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: 10118005
• 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 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10118005
• 关键词: Address; Adrenal Cortex Hormones; Air Movements; Airway Disease; Airway Resistance; Allergens; Allergic; Asthma; Attenuated; Benefits and Risks; Bone Marrow; Bronchoalveolar Lavage; Bronchodilator Agents; Caring; Chronic; Collaborations; Collagen; 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; 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; chronic airflow obstruction; clinical encounter; comorbidity; 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/完成工作的差距：阻塞性睡眠呼吸暂停（OSA）在哮喘患者中非常常见，并会加重气道疾病，但机制尚不清楚。慢性间歇性缺氧（CIH），OSA的标志性特征，可能是一个重要的贡献者。在我们最近发表的和初步的工作中，CIH暴露在过敏原诱导的大鼠气道炎症期间：1）引起气流限制; 2）增加近端气道中的支气管周围胶原沉积，并导致远端气道和实质的基质降解; 3）放大过敏原诱导的气道单核细胞的增加，其可能被非经典地激活并转化为更促纤维化的M2巨噬细胞表型; 4）与变应原协同作用，增加支气管肺泡灌洗液（BAL）中纤溶酶原激活物抑制剂-1（派-1）的表达和活性。有趣的是，这些特征都不会对吸入性皮质类固醇有反应。这些新的发现强调了合并OSA使哮喘恶化并导致肺功能不可逆损害的可能性。然而，这些发现提出了以下问题：i）中心气道阻力、小气道塌陷和肺实质弹性降低对CIH诱导的气流阻塞的贡献以及这些生理缺陷的可逆性; ii）我们的模型中单核细胞和巨噬细胞的表型、活化状态和roe;以及iii）派-1在CIH诱导的肺重塑和气流阻塞中的作用。缺乏对这些过程及其分子基础的了解，阻碍了对大部分患有OSA相互作用的哮喘患者开发更有效的治疗方法。假设/目的：长期目标是通过靶向其与OSA的相互作用来开发治疗哮喘的有效策略。本研究的目的是探讨室内尘螨（HDM）诱导的大鼠炎症反应中CIH诱导的气流阻塞和肺重塑的生理、细胞和分子机制。我们的数据使我们的中心假设，CIH诱导的气流阻塞过敏原挑战期间产生的阻力增加，近端和远端气道以及减少实质组织弹性，这是由于单核细胞衍生的M2巨噬细胞增加派-1的活性增加。为了解决这一假设，我们提出测试以下目的：1）在HDM气道炎症期间CIH诱导的下气道阻塞的生理机制; 2）CIH对肺单核细胞活化和巨噬细胞极化的影响; 3）派-1在CIH诱导的气流阻塞中的作用。设计图：四组（n=10/组）Brown-Norway大鼠将用HDM或盐水（SAL）致敏，并置于CIH与常氧（NORM）下6周，每周进行HDM或SAL激发。最后一次激发后两天，对于目标1，将在使用支气管扩张剂前后测量中央和远端气道以及肺弹性特性（弹性和顺应性）。在组织学上，我们将量化支气管胶原蛋白和平滑肌。对于目的2，将通过流式细胞术、定量（q）PCR和免疫组织化学对BAL和/或肺中的单核细胞和巨噬细胞（M1 vs. M2）进行定量。另一项研究将测试氯膦酸盐对骨髓源性巨噬细胞消耗的生理和组织学影响。对于目标3，将通过ELISA测量BAL和肺匀浆中的总PAI-1和活性PAI-1。另一个实验将测量派-1抑制在暴露于CIH与NORM并喂食常规食物或替普拉替宁的HDM激发大鼠中的生理和组织学作用。项目意义和创新：我们的项目是创新的，因为它是第一个深入研究临床常见的暴露，CIH，诱导气道阻塞和重塑的机制。这项研究将为患有OSA和哮喘的退伍军人提供有针对性的治疗。结果将与其他对退伍军人非常重要的肺部疾病相关，例如肺气肿和肺纤维化，这些疾病也与OSA相互作用，导致死亡率增加。