Biology of the human lung mucosa in aging and tuberculosis

衰老和结核病中人类肺粘膜的生物学

• 批准号: 9884702
• 负责人: Jordi B Torrelles
• 金额: $ 33.87万
• 依托单位: TEXAS BIOMEDICAL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至 2022-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9884702
• 关键词: Address; Adult; Affect; Age; Aging; Alveolar; Area; Binding; Biochemical; Biochemistry; Biological; Biological Markers; Cell Wall; Cells; Cellular biology; Chronic; Collaborations; Collectins; Complement; Defect; Deposition; Development; Diagnostic; Elderly; Elements; Environment; Enzymes; Epithelial Cells; Exposure to; Generations; High Pressure Liquid Chromatography; Human; Human Biology; Hydrolase; Immune; Impairment; In Vitro; Individual; Infection; Inflammaging; Inflammation; Inflammatory; Innate Immune System; Knowledge; Link; Lipids; Liquid substance; Lung; Lung infections; Maintenance; Modification; Molecular; Molecular Profiling; Mucosal Immune Responses; Mucous Membrane; Mus; Mycobacterium tuberculosis; Natural Immunity; Natural regeneration; Outcome; Oxidative Stress; Oxides; Peripheral; Persons; Phagocytes; Physiology; Play; Population; Predisposition; Process; Production; Proteins; Publishing; Pulmonary Surfactant-Associated Protein A; Pulmonary Surfactant-Associated Protein D; Research; Research Personnel; Respiratory physiology; Risk Factors; Role; Therapeutic; Time; Tuberculosis; Vaccines; Work; aged; alveolar epithelium; comparative; complement system; cytokine; design; immune function; impaired capacity; in vivo; in vivo evaluation; innovation; mouse model; negative affect; novel strategies; oxidation; oxidized lipid; pulmonary function; response; senescence; surfactant; trafficking; uptake

Age-associated immune defects are considered a primary risk factor for TB, but other factors such as the heightened systemic inflammatory state (inflammaging) observed in elderly individuals have not been previously considered. During infection, airborne Mycobacterium tuberculosis (M.tb) is deposited in the lung where it is exposed to different local environments over time. First, M.tb encounters the alveolar space, where it will be in direct contact with Alveolar Lining Fluid (ALF) components, notably surfactant and complement, for an undetermined period. We hypothesize that ALF, containing important innate immune determinants against M.tb infection, is functionally deficient in old age, largely as a result of oxidative stress, which negatively impacts the control of M.tb infection in the lung. ALF is generated, secreted and recycled by alveolar epithelial cells, and is essential for maintaining lung function. Some human ALF components [surfactant proteins A (SP- A) and D (SP-D), homeostatic hydrolytic enzymes (hydrolases), and lipids] are critical elements of the innate immune system during M.tb infection, playing an important role in M.tb-phagocyte encounters. Oxidative stress associated with low grade chronic inflammation that occurs during aging is expected to result in changes in ALF component production and activity. For example, alterations in surfactant lipids are predicted to negatively affect SP-A and SP-D function. We know little about how oxidative stress and low grade inflammation associated with aging impact M.tb infection progression in the lung. This knowledge gap limits our ability to design new approaches for the development of diagnostics, therapeutics and vaccines that are effective in the lung. Here we propose to determine the function of ALF components in the elderly human lung, and their impact on the establishment and progression of M.tb infection using in vitro and in vivo approaches. Our proposal is significant and innovative in the field of aging, determining how ALF soluble components in the elderly lung influence M.tb infection and outcome. Our studies are closely linked to Projects 2 & 3 (innate & adaptive responses to M.tb infection in aging, respectively) and synergize with Project 4 (circulating molecular signatures of aging).

结核病相关的免疫缺陷被认为是结核病的主要危险因素，但其他因素，如 在老年个体中观察到的升高的全身性炎症状态（炎症）尚未被发现。 以前考虑过。在感染过程中，空气传播的结核分枝杆菌（M.tb）沉积在肺中 在那里它随时间暴露于不同的局部环境。首先，结核分枝杆菌遇到肺泡腔， 它将与肺泡衬液（ALF）组分，特别是表面活性剂和补体直接接触， 一个不确定的时期。我们假设ALF含有重要的先天免疫决定因子， 结核分枝杆菌感染，在老年人中是功能缺陷的，主要是由于氧化应激， 影响肺结核感染的控制。ALF由肺泡上皮细胞产生、分泌和回收 细胞，并且对维持肺功能至关重要。一些人ALF组分[表面活性蛋白A（SP-1）] A）和D（SP-D），稳态水解酶（水解酶）和脂质]是先天性免疫缺陷的关键要素。 免疫系统在结核分枝杆菌感染过程中起重要作用，在结核分枝杆菌-吞噬细胞相遇中起重要作用。氧化应激 与衰老过程中发生的低度慢性炎症相关，预计会导致 ALF组件生产和活动。例如，表面活性剂脂质的改变被预测为负面的。 影响SP-A和SP-D功能。我们对氧化应激和低度炎症 与年龄相关的影响肺结核分枝杆菌感染进展。这种知识差距限制了我们的能力， 设计新的方法来开发有效的诊断、治疗和疫苗， 肺。在这里，我们建议确定老年人肺中ALF组分的功能，以及它们在老年人肺中的作用。 使用体外和体内方法对结核分枝杆菌感染的建立和进展的影响。我们 该提案在老化领域具有重要意义和创新性，确定了ALF可溶性成分如何在 老年人肺结核感染与预后的关系我们的研究与项目2和3（先天和 适应性反应结核分枝杆菌感染的老化），并协同项目4（循环分子 衰老的迹象）。