Selected Peptidases and Pulmonary Vascular Remodeling in Chronic Obstructive Pulm

项目简介：慢性低氧性肺动脉高压（PHTN）是一个主要的临床问题，是大多数肺和心脏疾病的并发症。慢性缺氧PHTN的发展是COPD的主要并发症，显著增加了COPD的不良预后和致死率。慢性阻塞性肺病中PHTN的患病率相当高。慢性阻塞性肺病患者在其临床病程早期出现不同程度的肺血管重构（PHTN的关键决定因素）。在像慢性阻塞性肺病这样复杂的疾病中，重塑需要多种因素的参与，包括吸烟、氧化应激、炎症和持续或间歇性缺氧。肺动脉（PA）内/外边界平滑肌细胞（SMCs）增生是结构改变的一个突出特征。整体膜肽酶在肺中含量相当高，在人肺血管重构中起重要作用。我们已经证明，其中一种肽酶Neprilysin （NEP）是慢性缺氧PHTN易感性的重要决定因素。NEP缺失小鼠对慢性缺氧有夸张的肺动脉高压反应，与野生型小鼠相比，常驻PA SMCs的生长增加。肺NEP表达减少对慢性缺氧的反应，机制未知；NEP的减少在远端血管中最为显著，在远端血管中早期PA SMC增殖和迁移发生。我们将检验总体假设：NEP降低与其他肽酶相比，易导致COPD患者肺血管重构增加。我们提出两个目标。首先，将NEP活性水平与“正常”和患病人类肺组织中的其他肽酶进行比较分析。我们将测试肽酶活性和/或表达的变化是否与COPD严重程度和肺血管重构（最终是PHTN）的临床特征平行。其次是利用免疫组织化学分析和激光捕获显微解剖，确定肺结构（血管vs气道vs肺泡壁）、位置（近端vs远端）和细胞类型（内皮细胞、平滑肌细胞或成纤维细胞）在最接近血管重构的地方显示NEP与其他肽酶表达的最大变化。这些研究可能有助于增加我们对慢性阻塞性肺病患者慢性缺氧PHTN易感性控制机制的理解，也可能确定新的治疗靶点来限制或逆转这一重要的临床问题。（摘要结束）

DESCRIPTION (provided by applicant): Project Summary: Chronic hypoxic pulmonary hypertension (PHTN) is a major clinical problem, complicating most lung and heart disorders. The development of chronic hypoxic PHTN is a major complication of COPD, adding significantly to the poor prognosis and lethality of COPD. The prevalence of PHTN in COPD is quite large. Patients with COPD develop varying degrees of pulmonary vascular remodeling (a key determinate of PHTN) early in their clinical course. In a disorder as complex as COPD, remodeling requires the participation of several factors, including cigarette smoke, oxidant stress, inflammation, and persistent or intermittent hypoxia. Proliferation of pulmonary artery (PA) smooth muscle cells (SMCs) at the medial/adventitial border is a prominent feature of the structural change. Integral membrane peptidases, found in fairly high abundance in the lung, could play an important role in human pulmonary vascular remodeling. We have shown that one of these peptidases, Neprilysin (NEP), is an important determinatn of susceptability to chronic hypoxic PHTN. NEP null mice have an exaggerated pulmonary hypertensive response to chronic hypoxia, and resident PA SMCs have increased growth compared to their wild type counterparts. Lung NEP expression decreases in response to chronic hypoxia by unknown mechanisms; the decrease in NEP is most striking in distal vessels where early PA SMC proliferation and migration occurs. We will test the Overall Hypothesis that: Decreased NEP vs other peptidases predisposes to the development of increased pulmonary vascular remodeling in COPD. We propose two aims. The first will involve analysis of NEP activity level compared to other peptidases in `normal' and diseased human lung tissue. We will test if change in peptidase activity and/or expression parallel clinical characteristics of COPD severity and pulmonary vascular remodeling (and ultimately PHTN). The second will be to determine the lung structure (vessel vs airway vs alveolar walls), location (proximal vs distal), and cell type (endothelial, smooth muscle, or fibroblast) exhibiting the greatest changes in NEP vs other peptidase expression in closest proximity to the most substantial vascular remodeling using immunohistochemical analyses and laser capture microdissection. These studies may help increase our understanding of mechanisms that control susceptibility to chronic hypoxic PHTN in COPD and could also identify new therapeutic targets to limit or reverse this important clinical problem. (End of Abstract) PUBLIC HEALTH RELEVANCE: Project Narrative: Elevated pressure in the blood vessels in the lung is called pulmonary hypertension. Pulmonary hypertension induced by exposure to low oxygen levels (hypoxia) is a major clinical problem and can be found in many patients with lung and heart disorders; when sustained, it can lead to heart failure. Pulmonary hypertension is a major and common complication of chronic obstructive pulmonary disease (COPD). An important factor in pulmonary hypertension is the abnormal structural change that occurs in the blood vessels. Smooth muscle cells in the wall of lung arteries may grow abnormally in response to hypoxia leading to increased vessel wall thickness and a reduction in the vessel diameter. A protein on the cell surface, Neprilysin, may play an important role in regulating susceptibility to pulmonary hypertension. Mice lacking the Neprilysin protein have increased pulmonary hypertension in response to low oxygen. The smooth muscle cells isolated from these mouse lungs also grow faster than normal cells. We plan to analyze Neprilysin in the lungs of patients with varying degrees of COPD and compare it to other related proteins. We will do this in two specific steps. The first step will involve analysis of Neprilysin and the other proteins in normal and diseased human lung tissue. We will then see if the levels of these proteins change in relation to the severity of the disease and extent of pulmonary vascular structural change (a marker of pulmonary artery hypertension). The second will be to determine the lung structure, location, and cell type that exhibits the greatest amount of change in protein expression. These studies may help increase our understanding of mechanisms that control susceptibility to chronic hypoxic pulmonary hypertension and could also identify new therapeutic targets to limit or reverse this important clinical problem.