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

基本信息

批准号：
10548807
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
项目类别：
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/10548807
关键词：
Address Adrenal Cortex Hormones Air Movements Airway Disease Airway Fibrosis 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 Persons 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 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 innovation macrophage monocyte mortality normoxia novel prevent protein expression public health relevance pulmonary function screening targeted treatment

项目摘要

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/工作完成的差距：阻塞性睡眠呼吸暂停（OSA）在哮喘患者中非常常见，并会加剧气道疾病，但其机制尚不清楚，慢性间歇性缺氧（CIH）是 OSA 的一个标志性特征，可能是一个重要的原因。在我们最近发表的初步工作中，在过敏原诱导的大鼠气道炎症期间暴露于 CIH：1) 导致气流受限；2) 支气管周围胶原沉积增加；近端气道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，其可能被非经典激活并极化成更促纤维化的 M2 巨噬细胞表型；4) 与过敏原协同作用，支气管肺泡灌洗液 (BAL) 中纤溶酶原激活剂抑制剂 - 1 (PAI-1) 的表达和活性增加。然而，这些特征均不会对吸入皮质类固醇产生反应。这些新发现强调了合并 OSA 可能使哮喘恶化并对肺功能造成不可逆转的损害。这些发现提出了以下问题：i) 中央气道阻力、小气道的影响。 CIH 引起的气流阻塞导致肺实质塌陷和弹性降低，以及这些生理缺陷的可逆性；ii) 单核细胞和巨噬细胞的表型、激活状态和卵子；在我们的模型中；以及 iii) PAI-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，阻碍了针对大部分患有这种相互作用的哮喘患者开发更有效的治疗方法。假设/目标：长期目标是通过针对哮喘与 OSA 的相互作用来开发治疗哮喘的有效策略。该提案的目的是测试 CIH 引起的气流阻塞和肺部的生理、细胞和分子机制。我们的数据使我们得出一个中心假设，即过敏原激发期间 CIH 引起的气流阻塞是由于近端和远端气道阻力增加以及实质组织弹性减少所致。随着 PAI-1 活性的增加，单核细胞来源的 M2 巨噬细胞增加。为了解决这一假设，我们建议测试以下目标：1）CIH 诱导的下气道阻塞的生理机制。 HDM 气道炎症期间；2) CIH 对肺单核细胞活化和巨噬细胞极化的影响；3) PAI-1 在 CIH 诱导的气流阻塞中的作用设计：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，在最后一次挑战后两天每周进行一次 HDM 或 SAL 挑战。目标 1、中央和远端气道以及肺弹性特性（弹性和顺应性）将在支气管扩张剂前后进行测量。对于目标 2，我们将量化支气管胶原和平滑肌（M1 与 M2）。 ) 将通过流式细胞术、定量 (q)PCR 和免疫组织化学对 BAL 和/或肺进行定量。另一项研究将测试生理学和组织学效应。对于目标 3，将通过 ELISA 测量 BAL 和肺匀浆中的 PAI-1 总量和活性 PAI-1 的骨髓来源 - 巨噬细胞消耗。项目意义和创新：我们的项目是创新的，因为它是对常见机制的首次深入研究。临床暴露，CIH，会引起气道阻塞和重塑。这项研究将为患有 OSA 和哮喘的退伍军人带来治疗方法，结果将与退伍军人高度重视的其他肺部疾病相关，例如肺气肿和肺纤维化。与 OSA 相互作用，导致死亡率增加。