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

抗原致敏气道上皮中 Cl 离子转运和 CFTR 基因表达

• 批准号: 10670564
• 负责人: KONDO Mitsuko
• 金额: $ 2.05万
• 依托单位: Tokyo Women's Medical University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1998
• 资助国家: 日本
• 起止时间: 1998 至 1999
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-10670564/
• 关键词: sensitization; airway epithelium; Cl ion; ion transport; CFTR; histamine; remodeling; IL-4; Clイオン; ヒスダミン

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.

1.抗原激发可增加致敏豚鼠气管内C1离子的转运。抗原激发可引起哮喘的高分泌。尽管参与哮喘的各种介质都能刺激C_1离子转运，但抗原攻击对C_1离子转运的直接影响尚不清楚。在致敏豚鼠气管Ussing小室中测定了阿米洛利存在下的短路电流(ISC)。卵清蛋白(OVA)攻击可引起ISC单相增加。用西咪替丁对气管进行吡拉明预处理，可显著抑制OA刺激引起的ISC(ISC)升高，并呈剂量依赖性。预先给予FK224或色甘酸钠也可抑制OA诱导的ISC。这些数据表明，抗原挑战激活致敏的肥大细胞释放组胺，组胺通过直接的上皮性作用和通过感觉C纤维增加C1离子的运输。反复抗原致敏诱导豚鼠气管上皮细胞重塑，通过上调CFTR1转运，IL-4在阐明慢性重塑哮喘气道高分泌机制中的作用。豚鼠每周4周注射OA，6周后进行评估。致敏组大鼠气管杯状细胞增生、阿米洛利刺激下的ISC和CTFR阳性上皮细胞均显著高于对照组。这些变化可被地塞米松、Th2抑制剂或抗IL-4抗体所抑制。我们的结论是：1)反复抗原致敏和激发可通过上调CFTR的表达诱导杯状细胞增殖和氯离子转运增加；2)Th2细胞因子，特别是IL-4可能参与了这些机制；3)类固醇和Th2抑制剂可能有助于治疗慢性哮喘的高分泌。

项目成果

近藤光子 他: "反復抗原感作による気道上皮のリモデリングと気道分泌亢進" 日本呼吸器学会雑誌. 37. 191 (1999)

Mitsuko Kondo 等人：“由于反复抗原致敏而导致气道上皮的重塑和气道分泌的增强”，日本呼吸学会杂志 37. 191 (1999)。

S.kanoh, M. Kondo et al: "Effect of FK506 on ATP-induced intracellular calcium oscillations in cow tracheal epithelium."Am. J, physiol.. 276. L891-L899 (1999)

S.kanoh、M. Kondo 等人：“FK506 对奶牛气管上皮中 ATP 诱导的细胞内钙振荡的影响”。

M.Kondo, J.Tamaoki, J.Nakata, A. Nagai: "Remodeled tracheal epithelium after repeated sensitization is ready for hypersecretion in guinea pigs."Am. J. Repir. Crit. Care Med.. 159. A37 (1999)

M.Kondo、J.Tamaoki、J.Nakata、A. Nagai：“反复致敏后重塑的气管上皮已准备好在豚鼠中分泌过多。”

M. kondo et al: "Remodeled tracheal epithelium after repeated sensitization is ready for hypersecretion in guinea pigs."Am. J. Respir. Crit. Care Med.. 159. A37 (1999)

M. kondo 等人：“反复致敏后重塑的气管上皮已准备好在豚鼠中分泌过多。”

M.Kondo, J.Tamaoki, S. Kanoh, et al.: "Antigen challenge increases Cl ion transport in sensitized guinea pig trachea."Proceeding of airway secretion research. 1. 77-81 (1999)

M.Kondo、J.Tamaoki、S. Kanoh 等人：“抗原攻击增加了致敏豚鼠气管中 Cl 离子的转运。”气道分泌研究进展。