Mechanisms of Chronic Intermittent Hypoxia Induced Airflow Obstruction during Allergic Lower Airway Inflammation

过敏性下气道炎症期间慢性间歇性缺氧引起气流阻塞的机制

• 批准号: 9552692
• 负责人: Mihaela Teodorescu
• 金额: --
• 依托单位: WM S. MIDDLETON MEMORIAL VETERANS HOSP
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9552692
• 关键词: Address; Adrenal Cortex Hormones; Airway Disease; Airway Resistance; Allergens; Allergic; Asthma; Attenuated; Benefits and Risks; Bone Marrow; Bronchoalveolar Lavage; Bronchodilator Agents; Caring; Chronic; Clinical; Collaborations; Collagen; Comorbidity; Data; Databases; Deposition; Development; Diagnosis; Dichloromethylene Diphosphonate; Disease; Distal; Enzyme-Linked Immunosorbent Assay; Exposure to; Fibrosis; Flow Cytometry; Functional disorder; Goals; Healthcare; Histologic; Histology; Hypoxia; Immunohistochemistry; Inflammation; Inflammatory; Inhalation; Investigation; Knowledge; Link; Literature; Lung; Lung diseases; Marrow; Measures; Modeling; Molecular; Morbidity - disease rate; Obstruction; Obstructive Sleep Apnea; Oxygen; Pathway interactions; Patients; Phenotype; Physiological; Plasminogen Activator Inhibitor 1; Positioning Attribute; Process; Property; Publishing; Pulmonary Emphysema; Pulmonary Fibrosis; Pyroglyphidae; Quality of life; Rat-1; Rattus; Rattus norvegicus; Research; Research Methodology; Resistance; Respiratory physiology; Rodent Model; Role; Saline; Services; Smooth Muscle; Structure; Structure of parenchyma of lung; System; Testing; Therapeutic; Tissues; Veterans; Work; airway inflammation; airway obstruction; airway remodeling; asthmatic patient; density; design; disorder control; effective intervention; effective therapy; experimental study; inhibitor/antagonist; innovation; macrophage; monocyte; mortality; novel; prevent; protein expression; public health relevance; screening; targeted treatment

 DESCRIPTION (provided by applicant): The Gap in Knowledge/ Work Accomplished: Obstructive sleep apnea (OSA) is highly common among patients with asthma and exacerbates the airways disease, but mechanisms are unknown. Chronic intermittent hypoxia (CIH), a hallmark feature of OSA, may be one important contributor. In our recently published and preliminary work, CIH exposure during allergen-induced airway inflammation in rats: 1) caused airflow limitation; 2) increased peribronchial collagen deposition in the proximal airways and led to matrix degradation of distal airways and parenchyma; 3) amplified the allergen-induced increase in airway monocytes, which may be non- classically activated and polarize into more pro-fibrotic M2 macrophage phenotype; 4) synergistically with the allergen, increased expression and activity of Plasminogen Activator Inhibitor - 1 (PAI-1) in bronchoalveolar lavage (BAL). Interestingly, none of these features would be responsive to inhaled corticosteroids. These novel findings underscore the potential of comorbid OSA to worsen asthma and cause irreversible detriments to lung function. However, these findings raise questions regarding: i) contributions of central airway resistance, small airway collapse and decreased elastance of lung parenchyma to CIH-induced airflow obstruction and reversibility of these physiologic deficits; ii) phenotype, activation state and roe of the monocytes and macrophages in our model; and iii) the role of PAI-1 in CIH-induced lung remodeling and airflow obstruction. Lack of understanding of these processes and their molecular underpinnings prevents development of more effective therapies for the large fraction of asthma patients suffering from the interaction with OSA. Hypothesis/ Aims: The long term goal is to develop effective strategies for treating asthma by targeting its interaction with OSA. The objective of this proposal is to test the physiological, cellular and molecular mechanisms underlying CIH-induced airflow obstruction and lung remodeling during House Dust Mites (HDM)-induced inflammation in rats. Our data led us to the central hypothesis that CIH-induced airflow obstruction during allergen challenge arises from increased resistance in proximal and distal airways along with reduced parenchymal tissue elastance, which result from increased monocyte-derived M2 macrophages with increased activity of PAI-1. To address this hypothesis, we propose to test the following Aims: 1) the physiologic mechanisms of CIH-induced lower airway obstruction during HDM airway inflammation; 2) the effect of CIH on lung monocyte activation and macrophage polarization; 3) the role of PAI-1 in CIH-induced airflow obstruction. Design: Four groups (n=10/group) of Brown-Norway rats will be sensitized with HDM or saline (SAL) and placed under CIH vs. normoxia (NORM) for 6 weeks, with weekly HDM or SAL challenges. Two days after last challenge, for Aim 1, central and distal airway, and lung elastic properties (elastance & compliance) will be measured pre & post bronchodilator. On histology, we will quantify the bronchial collagen and smooth muscle. For Aim 2, monocyte and macrophage (M1 vs. M2) will be quantified by flow cytometry, quantitative (q)PCR, and immunohistochemistry in BAL and/or lung. A separate study will test physiologic and histologic effects of marrow derived - macrophage depletion with clodronate. For Aim 3, total and active PAI-1 will be measured in BAL and lung homogenate by ELISA. An additional experiment will measure physiologic & histologic effects of PAI-1 inhibition in HDM-challenged rats exposed to CIH vs. NORM and fed regular chow or tiplaxtinin. Project Significance and Innovation: Our project is innovative, as it is the first in-depth investigation of the mechanisms whereby a commonly encountered clinical exposure, CIH, induces airway obstruction and remodeling. The study will lead to targeted therapies for Veterans afflicted with comorbid OSA and asthma. Results will be relevant to other lung diseases of high importance to Veterans, such as emphysema and pulmonary fibrosis, which also feature an interaction with OSA that relates with increased mortality.

 描述（由申请人提供）： 知识/工作的差距：阻塞性睡眠呼吸暂停（OSA）在哮喘患者中非常普遍，并加剧了气道疾病，但机制尚不清楚。 OSA的标志性特征慢性间歇性缺氧（CIH）可能是重要的贡献者。在我们最近发表的初步工作中，在过敏原引起的大鼠气道注射过程中，CIH暴露：1）引起气流限制； 2）增加了近端气道的周围胶原蛋白沉积，并导致远端气道和实质的基质降解； 3）扩展了过敏原诱导的气道单核细胞的增加，该单核细胞可能非经典地激活并极化为更纤维化的M2巨噬细胞表型； 4）与过敏原协同，在支气管肺泡灌洗中（BAL）中纤溶酶原激活剂抑制剂的表达和活性增加。这些特征将对继承皮质类固醇有反应。这些新颖的发现在合并症OSA的潜力中担心哮喘并造成不可逆转的损害肺功能。但是，这些发现提出了有关以下问题的问题：i）中央气道阻力，小气道崩溃以及肺实质对CIH引起的气流对象的弹性以及这些生理缺陷的可逆性的弹性； ii）我们模型中单核细胞和巨噬细胞的表型，激活状态和ROE； iii）PAI-1在CIH诱导的肺重塑和气流异常中的作用。缺乏对这些过程及其分子基础的理解，阻止了大量与OSA相互作用的哮喘患者的更有效疗法的发展。假设/目的：长期目标是通过针对其与OSA的相互作用来制定有效治疗哮喘的策略。该提案的目的是测试CIH引起的气流异常和肺部灰尘螨（HDM）诱导的大鼠炎症期间的物理，细胞和分子机制。我们的数据导致我们提出了一个中心假设，即CIH引起的过敏原挑战期间的气流反对反对是由近端和远端气道的耐药性增加，以及副群组织弹性的降低，这是由于单核细胞衍生的M2巨噬细胞增加而导致的，而PAI-1的活性增加了。为了解决这一假设，我们建议测试以下目的：1）在HDM气道注射期间，CIH引起的下气道降低的生理机制； 2）CIH对肺单核细胞激活和巨噬细胞极化的影响； 3）PAI-1在CIH诱导的气流异议中的作用。设计：棕色北方大鼠的四组（n = 10/组）将对HDM或盐水（SAL）敏感，并在CIH与Normoxia（Normoxia（Norm）（Normoxia（Normoxia）（Normoxia（Norm））中，每周有HDM或SAL挑战。最后挑战两天后，对于AIM 1，中央气道和远端气道以及肺弹性特性（弹性与合规性）将被测量支气管扩张剂前和后。关于组织学，我们将量化支气管胶原蛋白和平滑肌。对于AIM 2，将通过BAL和/或肺中的流式细胞仪，定量（Q）PCR和免疫组织化学来量化单核细胞和巨噬细胞（M1与M2）。一项单独的研究将测试衍生的骨髓 - 巨噬细胞部署的生理和组织学作用。对于AIM 3，将通过ELISA在BAL和肺匀浆中测量总PAI-1。另一个实验将测量PAI-1抑制在暴露于CIH与NORM的HDM挑战大鼠中的生理和组织学作用，并喂养常规的Chow或Tiplaxtinin。项目意义和创新：我们的项目具有创新性，因为它是对通常遇到临床暴露（CIH）引起气道异议和重塑的机制的首次深入研究。这项研究将导致对患有合并症OSA和哮喘的退伍军人的有针对性疗法。结果将与其他对退伍军人（例如肺气肿和肺纤维化）高度重要性的肺部疾病有关，这些疾病也具有与OSA的相互作用，与死亡率增加有关。