支气管哮喘中气道重构的研究状况

支气管哮喘是由嗜酸粒细胞（EOS）、肥大细胞和T细胞等多种炎性细胞参与的气道慢性炎症性疾病,气道重构是在气道炎症基础上气道壁损伤,在多种细胞、炎症介质、生长因子的参与下出现的不完全修复。本文从病理和发生机制的角度对哮喘的气道重构作一综述。     

支气管哮喘中气道重构的研究状况

支气管哮喘是由嗜酸粒细胞(EOS)、肥大细胞和T细胞等多种炎性细胞参与的气道慢性炎症性疾病,气道重构是在气道炎症基础上气道壁损伤,在多种细胞、炎症介质、生长因子的参与下出现的不完全修复.本文从病理和发生机制的角度对哮喘的气道重构作一综述.     

Structural aspects of airway remodeling in asthma

Airway remodeling in asthma is a complex process that involves structural changes in virtually all tissues of the airway wall. The histologic changes to the airways consist of epithelial proliferation and goblet cell differentiation, subepithelial fibrosis, airway smooth muscle (ASM) growth, angiogenesis, matrix protein deposition, gland hyperplasia and hypertrophy, and nerve proliferation. Cytokines, chemokines, and growth factors from inflammatory cells and structural cells contribute to remodeling. There are complex interactions among the various signaling pathways involving matrix metalloproteinases that are required for growth factor release. The physiologic consequences of remodeling are airway hyperresponsiveness from ASM growth and mucus hypersecretion from gland and goblet cell hyperplasia. Airway stiffening is a probable contributor to airway hyperresponsiveness through attenuation of the transmission of potently bronchodilating cyclical stress to the ASM during breathing. The epidermal growth factor receptor’s role in remodeling and its interaction with other potential causes of remodeling are discussed.     

Mechanisms of airway hyperresponsiveness in asthma

Abstract:   Airway hyperresponsiveness (AHR) is a fundamental abnormality in asthma. There are many potential factors contributing to the excessive airway response demonstrable on airway challenge. These range from abnormalities of airway smooth muscle, airway remodelling and airway inflammation to abnormalities in the neural control of airway calibre. None of these by themselves fully explains the abnormalities seen on the dose response curves of the asthmatic. In this review, the main mechanisms are described, together with recent evidence providing a pathway by which a number of these mechanisms may interact to cause AHR through abnormality in ventilation distribution and airway closure. There is now evidence for a close relationship between ventilation heterogeneity and AHR which could be exploited clinically.     

咳嗽变异性哮喘与气道重塑

咳嗽变异性哮喘（coughvariantasthma,CVA）是指以慢性咳嗽为主要或唯一症状的一种特殊类型哮喘,其病理生理改变与典型哮喘相同,若未及时诊治,约30％～40％可发展成为典型哮喘。气道炎细胞浸润和气道重塑是CVA的病理基础。CVA可称之为一种隐匿性哮喘,常被临床医师所忽略,患者失去正确的诊断与治疗。正确认识CVA的病理生理特征,对临床诊断和治疗具有重要的指导意义,可降低典型哮喘的发病率。本文就CVA与气道炎性反应和气道重塑的关系作一综述。     

支气管哮喘气道重塑研究进展

支气管哮喘(简称哮喘)是以气道慢性炎症和气道重塑为基本特征的慢性疾病.气道重塑的确切机制尚不清楚,目前认为主要与气道慢性炎症有关,上皮损伤及上皮间充质营养单位再活化在气道重塑发病中也起重要作用.治疗哮喘的传统药物对气道重塑作用有限,近年应用抗肿瘤坏死因子α、CpG-ODN、抗IgE抗体和抗Th2细胞因子等免疫调节剂治疗气道重塑,支气管热整形术是有创性治疗技术.     

Fractal geometry of airway remodeling in human asthma

RATIONALE: Airway wall remodeling is an important aspect of asthma. It has proven difficult to assess quantitatively as it involves changes in several components of the airway wall. OBJECTIVE: To develop a simple method for quantifying the overall severity of airway wall remodeling in asthmatic airways using fractal geometry. METHODS: Negative-pressure silicone rubber casts of lungs were made using autopsy material from three groups: fatal asthma, nonfatal asthma, and nonasthma control. All subjects were lifelong nonsmokers. A fractal dimension was calculated on two-dimensional digital images of each cast. RESULTS: Nonasthma control casts had smooth walls and dichotomous branching patterns with nontapering segments. Asthmatic casts showed many abnormalities, including airway truncation from mucous plugs, longitudinal ridges, and horizontal corrugations corresponding to elastic bundles and smooth muscle hypertrophy, respectively, and surface projections associated with ectatic mucous gland ducts. Fractal dimensions were calculated from digitized images using an information method. The average fractal dimensions of the airways of both the fatal asthma (1.72) and nonfatal asthma (1.76) groups were significantly (p<0.01 and p=0.032, respectively) lower than that of the nonasthma control group (1.83). The lower fractal dimension of asthmatic airways correlated with a decreased overall structural complexity and pathologic severity of disease. CONCLUSION: Fractal analysis is a simple and useful technique for quantifying the chronic structural changes of airway remodeling in asthma.     

Toll样受体与支气管哮喘气道重塑

气道重塑是除气道慢性炎症以外支气管哮喘的又一重要特征.近年来研究表明,Toll样受体可通过调节多种致气道重塑因子如生长因子、细胞因子、炎性介质、趋化因子等的生成和活化,最终导致气道重塑.     

The regulation of fibrosis in airway remodeling in asthma

Fibrosis is one of the key pathological features of airway remodeling in asthma. In the normal airway the amount of collagen and other extracellular matrix components is kept in equilibrium by regulation of synthesis and degradation. In asthma this homeostasis is disrupted due to genetic and environmental factors. In the airways of patients with the disease there is increased extracellular matrix deposition, particularly in the reticular basement membrane region, lamina propria and submucosa. Fibrosis is important as it can occur early in the pathogenesis of asthma, be associated with severity and resistant to therapy. In this review we will discuss current knowledge of relaxin and other key regulators of fibrosis in the airway including TGFβ, Smad2/3 and matrix metalloproteinases. As fibrosis is not directly targeted or effectively treated by current asthma drugs including corticosteroids, characterization of airway fibrosis and how it is regulated will be essential for the development of novel therapies for asthma.     

支气管哮喘气道重塑机制研究进展

气道重塑是一个复杂的过程,涉及气道上皮到外膜的所有组织.气道重塑产生的原因很多,但细胞过度增生、肥大和基质异常沉积的确切原因还不清楚,阐明这些因素无疑将为发展新的防止或逆转气道结构变化的治疗方法提供帮助.     

肌成纤维细胞在支气管哮喘气道结构重塑中的作用

肌成纤维细胞兼具成纤维细胞和平滑肌细胞的某些特征,来源于局部细胞的增殖,其他细胞的转化及循环中前体细胞的定植,在疤痕形成、肺纤维化等病理过程中发挥重要作用.研究显示其受支气管哮喘相关炎症因子及介质的调控,通过分泌细胞外基质及迁移功能而参与支气管哮喘气道重塑.深入了解肌成纤维细胞在支气管哮喘气道重塑中的作用有助于建立防治...     

双肺弥漫性病变性质待查

患者女,20岁,学生,主因“咳嗽、咯痰、喘息3月余,加重10余天”于2010年10月19日收入院。患者自述3个月前无明显诱因出现咳嗽、咯痰、喘息,于当地医院行胸部CT检查,CT示右肺中叶、左肺舌叶支气管扩张并感染,诊断为“支气管扩张合并感染、双肺细支气管炎”,给予抗炎（阿奇霉素、左氧氟沙星、头孢地尼）等对症治疗后症状有所好转。     

肌成纤维细胞在哮喘气道重塑中的作用

肌成纤维细胞（myofibroblast,MF）是一种介于平滑肌细胞（smooth muscle cell,SMC）和成纤维细胞（fibroblast,FB）之间的特殊类型的细胞,是一类分化了的FB,具有活跃的增殖和分泌胶原的能力,是细胞外基质（extracellular matrix,EMC）的主要来源。     

基质金属蛋白酶与支气管哮喘气道重塑

气道炎症和重塑是支气管哮喘(简称哮喘)的主要特征.细胞外基质(extracellular matrix,ECM)的降解和沉积失衡是导致呼吸道壁结构异常构建的重要原因,而基质金属蛋白酶(matrixmetailoproteinases,MMP)则是调节ECM代谢的主要限速酶.各种MMP及其抑制剂之间可以互相调节.也可作用于细胞因子等多种炎症因子.以增强或减弱其生物学效应.气道重塑的过程也是MMP在气道壁沉积的过程,因此对MMP及其抑制剂的深入研究,对哮喘炎症及气道重塑机制的进一步明确有着重要意义.本文着重就MMP的生物学特性以及它们在哮喘气道重塑中所起的作用进行综述.     

Reduced airway distensibility, fixed airflow limitation, and airway wall remodeling in asthma.

The airways of individuals with asthma are less distensible than normal and it has been assumed that this may be due to airway remodeling associated with chronic inflammation, although there are currently no available data directly relating these two aspects of asthma. We have therefore carried out a study of the relationship between airway distensibility (DeltaVD) and subepithelial reticular basement membrane (RBM) thickening as an index of airway remodeling, in a group of patients with relatively mild but symptomatic asthma. Our methods included a cross-sectional study of DeltaVD in patients with mild to moderate atopic asthma, with matched airway biopsy for structural components. We confirmed that DeltaVD was lower in patients with asthma than in normal individuals (19.8 +/- 1.1 versus 24.1 +/- 1.5; p < 0.05) and that RBM thickness was increased in patients with asthma (9.1 +/- 2.2 versus 7.7 +/- 1.2 microm; p < 0.01). There was a negative correlation between DeltaVD and RBM thickness in asthma (r = -0.37, p = 0.03) and positive correlations between percent predicted postbronchodilator large and small airway function (for percent predicted FEV(1 )versus DeltaVD, r = 0.59, p < 0.001). We conclude that, cross-sectionally, DeltaVD was related to airway remodeling (RBM thickening) and airflow limitation (percent predicted large and small airway function). Our findings support the hypothesis that DeltaVD is a physiologic test that is reflective of airway remodeling.     

Periostin在支气管哮喘气道重塑的作用

骨膜蛋白(Periostin)是一种由结缔组织细胞分泌的细胞外基质蛋白,存在于人类多种正常组织中.Periostin能够参与胶原形成、组织纤维化、上皮间充质转换、恶性肿瘤发展以及多种损伤修复机制.最新研究表明,在哮喘气道重塑的病理过程中,periostin作为IL-4及IL-13的下游信号通过自分泌或旁分泌的方式与其他细胞外基质蛋白相互作用参与上皮下纤维化.研究periostin在哮喘气道重塑中可能扮演的角色及其发挥作用的机制,可能对哮喘的防治提供新的思路.     

尿紧张素Ⅱ在支气管哮喘气道重塑中的作用

目的观察支气管哮喘(简称哮喘)大鼠及哮喘患者支气管管壁尿紧张素Ⅱ(UⅡ)的变化,探讨UⅡ在哮喘发病及气道重塑中的作用。方法将20只一级雄性Wistar大鼠分为对照组和哮喘组,每组10只。哮喘组大鼠采用卵白蛋白10mg腹腔内注射及雾化吸入(5mg)处理建立大鼠哮喘模型;肺组织切片经苏木精伊红(HE)染色,采用图像分析技术测量大鼠支气管管腔的内周长(Pi)、管壁面积(WA)、平滑肌面积(WAm),以WA/Pi和WAm/Pi反映其气道重塑情况;对哮喘大鼠和5例哮喘患者肺组织切片采用链亲和素蛋白过氧化物酶(SP)免疫组织化学法染色检测支气管UⅡ的表达变化,以灰度扫描和计数UⅡ阳性染色细胞数判断其表达强度。结果哮喘组大鼠WA/Pi、WAm/Pi分别为(24.1±2.4)μm2/μm、(5.3±1.9)μm2/μm,与对照组[(16.5±1.7)μm2/μm、(3.8±1.2)μm2/μm]比较差异有统计学意义(t分别=3.892、3.785,P均<0.01);哮喘大鼠支气管UⅡ的表达强度为2.46±0.15,与对照组(1.26±0.11)比较差异有统计学意义(t=6.236,P<0.01);UⅡ的表达强度与WAm/Pi呈正相关(r=0.712,P<0.01);UⅡ阳性染色细胞百分数为(82±8)%,与对照组[(22±8)%]比较差异也有统计学意义(t=19.102,P<0.01);哮喘患者支气管UⅡ的表达强度为2.61±0.19,与对照组(1.36±0.12)比较差异有统计学意义(t=7.374,P<0.01);UⅡ阳性染色细胞百分数为(75±9)%,与对照组[(27±7)%]比较差异有统计学意义(t=16.236,P<0.01)。结论哮喘气道UⅡ的表达和合成明显增加,其可能与哮喘发病及其气道重塑具有密切的关系。     

Epithelial cell proliferation contributes to airway remodeling in severe asthma

RATIONALE: Despite long-term therapy with corticosteroids, patients with severe asthma develop irreversible airway obstruction. OBJECTIVES: To evaluate if there are structural and functional differences in the airway epithelium in severe asthma associated with airway remodeling. METHODS: In bronchial biopsies from 21 normal subjects, 11 subjects with chronic bronchitis, 9 subjects with mild asthma, and 31 subjects with severe asthma, we evaluated epithelial cell morphology: epithelial thickness, lamina reticularis (LR) thickness, and epithelial desquamation. Levels of retinoblastoma protein (Rb), Ki67, and Bcl-2 were measured, reflecting cellular proliferation and death. Terminal deoxynucleotidyl-mediated dUTP nick end labeling (TUNEL) was used to study cellular apoptosis. MEASUREMENTS AND MAIN RESULTS: Airway epithelial and LR thickness was greater in subjects with severe asthma compared with those with mild asthma, normal subjects, and diseased control subjects (p=0.009 and 0.033, respectively). There was no significant difference in epithelial desquamation between groups. Active, hypophosphorylated Rb expression was decreased (p=0.002) and Ki67 was increased (p<0.01) in the epithelium of subjects with severe asthma as compared with normal subjects, indicating increased cellular proliferation. Bcl-2 expression was decreased (p<0.001), indicating decreased cell death suppression. There was a greater level of apoptotic activity in the airway biopsy in subjects with severe asthma as compared with the normal subjects using the TUNEL assay (p=0.002), suggesting increased cell death. CONCLUSIONS: In subjects with severe asthma, as compared with subjects with mild asthma, normal subjects, and diseased control subjects, we found novel evidence of increased cellular proliferation in the airway contributing to a thickened epithelium and LR. These changes may contribute to the progressive decline in lung function and airway remodeling in patients with severe asthma.