Cl ion transport and CFTR gene expression in antigen sensitized airway epithelium

1.抗原激发增加致敏豚鼠气管C1离子转运抗原激发引起哮喘高分泌。尽管参与哮喘的各种介质刺激C1离子转运，但抗原攻击对C1离子转运的直接影响尚不清楚。在致敏豚鼠气管上，在Ussing室中测定了阿米洛利存在时的短路电流（Isc）。卵清蛋白（OA）激发诱导Isc的双相增加。用吡拉明预处理气管可明显抑制OA诱导的Isc（△Isc）的增加，但对西咪替丁无明显影响。FK 224或色甘酸钠预处理也能抑制OA诱导的△Isc。结论：1.抗原刺激致敏肥大细胞后释放组胺，组胺通过直接作用于上皮细胞和感觉C纤维增加C1离子转运。反复抗原致敏通过CFTR上调诱导豚鼠气管上皮重塑和C1转运的升高; IL-4的作用为了阐明慢性重塑哮喘气道中高分泌的机制，豚鼠每周注射OA，四周，并在第6周进行评估。与对照组相比，致敏气管杯状细胞增生、Ussing室中阿米洛利存在下的Isc和CTR阳性上皮细胞显著增加。这些变化可被地塞米松、Th 2抑制剂或抗IL-4抗体所抑制。结论：1）反复抗原致敏和激发可通过上调CFTR表达诱导杯状细胞增生和Cl离子转运增加; 2）Th 2细胞因子，尤其是IL-4可能参与了这些机制; 3）激素和Th 2抑制剂可能有助于治疗慢性哮喘的高分泌。

1. Antigen challenge increases C1 ion transport in sensitized guinea pig tracheaAntigen challenge causes hypersecretion in asthma. Allthough various mediators involved in asthma stimulate C1 ion transport, the direct effect of antigen challenge on C1 ion transport remains unclear. The short circuit current (Isc) in the presence of amiloride was measured in Ussing chamber in sensitized guinea pig tracheas. Ovalbumin (OA)-challenge induced monophasic increase in Isc. Pretreatment of the trachea with pyrilamine, but not cimetidine significantly inhibited OA-challenge induced increase in Isc (△Isc) in a dosedependent manner. Pretreatment with FK224 or sodium cromogycate also inhibited OA-induced △Isc. These data suggest that activation of sensitized mast cells by antigen challenge releases histamine, which increases C1 ion transport through direct epithelial action and via sensory C-fibers.2. Repeated antigen sensitization induces epithelial remodeling and elevation of C1 transport by CFTR upregulation in guinea pig trachea ; the role of IL-4To elucidate the mechanism of hypersecretion in chronic remodeled asthmatic airway, guinea pigs were injected with OA weekly four weeks, and assessed on the 6th week. Goblet cell hyperplasia, Isc in the presence of amiloride in Ussing chamber and CTFR-positive epithelial cells were significantly increased in sensitized trachea as compared with the control animals. These changes were inhibited by dexamethasone, Th2 inhibitor, or anti IL-4 antibody. We concluded that 1) repeated antigen sensitization and challenges induce goblet cell hyperplasia and elevation of Cl ion transport by upregulated CFTR expression, 2) Th2 cytokines, especially IL-4 may be involved in these mechanisms, 3) steroid and Th2 inhibitor may be useful for the treatment of hypersecretion in chronic asthma.