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).

与年龄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，例如 在老年人中观察到的系统性炎症状态（炎症）尚未 先前考虑的。在感染期间，空气中的分枝杆菌结核病（M.TB）沉积在肺中 随着时间的流逝，它暴露于不同的本地环境。首先，M.TB遇到肺泡空间 它将直接与肺泡衬里（ALF）组件直接接触，特别是表面活性剂和补体 一个不确定的时期。我们假设ALF包含重要的先天免疫决定因素 M.TB感染，在老年功能上缺乏，主要是由于氧化应激而导致的。 影响肺中M.TB感染的控制。 ALF由肺泡上皮产生，分泌和回收 细胞，对于维持肺功能至关重要。一些人类ALF成分[表面活性剂蛋白A（SP-） A）和D（SP-D），稳态的水解酶（水解酶）和脂质是先天性的关键元素 M.TB感染期间的免疫系统，在M.TB - 表现体相遇中起重要作用。氧化应激 与低年级慢性炎症相关的衰老期间会导致变化 ALF组件的生产和活动。例如，表面活性剂脂质的改变被预测为负 影响SP-A和SP-D功能。我们对氧化应激和低级炎症的了解一无所知 与衰老有关肺部的衰老影响M.TB感染的进展。这些知识差距限制了我们的能力 设计新方法，用于开发有效的诊断，治疗剂和疫苗 肺。在这里，我们建议确定ALF成分在老年人肺中的功能，及其 使用体外和体内方法对M.TB感染的建立和进展影响。我们的 提案在衰老领域具有重要意义和创新性，确定了ALF可溶性成分如何 老年肺影响M.TB感染和预后。我们的研究与项目2和3密切相关（先天和 分别对衰老中M.TB感染的自适应反应）并与项目4协同作用（循环分子 衰老的签名）。