More muscle in asthma, but where did it come from?
More muscle in asthma, but where did it come from?
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哮喘患者肌肉增多，但它从哪里来呢？
DOI：
10.1164/rccm.201203-0457ed
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发表时间：
2012
影响因子：
24.7
通讯作者：
A. Stewart
中科院分区：
文献类型：
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作者：
A. Stewart
哮喘个体的气道壁显示出显著的结构变化，包括以下：上皮损失区域、上皮内嗜酸性粒细胞的存在、杯状细胞化生、上皮下网状基底膜增厚、血管分布增加和上皮下结缔组织的炎性细胞浸润。增厚的气道平滑肌（ASM）层更靠近上皮（1，2）。ASM增生在重度哮喘中更为突出。在活检（1）和尸检研究（3）中报告了近端气道ASM肥大，但并不总是观察到（4）。这些结构变化继续引起哮喘研究人员的兴趣，因为它们与气道高反应性、固定气道阻塞和对深吸气的支气管扩张反应丧失有关。然而，这些功能对哮喘严重程度的影响的性质和程度仍有争议，因为证据仅限于相关研究的推论。詹姆斯和他的同事在本期杂志上发表的文章（pp. 1058-1064）包括对哮喘死后气道的最大系统结构研究（5）。合并来自多个中心的数据需要仔细分析潜在的系统差异，因为固定、采样和样本可用性在一些合作中心之间存在差异。研究人员使用体视学方法关注ASM占据的体积和该体积的组成：ASM的数密度，ASM的大小和ASM层内细胞外基质（ECM）的体积。在0.5 mm薄切片上用Masson三色染色组织以估计ECM或ASM细胞占据的面积，并将苏木精用于使用光学Disector分析的30 mm厚切片以估计ASM细胞的数密度。尽管哮喘患者存在增厚的ASM层是没有争议的，但其原因仍有争议，增生、肥大和ECM扩张都被认为是原因。James及其同事报告称，非致死性和致死性哮喘的ASM肥大在更近端的气道中明显，而在致死性哮喘的所有气道中均检测到增生，但仅限于非致死性哮喘的近端气道。与ASM数量的增加相比，肥大反应是适度的。致死性哮喘组ECM体积大于非致死性哮喘组和对照组，但ECM所占面积分数显著下降。鉴于最近的研究表明，ECM可以被ASM重塑为显著减少的体积和更紧密的原纤维包装，这一下降是有趣的，其过程不受β 2-肾上腺素受体激动剂或糖皮质激素的抑制（6，7）。致命性哮喘中ECM密度（即脱水重量/体积）是否增加仍有待确定。总的来说，James及其同事的研究结果表明，增生而不是肥大或ECM扩张是ASM体积增加的主要原因。James及其同事的主要结论是哮喘持续时间对平滑肌层增厚程度的影响很小（5）。哮喘严重程度的分析并没有发现进一步的重大关联超出了致命性和非致命性病例的比较。哮喘持续时间对气道重塑程度明显缺乏影响，这与许多研究一致，这些研究表明重塑是哮喘自然史中的早期事件。据报道，在短期哮喘儿童的活检中发现了ASM增生（8），...
The airway wall of individuals with asthma displays prominent structural changes including the following: areas of epithelial loss, the presence of intraepithelial eosinophils, goblet cell metaplasia, subepithelial reticular basement membrane thickening, increased vascularity, and inflammatory cell infiltration of the subepithelial connective tissue. Thickened layers of airway smooth muscle (ASM) lie closer to the epithelium (1, 2). ASM hyperplasia is more prominent in severe asthma. Hypertrophy of ASM in proximal airways has been reported in biopsy (1) and in post mortem studies (3), but is not always observed (4). These structural changes continue to intrigue those active in asthma research, because they are linked to airway hyperresponsiveness, fixed airway obstruction, and loss of bronchodilator response to deep inspiration. However, the nature and extent of these functional impacts on asthma severity is still debated, as evidence is limited to inferences from correlative studies. The article by James and colleagues in this issue of the Journal (pp. 1058–1064) comprises the largest systematic structural investigation of post mortem airways in asthma (5). The consolidation of data from multiple centers required careful analysis of potential systematic differences, as fixation, sampling, and specimen availability differed between some of the collaborating centers. The investigators used a stereological approach to focus on the volume occupied by ASM and the composition of this volume: the numerical density of ASM, the size of ASM, and the volume of extracellular matrix (ECM) within the ASM layer. Tissue was stained with Masson’s trichrome on thin 0.5-mm sections to estimate areas occupied by ECM or ASM cells, and hematoxylin was used for thick 30-mm sections analyzed using an optical disector to estimate the numerical density of ASM cells. Although the presence of a thickened ASM layer in individuals with asthma is uncontroversial, the reasons for it are still contested, with hyperplasia, hypertrophy, and ECM expansion all thought to contribute. James and coworkers report that ASM hypertrophy in nonfatal and fatal asthma is evident in more proximal airways, whereas hyperplasia is detected in all airways of fatal asthma, but is limited to proximal airways of nonfatal asthma. The hypertrophic response is modest by comparison with the increase in ASM number. The volume of ECM in fatal asthma is greater than either the nonfatal asthma or the control groups, but the fractional area occupied by ECM declined significantly in fatal asthma. This decline is interesting in light of recent studies showing that ECM can be remodeled by ASM to markedly reduced volumes and much tighter fibril packing by processes that are not inhibited by b2-adrenoceptor agonists agents or glucocorticoids (6, 7). Whether the ECM density (ie, dehydrated weight/volume) is increased in fatal asthma remains to be established. Collectively, the findings of James and colleagues suggest that hyperplasia, rather than either hypertrophy or ECM expansion, is the dominant reason for the increase in ASM volume.The principal conclusion of James and coworkers is that there is little effect of asthma duration on the extent of smooth muscle layer thickening (5). Analysis of asthma severity did not reveal further significant associations beyond those identified by comparison of fatal and nonfatal cases. The apparent lack of effect of asthma duration on the extent of airway remodeling is consistent with a number of studies suggesting that remodeling is an early event in the natural history of asthma. ASM hyperplasia has been reported in biopsies of children with asthma of short duration (8), as has …
DOI：
10.1513/pats.200704-048vs
发表时间：
2012-12
期刊：
Proceedings of the American Thoracic Society
影响因子：
--
作者：
Wenwu Zhang;S. Gunst
通讯作者：
Wenwu Zhang;S. Gunst
DOI：
10.1164/rccm.200311-1529oc
发表时间：
2004-05-01
影响因子：
24.7
作者：
Woodruff, PG;Dolganov, GM;Fahy, JV
通讯作者：
Fahy, JV