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

基本信息

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
项目类别：
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

项目摘要

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（由适用提供）：每年在美国超过200,000名受试者发生急性肺损伤，受影响的个体中有40％以上屈服于这种疾病。老年患者代表了急性肺损伤患者的数量不成比例，但导致这种易感性提高的因素尚不清楚。我们现在有证据表明，衰老使肺部通过建立“促纤维化”状态的肺部容易失修，该状态仅在暴露于受伤药物后才释放出来。当比较2个月零24个月大的小鼠时，我们发现，在基线时，感觉小鼠的肺会显示出促纤维化生长因子转化生长因子β，其受体TGF-¿RI的表达增加，其主要的细胞内透射剂Smad3；纤连蛋白剪接变体EDA，一种与肺纤维发生有关的基质糖蛋白；以及蛋白酶MMP2和MMP9。我们还发现，从感觉小鼠肺收获的成纤维细胞显示THY-1的表达降低。 THY-1阴性成纤维细胞促进纤维化反应。重要的是，当暴露于博来霉素时，较早的动物表现出更大的纤维化，如组织学上所证明的，并通过定量羟基丙烯蛋白。鉴于上述发现的重要性，我们将注意力转向了促进这些事件的因素。该搜索使我们研究了氧化应激的作用。已经表明，古老的动物（和人类）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了肺成纤维细胞增殖，肌成纤维细胞转差和TGF- - 和纤连蛋白体外的表达。基于上述情况，我们假设通过氧化半胱氨酸/胱氨酸氧化还原电位，衰老会导致“促纤维化”状态，从而使宿主容易失真和损伤后急性肺损伤。该假设将通过检查外胞外半胱氨酸/胱氨酸氧化还原电位的氧化如何通过确定营养干预措施作为预防策略的影响来促进感官鼠肺中的促纤维化状态，并通过测试这种pro-Elibolotic在BronChoalalveleal apolagotolation flas anthants nearthans nearts Plunans and Hantans vers versants and versants and versants and versants的证据。公共卫生相关性：急性肺损伤的发病率和死亡率在古老的患者中更为常见。许多报告表明，肺部受伤后被证明会失修，但造成这种情况的机制仍然不完全理解。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）会在sensence肺中诱导“纤维化”状态，从而增加对急性肺损伤的敏感性。该项目试图探索这种可能性，以期确定可以作为预防疗法的饮食干预措施。