Foster Paul S, Yang Ming, Herbert Cristan, Kumar Rakesh K
Department of Biochemistry and Molecular Biology, John Curtin School of Medical Research, Australian National University, Canberra, Australia.
Lab Invest. 2002 Apr;82(4):455-62. doi: 10.1038/labinvest.3780438.
Asthma is an acute-on-chronic inflammatory disease of the airways, characterized by airflow obstruction and hyper-reactivity of the airways to a variety of stimuli. Chronic asthma is associated with remodeling of the airway wall, which may contribute to hyper-reactivity and fixed airflow obstruction. We used an improved mouse model of chronic asthma to investigate the role of CD4(+) T-lymphocytes in airway remodeling and hyper-reactivity. Animals functionally depleted of CD4(+) T-lymphocytes by repeated administration of a monoclonal antibody exhibited markedly decreased airway responsiveness. In addition, these mice had greatly diminished subepithelial fibrosis, epithelial thickening, and mucous cell hyperplasia/metaplasia. Chronic inflammation in the airway wall was moderately reduced, with a marked decrease in the accumulation of immunoglobulin-synthesizing plasma cells. However, intraepithelial accumulation of eosinophils was not significantly inhibited and airway epithelial expression of eotaxin was undiminished. This work provides the first experimental evidence that CD4(+) T-lymphocytes play a crucial role in the pathogenesis of the lesions of chronic asthma and lends support to the notion that functional inhibition of these cells may be an important therapeutic target.
哮喘是一种气道的慢性炎症急性发作性疾病，其特征为气流阻塞以及气道对多种刺激的高反应性。慢性哮喘与气道壁重塑相关，这可能导致高反应性和固定性气流阻塞。我们使用一种改良的慢性哮喘小鼠模型来研究CD4(+) T淋巴细胞在气道重塑和高反应性中的作用。通过反复给予单克隆抗体使CD4(+) T淋巴细胞功能耗竭的动物，其气道反应性显著降低。此外，这些小鼠的上皮下纤维化、上皮增厚以及黏液细胞增生/化生明显减轻。气道壁的慢性炎症有一定程度的减轻，合成免疫球蛋白的浆细胞聚集明显减少。然而，上皮内嗜酸性粒细胞的聚集未受到明显抑制，且气道上皮中嗜酸性粒细胞趋化因子的表达未减少。这项工作提供了首个实验证据，表明CD4(+) T淋巴细胞在慢性哮喘病变的发病机制中起关键作用，并支持了对这些细胞进行功能抑制可能是一个重要治疗靶点的观点。
