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Regional Hypoxia Impacts the Heterogeneity of Inflammatory Lung Disease

区域缺氧影响炎症性肺病的异质性

基本信息

批准号：
8881421
负责人：
ALIX ASHARE
金额：
$ 45.77万
依托单位：
DARTMOUTH COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-01 至 2020-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8881421
关键词：
Acute Angiotensin II Anti-Inflammatory Agents Anti-inflammatory Area Asthma Bronchiectasis Bronchoalveolar Lavage Fluid Chronic Chronic Obstructive Airway Disease Clinical Medicine Cystic Fibrosis Data Development Disease Disease Progression Distal Dose Enzyme Gene Exhibits FDA approved Functional disorder Gases Generations Genetic Polymorphism Goals Heterogeneity Human Hypoxia Immune response Infection Inflammation Inflammation Mediators Inflammatory Inflammatory Response Investigation Knowledge Lobe Losartan Lung Lung Inflammation Lung diseases Macrophage Activation Magnetic Resonance Imaging Mediating Mission Mucous body substance Neutrophil Infiltration Pathogenesis Peptidyl-Dipeptidase A Pharmaceutical Preparations Plague Play Plug-in Production Pseudomonas aeruginosa Public Health Pulmonary Cystic Fibrosis Research Respiratory Failure Risk Factors Role Severities Severity of illness Signal Transduction Stimulus Study models Techniques Testing Tissues Translations Work base cystic fibrosis patients cytokine design human disease human subject improved inflammatory lung disease inhibitor/antagonist innovation insight killings lower lung lobe lung upper lobe macrophage novel novel therapeutic intervention pathogen public health relevance receptor regional difference response

项目摘要

DESCRIPTION (provided by applicant): Despite significant advances in the understanding of chronic inflammatory lung diseases, data describing the mechanisms underlying regional heterogeneity of disease are lacking. Inflammatory lung diseases such as cystic fibrosis (CF) are characterized by transient and regional mucus plugging, resulting in regions of the lung being subject to acute hypoxia. In CF lung disease, bronchiectasis tends to begin and become most extensive in the upper lobes despite the fact that transient mucus plugging occurs throughout the CF lung. Our preliminary data demonstrate that resident lung macrophages (LMs) in the upper lobe exhibit a more robust inflammatory response to hypoxia compared to lower lobe LMs. Hypoxia is known to cause enhanced inflammation in other tissues via various mechanisms, including increased production of angiotensin II (ANGII). Interestingly, recent studies have shown that a polymorphism in the human angiotensin converting enzyme (ACE) gene, which results in elevated ANGII, is associated with increased severity of lung disease in CF. ANGII has receptors on LMs. LMs are major contributors to the innate immune response and are critical for cytokine secretion and neutrophil recruitment. We found a dose-dependent increase in inflammatory cytokine production by healthy human LMs following treatment with ANGII. We also found increased ANGII in bronchoalveolar lavage (BAL) fluid from CF subjects and, interestingly, these levels were highest in the upper lobes, where bronchiectasis is most prominent. Based upon these data, the overarching hypothesis of this proposal is that hypoxia causes a more aggressive inflammatory response by upper lobe LMs compared to lower lobe LMs via enhanced production of ANGII. Furthermore, we hypothesize that hypoxia induced ANGII is a key factor in the development of regional heterogeneity of CF lung disease. In Aim 1, we will test the hypothesis that hypoxia enhances inflammation but decreases bacterial killing by upper lobe LMs isolated from healthy subjects compared to lower lobe LMs. In Aim 2, we will test the hypothesis that the increased inflammatory response to hypoxia of healthy upper lobe LMs is caused by ANGII and can be blocked by treatment with the ANGII type I (AT1) receptor blocker, losartan. In Aim 3, we will test the hypothesis that, in subjects with CF, LMs isolated from hypoxic regions of the upper lobe, as determined using the novel technique of hyperpolarized gas magnetic resonance imaging, generate increased ANGII and inflammatory cytokines compared to LMs isolated from hypoxic regions of the lower lobe. These studies will determine novel anti-inflammatory strategies to halt the progression of CF lung disease, including the potential repurposing of the AT1 receptor blocker losartan, and to use this work as a model for the study of other inflammatory lung diseases including COPD and asthma.