentiation

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.

描述（由申请人提供）：美国每年有超过200，000例受试者发生急性肺损伤，超过40%的受影响个体死于这种疾病。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仍不清楚。我们现在有证据表明，老化使肺容易通过建立一个“促纤维化”的状态，只有在暴露于有害物质后才释放出来而破损。当比较2月龄和24月龄的小鼠时，我们发现，在基线时，衰老小鼠的肺显示促纤维化生长因子转化生长因子β、其受体TGF-β RI及其主要细胞内转导子Smad 3、纤连蛋白剪接变体EDA（一种与肺纤维化相关的基质糖蛋白）以及蛋白酶MMP 2和MMP 9的表达增加。我们还发现，从衰老小鼠肺中采集的成纤维细胞显示Thy-1表达降低; Thy-1阴性成纤维细胞促进纤维化反应。重要的是，当暴露于博莱霉素时，老年动物显示出更大的纤维化，如组织学和羟脯氨酸定量所示。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。已经显示，老年动物（和人）表现出其血浆半胱氨酸/胱氨酸氧化还原电位的氧化。我们证明，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，TGF-β和纤连蛋白的表达在体外。基于以上所述，我们假设老化通过半胱氨酸/胱氨酸氧化还原电位的氧化导致“促纤维化”状态，其使得宿主在损伤后易于破损和发生急性肺损伤。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鼠肺中的促纤维化状态，通过确定营养干预作为预防策略的影响，以及通过测试年轻人与老年人的支气管肺泡灌洗液中的这种促纤维化状态的证据来研究该假设。 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常见。许多报告表明，衰老的肺容易在损伤后破损，但对此负责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/胱氨酸氧化还原电位的氧化）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。该项目旨在探索这种可能性，希望确定可以作为预防性治疗的饮食干预措施。