Angiogenesis in chronic lung disease

Chronic lung diseases like COPD, severe progressive pulmonary hypertension (PH), and interstitial lung diseases all have a lung vascular disease component. Cellular and molecular mechanisms of pulmonary vascular remodeling have been experimentally explored in many animal models, and it is now clear that microvessels are involved. In emphysema patients, there is a loss of lung microvessels, and in many forms of severe PH there is obliteration of precapillary arterioles by angioproliferation. Thus, COPD/emphysema and severe angioproliferative PH are on the opposite ends of a spectrum of vascular biology responses. Animal experiments have provided insight regarding some of the initiating events that shape the various forms of pulmonary vascular remodeling. In pulmonary fibrosis and in the postinjury phase of acute lung injury, the angiogenic/angiostatic balance is also affected. This review will therefore discuss angiogenesis in several chronic lung diseases and will speculate on how altered vascular homeostasis may contribute to lung disease development.     

血管内皮生长因子与慢性阻塞性肺疾病的肺血管重构

血管内皮生长因子（VEGF）具有促进血管内皮细胞增殖和血管生成的作用。研究表明，VEGF在慢性阻塞性肺疾病（COPD）的肺血管重构中起着重要作用，进而加重其气道阻力和气道炎症，影响COPD的预后。如何使VEGF保持一个合适的水平有待于我们进一步的研究。     

Decreased level of vascular endothelial growth factor in bronchoalveolar lavage fluid of normal smokers and patients with pulmonary fibrosis

Vascular endothelial growth factor (VEGF) plays multifunctional roles in both the development of vasculature and the maintenance of vascular function. A decrease in VEGF reduces angiogenesis and induces apoptosis of vascular endothelial cells. Inhibition of the VEGF receptor causes endothelial cell apoptosis and emphysema. We postulated that VEGF concentrations might be reduced in patients with chronic lung diseases. The level of VEGF was evaluated by enzyme-liked immunosorbent assay in bronchoalveolar lavage fluid (BALF) from normal smokers, nonsmoking volunteers, idiopathic pulmonary fibrosis, pulmonary fibrosis associated with a connective tissue disease, and sarcoidosis. The isoforms of VEGF in BALF were determined by high-performance liquid chromatography. VEGF in nonsmoking volunteers was detectable at a high concentration. In contrast, VEGF in most of the normal smokers was below the detectable limit. The VEGF found in nonsmoking volunteers BALF was VEGF165. VEGF was significantly decreased in idiopathic pulmonary fibrosis, pulmonary fibrosis associated with a connective tissue disease, and sarcoidosis compared with nonsmoking volunteers. The smoking patients showed a further decrease in VEGF. These data suggest that the decrease in VEGF in smokers and patients with chronic lung diseases may reduce angiogenesis and induce apoptosis of vascular endothelial cells.     

Antiangiogenesis therapy for endometriosis

It is known that angiogenesis is of pivotal importance for the development of endometriosis. However, in the treatment of endometriosis patients, prevention of endometriosis lesion development only will not be sufficient as a therapy. Treatment options, aimed at interfering with established lesions, have to be developed. In this study we evaluated whether inhibition of angiogenesis by angiostatic therapy is also effective in antagonizing the sustentation of endometriosis. We evaluated the effect of the angiostatic compounds antihuman vascular endothelial growth factor, TNP-470, endostatin, and anginex on the growth of established endometriosis lesions in the nude mouse model. We show that human endometrium in the proliferative endometrium is highly angiogenic and that vascular endothelial growth factor-A is the most important angiogenesis promotory factor. The angiostatic compounds significantly decreased microvessel densities and the number of established endometriosis lesions. In the remaining lesions, the number of pericyte-protected vessels is not different in control and treated mice; however, the number of unprotected vessels was significantly reduced in the groups treated with the angiostatic agents. Our data demonstrate that inhibitors of angiogenesis effectively interfere with the maintenance and growth of endometriosis by inhibiting angiogenesis. This suggests that the use of angiostatic agents may be promising as a therapy for endometriosis.     

血管内皮生长因子与慢性阻塞性肺疾病继发肺动脉高压的关系

血管内皮生长因子(vascular endothelial growth factor,VEGF)是一种重要的血管内皮细胞丝裂原和通透因子.肺血管的重塑与慢性阻塞性肺疾病(chronic obstructive pulmonary disease,COPD)继发肺动脉高压密切相关.VEGF贯穿于COPD发展的全过程,在COPD的不同时期呈现不同的表达水平,发挥不同的生物学作用.气道炎症、低氧等因素可以在COPD早期促进VEGF及其受体的表达上调从而导致肺血管重塑的发生发展,VEGF也可以对COPD后期继发肺动脉高压时的重度肺血管重塑起到一定的修复作用.通过阐述VEGF、COPD肺血管重塑及继发肺动脉高压之间的相互关系,可以对COPD继发肺动脉高压的诊断和治疗提供新的思路.     

慢性气道炎症大鼠肺血管结构和生长因子变化的实验研究

目的探讨慢性气道炎症与肺血管重建的相关关系以及慢性气道炎症对斑管内皮生长因子（VEGF）及内皮素-1（ET-1）的影响。方法复制慢性支气管炎和肺气肿动物模型。用图像分析仪观察支气管肺组织和肺血管结构病理变化情况。酶联免疫法检测血清VEGF。放射免疫法测定血浆ET-1水平。结果模型组大鼠发生明显的慢性气道炎症和肺气肿改变。细小支气管中膜肌层增厚，但肺血管结构与对照组比较无明显改变．血清VEGF和血浆ET-书平与对照组比较亦无显著性差异（P〉0．05）。结论 慢性气道炎症对大鼠肺血管重建和、VEGF和ET-1无明显直接影响。但慢性气道炎症的持续发展是慢性阻塞性肺疾病（COPD）产生低氧的主要病理基础，因此对COPD的防治重点之一应放在气道炎症的防治。     

血管内皮生长因子与慢性阻塞性肺疾病

慢性阻塞性肺疾病是一个发病率和死亡率都很高的慢性疾病，其发病机制涉及肺内细胞的凋亡，肺实质细胞的减少，炎性细胞的浸润和气道、血管的重构。血管内皮生长因子作为一个可特异作用于内皮细胞，调节血管内皮细胞生长、分化、修复及发挥功能的重要因子，与慢性阻塞性肺疾病的发生有着密切的联系。     

Is alveolar destruction and emphysema in chronic obstructive pulmonary disease an immune disease?

The alveolar destruction leading to airspace enlargement in patients with end-stage chronic obstructive pulmonary disease (COPD) is frequently progressive, despite smoking cessation. Several laboratories have accumulated data demonstrating the presence of immune cells in bronchial biopsy specimens and lung tissue sections from patients with COPD. Recently, the accumulation of T and B lymphocytes, often forming follicles, in the lung parenchyma from patients with severe COPD has been reported. In addition, it has been postulated that there might be an autoimmune component to COPD. T-cell receptor analysis has provided data consistent with the concept of T-cell clones in the lung tissue from patients with COPD. Against this background, we developed a model of autoimmune emphysema in adult rats. Based on published data showing that immunization of mice with human umbilical vein endothelial cells (HUVECs) causes production of anti-vascular endothelial growth factor (VEGF) receptor II (KDR) antibodies, and our own data indicating that administration of a VEGF receptor blocker in adult rats causes emphysema, we reasoned that intraperitoneal injection of HUVECs in rats would generate both anti-VEGF receptor antibodies and emphysema. Indeed, intraperitoneal injection of HUVECs caused emphysema. We further explored the autoimmune nature of this model, identified KDR antibodies in the serum of HUVEC-immunized rats, and injected serum from the emphysematous rats into naive rats and mice, which resulted in emphysema. Presently, we are in the process of investigating whether cigarette smoke extract causes emphysema. We recently identified anti-endothelial cell antibodies in the serum of patients with end-stage emphysema.     

血管内皮生长因子在慢性阻塞性肺疾病中的作用

慢性阻塞性肺疾病（chronic obstructive pulmonary disease,COPD）由于日益增长的发病率和痫死率成为全世界主要的健康问题。但是,疾病的确切发病机制还没有被阐明。血管内皮生长因子（Vasculare ndothelial growth factor,VEGF）足血管形成的有效介质．对肺的发育和生理有多重作用。VEGF广泛存在于肺组织,对COPD的两种主要病理生理学表现型（肺气肿和慢性支气管炎）起了很重要的作用,观诵对临床的角度研究VEGF在COPD中的作用。     

血管内皮生长因子和内皮抑素在肺纤维化中的作用

血管内皮牛长因子是一种生长因子,在正常肺组织和多种肺部疾病中均有表达.通过血管内皮牛长因子受体发挥生理作用,具有促进内皮细胞分裂增殖、促血管生成、增加血管通透性及抗凋亡等作用.内皮抑素是一种内源性血管生成抑制剂,可以抑制血管内皮细胞增殖、迁移并诱导其调亡,从而达到抑制血管生成作用.在肺纤维化中二者均有异常表达,但具体作...     

The epidemiology of vascular dysfunction relating to chronic obstructive pulmonary disease and emphysema

Cor pulmonale has long been described in very severe chronic obstructive pulmonary disease (COPD) and emphysema. Cross-sectional results from population-based studies show that left ventricular filling and a variety of vascular measures in the systemic circulation are abnormal in preclinical COPD and emphysema and that a predominant vascular change in COPD and emphysema is endothelial and microvascular dysfunction. These findings suggest that pulmonary vascular changes may occur early in COPD and emphysema and might contribute to pathogenesis. However, longitudinal epidemiologic studies with direct measures of the pulmonary vasculature are lacking; therefore, inferences are limited at present. New imaging-based approaches to the assessment of the pulmonary vasculature are applicable to epidemiologic studies and may help in defining the relationship of pulmonary vascular damage to progression of COPD and emphysema. These measures may also provide imaging-based surrogate markers, and novel therapeutics targeted to the pulmonary vasculature might reduce symptoms and improve function in these common diseases.     

Vascular Endothelial Growth Factor as a Key Inducer of Angiogenesis in the Asthmatic Airways

Asthma is a chronic inflammatory disease of the airways characterized by structural airway changes, which are known as airway remodeling, including smooth muscle hypertrophy, goblet cell hyperplasia, subepithelial fibrosis, and angiogenesis. Vascular remodeling in asthmatic lungs results from increased angiogenesis, which is mainly mediated by vascular endothelial growth factor (VEGF). VEGF is a key regulator of blood vessel growth in the airways of asthma patients by promoting proliferation and differentiation of endothelial cells and inducing vascular leakage and permeability. In addition, VEGF induces allergic inflammation, enhances allergic sensitization, and has a role in Th2 type inflammatory responses. Specific inhibitors of VEGF and blockers of its receptors might be useful to control chronic airway inflammation and vascular remodeling, and might be a new therapeutic approach for chronic inflammatory airway disease like asthma.     

慢性阻塞性肺疾病患者肺组织中血管内皮生长因子和诱生型一氧化氮合酶的表达及吸烟的影响

目的探讨慢性阻塞性肺疾病（COPD）患者肺组织中血管内皮生长因子（VEGF）、诱生型一氧化氮合酶（iNOS）的表达情况及吸烟对二者表达的影响。方法取46例因肺癌行肺叶切除患者的癌旁组织，依据吸烟及肺功能情况分成：（1）吸烟伴COPD组19例；（2）吸烟不伴COPD组12例；（3）不吸烟不伴COPD组15例。用免疫组化法检测肺组织VEGF及iNOS的表达。结果吸烟不伴COPD组（1．50±0．39，1．45±0．41）与不吸烟不伴COPD组（1．18±0．33，1．09±0．41）比较，肺组织VEGF、iNOS表达增强；吸烟伴COPD组（2．19±0．51，2．39±0．45）与不吸烟不伴COPD组比较表达明显增强。肺组织VEGF表达与iNOS表达呈明显正相关（r=0．78，P〈0．01）。肺组织VEGF表达与FEV。呈明显负相关（r=-0．67，P〈0．01）。结论吸烟以及轻度COPD患者肺组织VEGF、iNOS表达上调，iNOS、VEGF的过度表达可能参与COPD患者气道与血管重建和气流受限的过程。     

Angiogenesis in pulmonary fibrosis: too much or not enough?

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and usually fatal disease, based on a multifaceted and incompletely understood pathogenesis. Some of the cellular and molecular mechanisms of vascular remodeling have been experimentally explored, and it is obvious that alterations of microvessels are involved in IPF. These can, among others, lead to the development of pulmonary hypertension. In order to understand the process of vascular integrity and repair, it is necessary to identify the factors associated with angiogenesis in IPF. A delicate balance of angiogenic and angiostatic factors regulates vessel homeostasis in normal physiologic conditions in the lungs. Although earlier studies have proposed that IPF is associated with an increase of angiogenesis, there is some more recent evidence that angiogenesis in fibrotic lungs may actually be decreased, causing some controversy in the literature in this area. This review, therefore, discusses the concept of angiogenesis in pulmonary fibrosis and speculates on how the spatial and temporal heterogeneity of IPF might explain the controversial findings about vessel density in fibrotic lungs.     

CXCL11 attenuates bleomycin-induced pulmonary fibrosis via inhibition of vascular remodeling

Aberrant vascular remodeling is a central hallmark for the development and progression of idiopathic pulmonary fibrosis. The mechanisms underlying the pathophysiologic alterations, however, are poorly understood. A recent phase II trial of interferon gamma-1b has demonstrated a trend toward a decrease in profibrotic and proangiogenic biologic markers, and upregulation of lung CXCL11 mRNA and bronchoalveolar lavage fluid and plasma protein levels of CXCL11. We hypothesized that net aberrant vascular remodeling seen during the pathogenesis of fibroplasia and deposition of extracellular matrix during bleomycin-induced pulmonary fibrosis can be attenuated by treatment with the angiostatic ELR(-) CXC chemokine, CXCL11. In a preclinical model, systemic administration of CXCL11 reduced pulmonary collagen deposition, procollagen gene expression, and histopathologic fibroplasia and extracellular matrix deposition in the lung of bleomycin-treated mice. CXCL11 treatment significantly reduced bleomycin-induced pulmonary fibrosis without altering specific lung leukocyte populations. CXCR3 is not expressed on fibroblasts and CXCL11 had no direct functional effect on pulmonary fibroblasts. The angiogenic activity in the lung was significantly decreased, however, and CXCL11 treatment reduced the total number of endothelial cells in the lung following bleomycin exposure. The results suggest that CXCL11 inhibits pulmonary fibrosis by altering aberrant vascular remodeling.     

Hypoxia paradoxically inhibits the angiogenic response of isolated vessel explants while inducing overexpression of vascular endothelial growth factor

This study was designed to investigate how changes in O₂ levels affected angiogenesis in vascular organ culture. Although hypoxia is a potent inducer of angiogenesis, aortic rings cultured in collagen paradoxically failed to produce an angiogenic response in 1–4 % O₂. Additionally, aortic neovessels preformed in atmospheric O₂ lost pericytes and regressed at a faster rate than control when exposed to hypoxia. Aortic explants remained viable in hypoxia and produced an angiogenic response when returned to atmospheric O₂. Hypoxic aortic rings were unresponsive to VEGF, while increased oxygenation of the system dose-dependently enhanced VEGF-induced angiogenesis. Hypoxia-induced refractoriness to angiogenic stimulation was not restricted to the aorta because similar results were obtained with vena cava explants or isolated endothelial cells. Unlike endothelial cells, aorta-derived mural cells were unaffected by hypoxia. Hypoxia downregulated expression in aortic explants of key signaling molecules including VEGFR2, NRP1 and Prkc-beta while upregulating expression of VEGFR1. Medium conditioned by hypoxic cultures exhibited angiostatic and anti-VEGF activities likely mediated by sVEGFr1. Hypoxia reduced expression of VEGFR1 and VEGFR2 in endothelial cells while upregulating VEGFR1 in macrophages and VEGF in both macrophages and mural cells. Thus, changes in O₂ levels profoundly affect the endothelial response to angiogenic stimuli. These results suggest that hypoxia-induced angiogenesis is fine-tuned by complex regulatory mechanisms involving not only production of angiogenic factors including VEGF but also differential regulation of VEGFR expression in different cell types and production of inhibitors of VEGF function such as sVEGFR1.     

慢性阻塞性肺疾病合并肺动脉高压的发病机制研究进展

肺动脉高压(pulmonary hypertension,PH)是慢性阻塞性肺疾病(chronic obstructivepulmonary disease,COPD)的一个重要合并症.COPD合并PH是逐渐发生和进展的,最初于运动或睡眠时出现,逐渐发展为休息时即存在PH,运动、睡眠或病情恶化时进一步升高.COPD相关的PH多为轻到中度,但某些COPD患者可表现为"不成比例"的PH.香烟烟雾、炎症产物引起内皮损害,造成内皮功能失调;慢性低氧引起肺血管收缩;肺血管重构导致管腔变小,血管膨胀性降低,阻力增加;重度肺气肿时肺毛细血管的丧失等均与COPD时的PH相关.     

Pro-angiogenic hematopoietic progenitor cells and endothelial colony-forming cells in pathological angiogenesis of bronchial and pulmonary circulation

Dysregulation of angiogenesis is a common feature of many disease processes. Vascular remodeling is believed to depend on the participation of endothelial progenitor cells, but the identification of endothelial progenitors in postnatal neovascularization remains elusive. Current understanding posits a role for circulating pro-angiogenic hematopoietic cells that interact with local endothelial cells to establish an environment that favors angiogenesis in physiologic and pathophysiologic responses. In the lung, increased and dysregulated angiogenesis is a hallmark of diseases of the bronchial and pulmonary circulations, manifested by asthma and pulmonary arterial hypertension (PAH), respectively. In asthma, T_Helper-2 immune cells produce angiogenic factors that mobilize and recruit pro-inflammatory and pro-angiogenic precursors from the bone marrow into the airway wall where they induce angiogenesis and fuel inflammation. In contrast, in PAH, upregulation of hypoxia-inducible factor (HIF) in vascular cells leads to the production of bone marrow-mobilizing factors that recruit pro-angiogenic progenitor cells to the pulmonary circulation where they contribute to angiogenic remodeling of the vessel wall. This review focuses on current knowledge of pro-angiogenic progenitor cells in the pathogenesis of asthma and PAH.     

Imbalance between vascular endothelial growth factor and endostatin in emphysema.

Vascular endothelial growth factor (VEGF) stimulates endothelial cell proliferation, and endostatin directly antagonises the biological effects of VEGF. The maintenance of pulmonary endothelial cells is also thought to depend upon the local balance of VEGF and endostatin in the lung. Therefore, this study was designed to determine whether there is an imbalance between VEGF and endostatin levels in patients with pulmonary emphysema. VEGF and endostatin levels were simultaneously measured from 25 emphysema patients and 12 normal control subjects, and their correlation and balance in induced sputum was evaluated. VEGF levels in induced sputum were significantly lower in emphysema patients (854 +/- 307 pg x mL(-1)) than in normal controls (1,791 +/- 1,192 pg x mL(-1)). In contrast, there was no significant difference in endostatin levels among the two groups. Therefore, the ratio of VEGF to endostatin levels was markedly lower in emphysema patients (4.5 +/- 1.8) than in normal controls (8.1 +/- 2.6). Moreover, VEGF levels were correlated with endostatin levels in normal controls but not in emphysema patients. In addition, the ratio of VEGF to endostatin levels was correlated with forced expiratory volume in one second (FEV1), FEV1/forced vital capacity and carbon monoxide diffusing capacity of the lung in emphysema patients. The findings in this study suggest that there is an imbalance between vascular endothelial growth factor and endostatin levels in induced sputum from emphysema patients.