Corticosteroids correct aberrant CFTR localization in the duct and regenerate acinar cells in autoimmune pancreatitis.
Corticosteroids correct aberrant CFTR localization in the duct and regenerate acinar cells in autoimmune pancreatitis.
复制标题
皮质类固醇在自身免疫性胰腺炎中纠正管道中的异常CFTR定位和再生腺泡细胞。
DOI：
10.1053/j.gastro.2010.01.001
复制
发表时间：
2010-05
期刊：
影响因子：
29.4
通讯作者：
Goto H
中科院分区：
文献类型：
--
作者：
Ko SB;Mizuno N;Yatabe Y;Yoshikawa T;Ishiguro H;Yamamoto A;Azuma S;Naruse S;Yamao K;Muallem S;Goto H
皮质类固醇目前被广泛接受为自身免疫性胰腺炎（AIP）的一种治疗方法。然而，类固醇治疗改善AIP的分子机制在很大程度上仍然未知。本研究的目的是阐明皮质类固醇改善AIP胰腺外分泌功能和组织病理学的细胞机制。
通过促胰液素刺激功能试验评估胰腺外分泌功能，并在诊断时以及类固醇治疗开始3个月后对胰腺活检标本进行组织学分析处理。通过免疫组织化学测定蛋白质的表达和定位。对免疫球蛋白（Ig）G4阳性浆细胞的分析用于验证AIP中的炎症。
类固醇治疗使胰腺切片中IgG4阳性浆细胞的数量减少，表明炎症减轻。大多数AIP患者的液体、碳酸氢盐（HCO₃⁻）和消化酶分泌均受损。皮质类固醇改善了HCO₃⁻和消化酶的分泌。在胰腺导管HCO₃⁻分泌中起核心作用的囊性纤维化跨膜传导调节因子（CFTR），在治疗前大部分错误定位在导管细胞的细胞质中。皮质类固醇纠正了CFTR向顶膜的定位，这解释了HCO₃⁻分泌的改善。类固醇治疗导致腺泡细胞再生，这解释了消化酶分泌的恢复。
皮质类固醇通过使腺泡细胞再生和纠正胰腺导管细胞中CFTR的定位，减轻AIP患者的炎症并恢复消化酶和HCO₃⁻的分泌。CFTR的错误定位可能解释了其他形式胰腺炎中HCO₃⁻分泌异常的原因。
Corticosteroids are now widely accepted as a treatment for autoimmune pancreatitis (AIP). However, the molecular mechanism by which steroid treatment improves AIP remains largely unknown. The aim of this study was to elucidate cellular mechanisms by which corticosteroids improve both pancreatic exocrine function and histopathology in AIP. Pancreatic exocrine function was evaluated by the secretin-stimulated function test and pancreatic biopsy specimens were processed for histologic analysis at the time of diagnosis and 3 months after initiation of steroid treatment. Expression and localization of proteins was assayed by immunohistochemistry. Analysis of immunoglobulin (Ig)G4-positive plasma cells was used to verify inflammation in AIP. The number of IgG4-positive plasma cells in pancreatic sections was decreased by steroid treatment, indicating reduced inflammation. Fluid, bicarbonate (HCO3−), and digestive enzyme secretions all were impaired in most patients with AIP. Corticosteroids improved both HCO3− and digestive enzyme secretion. A large fraction of the cystic fibrosis transmembrane conductance regulator (CFTR), which plays a central role in pancreatic duct HCO3− secretion, was mislocalized to the cytoplasm of duct cells before treatment. Corticosteroids corrected the localization of CFTR to the apical membrane, accounting for the improved HCO3− secretion. Steroid treatment resulted in regeneration of acinar cells, accounting for restored digestive enzyme secretion. Corticosteroids reduce inflammation and restore both digestive enzyme and HCO3− secretion in patients with AIP by regenerating acinar cells and correcting CFTR localization in pancreatic duct cells. Mislocalization of CFTR may explain aberrant HCO3− secretion in other forms of pancreatitis.
登录
查看更多内容
DOI：
10.2165/00151829-200504040-00004
发表时间：
2005-01-01
期刊：
Treatments in respiratory medicine
影响因子：
--
作者：
Chmiel, James F;Konstan, Michael W
通讯作者：
Konstan, Michael W
影响因子：
158.5
作者：
Hamano, H;Kawa, S;Kiyosawa, K
通讯作者：
Kiyosawa, K
影响因子：
158.5
作者：
Cohn, JA;Friedman, KJ;Jowell, PS
通讯作者：
Jowell, PS
影响因子：
2.9
作者：
Kitagawa, M;Naruse, S;Hayakawa, T
通讯作者：
Hayakawa, T
影响因子：
6.3
作者：
Okazaki, Kazuichi;Kawa, Shigeyuki;Otsuki, Makoto
通讯作者：
Otsuki, Makoto