Regional Hypoxia Impacts the Heterogeneity of Inflammatory Lung Disease

区域缺氧影响炎症性肺病的异质性

• 批准号: 9307968
• 负责人: ALIX ASHARE
• 金额: $ 39.88万
• 依托单位: DARTMOUTH COLLEGE
• 依托单位国家: 美国
• 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/9307968
• 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; Enzymes; Exhibits; FDA approved; Functional disorder; Gases; Generations; Genetic Polymorphism; Goals; Heterogeneity; Human; Hypoxia; Infection; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Innate Immune 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; Play; Plug-in; Production; Pseudomonas aeruginosa; Public Health; Pulmonary Cystic Fibrosis; Pulmonary Fibrosis; Research; Respiratory Failure; Risk Factors; Role; Severities; Severity of illness; Signal Transduction; Stimulus; Study models; Techniques; Testing; Tissues; Translations; United States National Institutes of Health; Work; base; cystic fibrosis patients; cytokine; design; disease heterogeneity; human disease; human subject; improved; inflammatory lung disease; inhibitor/antagonist; innovation; insight; killings; lung lobe; lung upper lobe; macrophage; novel; novel therapeutic intervention; pathogen; public health relevance; receptor; regional difference; response

 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.

 描述（由申请人提供）：尽管对慢性炎性肺病的理解有了显著进展，但缺乏描述疾病区域异质性机制的数据。炎性肺病如囊性纤维化（CF）的特征在于短暂的和区域性的粘液堵塞，导致肺的区域经受急性缺氧。在CF肺病中，支气管扩张倾向于开始并在上叶变得最广泛，尽管在整个CF肺中发生短暂的粘液堵塞。我们的初步数据表明，与下叶肺巨噬细胞（LM）相比，上叶肺巨噬细胞（LM）对缺氧表现出更强烈的炎症反应。已知缺氧通过各种机制引起其他组织中的炎症增强，包括血管紧张素II（ANGII）的产生增加。有趣的是，最近的研究表明，在人类血管紧张素转换酶（ACE）基因的多态性，导致升高ANGII，与肺疾病的严重程度增加CF。ANGII在LM上具有受体。LM是先天免疫应答的主要贡献者，并且对于细胞因子分泌和中性粒细胞募集至关重要。我们发现在用ANGII治疗后，健康人LM的炎性细胞因子产生呈剂量依赖性增加。我们还发现CF受试者的支气管肺泡灌洗液（BAL）中ANGII增加，有趣的是，这些水平在支气管扩张最突出的上叶中最高。基于这些数据，该提议的首要假设是，与下叶LM相比，缺氧通过增强的ANGII产生引起上叶LM的更具侵略性的炎症反应。此外，我们假设缺氧诱导的ANGII是CF肺病区域异质性发展的关键因素。在目的1中，我们将检验以下假设：与下叶LM相比，缺氧增强炎症，但减少从健康受试者分离的上叶LM的细菌杀伤。在目的2中，我们将检验以下假设：健康上叶LM对缺氧的炎症反应增加是由ANGII引起的，并且可以通过用ANGII I型（AT1）受体阻断剂氯沙坦治疗来阻断。在目标3中，我们将检验以下假设：在患有CF的受试者中，与从下叶的缺氧区域分离的LM相比，从上叶的缺氧区域分离的LM（如使用超极化气体磁共振成像的新技术所确定的）产生增加的ANGII和炎性细胞因子。这些研究将确定新的抗炎策略，以阻止CF肺病的进展，包括AT1受体阻滞剂氯沙坦的潜在再利用，并将这项工作用作其他炎症性肺病（包括COPD和哮喘）研究的模型。