背景：严重的难治性哮喘有几种临床变异：伴持续气流受限的哮喘，脆性哮喘和致死性哮喘。但不同疾病表现的致病机制差异目前尚不清楚。

    目的：通过分析支气管黏膜的细胞结构和基因表达，评价I型脆性哮喘、伴持续气流受限的哮喘及轻至中度哮喘的形态学和分子特性。

    方法：42名哮喘患者接受支气管镜检查，其中10名为脆性哮喘患者，10名为伴严重持续性气流受限患者，22名为轻至中度哮喘患者。主要分析支气管黏膜的形态学和细胞学特性。实时定量PCR检测气管黏膜ADRB2、HRH1和CHRM3基因的表达水平。

    结果：轻至中度哮喘患者的嗜酸性粒细胞为29.48/mm²，95%CI为25.24-33.72；中性粒细胞为40.13/mm²，95%CI为32.77-47.49。然而，在脆性哮喘患者中，组织细胞-巨噬细胞为65.80/mm²，95%CI为56.95-74.65，而淋巴细胞为52.94/mm²，95%CI为42.83-63.06。在持续气流受限患者中，中性粒细胞明显升高（81.11/mm²；95%CI为58.33-103.8）。与轻至中度哮喘患者相比，严重哮喘患者的M3胆碱受体和β₂肾上腺素能受体表达显著增加。结果显示，CHRM3（57.17%；95%CI：55.04-59.29）和HRH1 （38.82%；95%CI：35.84-41.81）mRNA表达在脆性哮喘患者中显著增加。ADRB2基因表达在持续气流受限患者中表达最高（71.41%；95%CI：63.54-85.09）。

    结论：严重哮喘的临床异质性在炎症和支气管收缩相关的形态学和分子特征方面存在显著差异。

Selivanova PA, et al. J Asthma. 2010 Apr;47(3):269-275.

Morphological and molecular characteristics of "difficult" asthma.

Selivanova PA, Kulikov ES, Kozina OV, Gereng EA, Freidin MB, Ogorodova LM.

Department of Therapy, Siberian State Medical University, Tomsk 634050, Russian Federation. p.selivanova@mail.ru

Abstract

BACKGROUND: There are several clinical variants of severe difficult-to-treat asthma: asthma with persistent airflow limitation, brittle asthma, and fatal asthma; but the differences between the pathogenetic mechanisms underlying the disease heterogeneity are unknown.

OBJECTIVES: The aim was to evaluate the morphological and molecular characteristics of brittle asthma type I and asthma with persistent airflow limitation compared to mild-to-moderate asthma, by the analysis of the cellular structure and gene expression in the bronchial mucosa.

METHODS: Bronchoscopic evaluation was performed in 42 asthmatic patients: 10 with brittle asthma, 10 with severe asthma with persistent airflow limitation, and 22 with mild-to-moderate asthma. Morphometric and cytological analyses of the bronchial mucosa were performed. The mRNA levels for the ADRB2, HRH1, and CHRM3 genes in the bronchial mucosa were measured by quantitative real-time polymerase chain reaction (PCR).

RESULTS: A predominance of eosinophils (29.48/mm(2), 95% confidence interval [CI] 25.24-33.72) and neutrophils (40.13/mm(2), 95% CI 32.77-47.49) was observed in patients with mild-to-moderate asthma; however, histiocytes-macrophages (65.80/mm(2), 95% CI 56.95-74.65) and lymphocytes (52.94/mm(2), 95% CI 42.83-63.06) were more common in patients with brittle asthma, and neutrophil counts (81.11/mm(2), 95% CI 58.33-103.89) were significantly increased in subjects with persistent airflow limitation. An increase in the expression of the M(3)-cholinoreceptor and the beta(2)-adrenoreceptor genes was demonstrated in severe asthmatics compared to mild-to-moderate asthma patients. Significantly higher levels of CHRM3 (57.17%, 95% CI 55.04-59.29) and HRH1 (38.82%, 95% CI 35.84-41.81) mRNAs were observed in patients with brittle asthma. The level of ADRB2 gene expression (71.41%, 95% CI 63.54-85.09) was maximal in patients with asthma with persistent airflow limitation.

CONCLUSIONS: There is evidence of significantly different morphological characteristics and molecular mechanisms of inflammation and bronchoconstriction underlying the clinical heterogeneity of severe asthma.