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

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 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.