Ohno I, Nitta Y, Yamauchi K, Hoshi H, Honma M, Woolley K, O'Byrne P, Tamura G, Jordana M, Shirato K
First Department of Internal Medicine, Tohoku University School of Medicine, Sendai, Japan.
Am J Respir Cell Mol Biol. 1996 Sep;15(3):404-9. doi: 10.1165/ajrcmb.15.3.8810646.
The increase in thickness of bronchial walls by such structural changes as subepithelial fibrosis contributes to the severity and chronicity of asthma by amplifying airway narrowing. However, the pathogenesis of this structural alteration is not known. Transforming growth factor beta 1 (TGF beta 1) is known to have biologic activities relevant to the cellular and molecular events in subepithelial fibrosis, such as the deposition of collagen I and III and the increase of myofibroblasts beneath the epithelial basement membrane. Therefore, we examined TGF beta 1 gene expression in bronchial biopsy tissues from five severe asthmatics, five mild asthmatics, and five normal subjects using in situ hybridization combined with histochemical staining. Cells expressing TGF beta 1 mRNA were detected in tissues from four normal subjects, one mild asthmatic, and five severe asthmatics. The density of positive cells in severe asthmatic tissues (52.1 +/- 22.7, mean +/- SD/mm2) was significantly greater than that in mild asthmatic tissues (1.0 +/- 1.9/mm2, P < 0.01) or normal tissues (10.5 +/- 10.6/mm2, P < 0.02). The density in mild asthmatic tissues was not significantly different from that in normal tissues. The vast majority of positive cells in severe (99.1 +/- 1.7%) and mild (100%) asthmatic tissues were identified as eosinophils. In contrast, eosinophils constituted a small portion of positive cells (20.8 +/- 21.6%) in normal tissues. These results indicated that TGF beta 1 mRNA was overexpressed in severe asthmatics and that the main source of the mRNA was eosinophils, suggesting that eosinophils play an important role in the pathogenesis not only of inflammation but also of structural changes, such as subepithelial fibrosis, in asthmatic airways.
支气管壁厚度因上皮下纤维化等结构变化而增加，通过加剧气道狭窄，促使哮喘病情加重并呈慢性化。然而，这种结构改变的发病机制尚不清楚。已知转化生长因子β1（TGFβ1）具有与上皮下纤维化中的细胞和分子事件相关的生物学活性，如I型和III型胶原的沉积以及上皮基底膜下肌成纤维细胞的增加。因此，我们采用原位杂交结合组织化学染色的方法，检测了5名重度哮喘患者、5名轻度哮喘患者和5名正常受试者支气管活检组织中TGFβ1基因的表达。在4名正常受试者、1名轻度哮喘患者和5名重度哮喘患者的组织中检测到表达TGFβ1 mRNA的细胞。重度哮喘组织中阳性细胞密度（52.1±22.7，平均值±标准差/mm²）显著高于轻度哮喘组织（1.0±1.9/mm²，P<0.01）或正常组织（10.5±10.6/mm²，P<0.02）。轻度哮喘组织中的密度与正常组织无显著差异。重度（99.1±1.7%）和轻度（100%）哮喘组织中绝大多数阳性细胞被鉴定为嗜酸性粒细胞。相比之下，嗜酸性粒细胞在正常组织的阳性细胞中占一小部分（20.8±21.6%）。这些结果表明，TGFβ1 mRNA在重度哮喘患者中过度表达，且该mRNA的主要来源是嗜酸性粒细胞，提示嗜酸性粒细胞不仅在哮喘气道炎症的发病机制中起重要作用，而且在诸如上皮下纤维化等结构变化的发病机制中也起重要作用。
