上皮细胞增殖在重度哮喘气道重塑中起作用。
Epithelial cell proliferation contributes to airway remodeling in severe asthma.
作者信息
Cohen Lance, E Xueping, Tarsi Jaime, Ramkumar Thiruvamoor, Horiuchi Todd K, Cochran Rebecca, DeMartino Steve, Schechtman Kenneth B, Hussain Iftikhar, Holtzman Michael J, Castro Mario
机构信息
Department of Medicine, Washington University School of Medicine, Campus Box 8052, 660 South Euclid Avenue, St. Louis, MO 63110-1093, USA.
出版信息
Am J Respir Crit Care Med. 2007 Jul 15;176(2):138-45. doi: 10.1164/rccm.200607-1062OC. Epub 2007 Apr 26.
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.
理论依据
尽管长期使用皮质类固醇进行治疗，但重度哮喘患者仍会出现不可逆的气道阻塞。
目的
评估与气道重塑相关的重度哮喘患者气道上皮在结构和功能上是否存在差异。
方法
在对21名正常受试者、11名慢性支气管炎患者、9名轻度哮喘患者和31名重度哮喘患者进行的支气管活检中，我们评估了上皮细胞形态：上皮厚度、网状板（LR）厚度和上皮脱屑情况。测量了视网膜母细胞瘤蛋白（Rb）、Ki67和Bcl-2的水平，以反映细胞增殖和死亡情况。采用末端脱氧核苷酸转移酶介导的dUTP缺口末端标记法（TUNEL）研究细胞凋亡。
测量结果与主要结果
与轻度哮喘患者、正常受试者和患病对照受试者相比，重度哮喘患者的气道上皮和LR厚度更大（分别为p = 0.009和0.033）。各组之间上皮脱屑情况无显著差异。与正常受试者相比，重度哮喘患者上皮中活性低磷酸化Rb表达降低（p = 0.002），Ki67增加（p < 0.01），表明细胞增殖增加。Bcl-2表达降低（p < 0.001），表明细胞死亡抑制作用减弱。与正常受试者相比，重度哮喘患者气道活检中使用TUNEL法检测到的凋亡活性水平更高（p = 0.002），提示细胞死亡增加。
结论
与轻度哮喘患者、正常受试者和患病对照受试者相比，在重度哮喘患者中，我们发现气道中细胞增殖增加的新证据，这导致上皮和LR增厚。这些变化可能导致重度哮喘患者肺功能逐渐下降和气道重塑。
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