Regional Hypoxia Impacts the Heterogeneity of Inflammatory Lung Disease

 描述(申请人提供)：尽管对慢性炎症性肺部疾病的认识有了很大的进步，但缺乏描述疾病区域异质性的潜在机制的数据。囊性纤维化(CF)等炎症性肺部疾病的特点是一过性和局部粘液堵塞，导致肺内某些区域处于急性缺氧状态。在慢性阻塞性肺疾病中，尽管短暂性粘液堵塞在整个慢性阻塞性肺疾病中发生，但支气管扩张症往往始于肺上叶，并变得最广泛。我们的初步数据表明，与下叶巨噬细胞相比，上叶的常驻肺巨噬细胞(LMS)对缺氧表现出更强烈的炎症反应。已知低氧通过各种机制导致其他组织炎症增强，包括增加血管紧张素II(AngII)的产生。有趣的是，最近的研究表明，导致血管紧张素转换酶(Angii)升高的人类血管紧张素转换酶(ACE)基因多态性与CF肺部疾病严重程度的增加有关。Angii在LMS上有受体。LMS是天然免疫反应的主要贡献者，对细胞因子的分泌和中性粒细胞的募集至关重要。我们发现，经血管紧张素转换酶治疗后，健康人LMS的炎性细胞因子产生呈剂量依赖性增加。我们还发现，慢性阻塞性肺疾病患者的支气管肺泡灌洗液(BAL)中血管紧张素Ⅱ水平升高，有趣的是，这些水平在上肺叶最高，这是支气管扩张最突出的地方。基于这些数据，这一建议的首要假设是，与下叶LMS相比，低氧通过促进血管紧张素Ⅱ的产生，导致上叶LMS更具侵袭性的炎症反应。此外，我们假设低氧诱导的血管紧张素转换酶是慢性肺病区域异质性发展的一个关键因素。在目标1中，我们将检验这一假设，即与下叶LMS相比，从健康受试者中分离的上叶LMS可增强炎症，但减少细菌杀灭。在目标2中，我们将验证一种假设，即健康的上叶LMS对缺氧的炎症反应增加是由血管紧张素转换酶引起的，并可被血管紧张素转换酶I(AT1)受体阻滞剂氯沙坦阻断。在目标3中，我们将测试一种假设，即在CF患者中，与从下叶缺氧区分离的LMS相比，从上叶缺氧区分离的LMS与从下叶缺氧区分离的LMS相比，产生更多的Angii和炎症细胞因子。这些研究将确定阻止慢性阻塞性肺疾病进展的新的抗炎策略，包括AT1受体阻滞剂氯沙坦的潜在再利用，并将这项工作用作包括COPD和哮喘在内的其他炎症性肺部疾病的研究模型。

 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.