Mizoguchi Emiko, Xavier Ramnik J, Reinecker Hans-Christian, Uchino Hirofumi, Bhan Atul K, Podolsky Daniel K, Mizoguchi Atsushi
Center for the Study of Inflammatory Bowel Diseases and Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, USA.
Gastroenterology. 2003 Jul;125(1):148-61. doi: 10.1016/s0016-5085(03)00665-6.
BACKGROUND & AIMS: Colonic crypt elongation occurs during both chronic colitis and in the recovery phase of acute colitis. The impact of these alterations on epithelial cell functions is not fully defined.
DNA microarray analysis of freshly isolated colonic epithelial cells (CECs) from acute and chronic colitis was performed, and the results were confirmed by reverse transcription polymerase chain reaction. Localization of the selected molecules was examined by immunohistochemistry using newly generated antibodies. The function of selected molecules detected in this study was examined by administering the specific inhibitors in dextran sodium sulfate (DSS) colitis.
Several detoxification-associated molecules, which contribute to prevent inflammation by regulating physiological balance under normal conditions, were markedly down-regulated, and anti-inflammatory molecules, which are not normally expressed, were up-regulated in the CEC under the chronic colitis. Among the detoxification-associated molecules, carbonic anhydrase IV was specifically down-regulated in CEC of Th2- but not Th1-mediated colitis. Functionally, inhibition of carbonic anhydrase activity led to the enhancement of recovery from DSS-induced acute colitis by directly stimulating CEC proliferation. Increased expression of regeneration-associated molecules such as regenerating gene-III gamma was detectable in the CEC of acute and chronic colitis but not in the recovery phase of colitis. The expression of this molecule was restricted in surface epithelium and upper crypts but not lower crypts.
These studies suggest that functional alterations, which result in either the exacerbation or the suppression of colitis, coexist in the CEC during chronic colitis. CEC functions are likely to be differentially regulated in the context of the stage and mechanism of colitis.
结肠隐窝延长在慢性结肠炎和急性结肠炎恢复期均会出现。这些改变对上皮细胞功能的影响尚未完全明确。
对急性和慢性结肠炎患者新鲜分离的结肠上皮细胞（CEC）进行DNA微阵列分析，并通过逆转录聚合酶链反应对结果进行确认。使用新生成的抗体通过免疫组织化学检查所选分子的定位。通过在葡聚糖硫酸钠（DSS）结肠炎中给予特异性抑制剂来检测本研究中检测到的所选分子的功能。
在慢性结肠炎的CEC中，几种在正常条件下通过调节生理平衡有助于预防炎症的解毒相关分子显著下调，而通常不表达的抗炎分子上调。在解毒相关分子中，碳酸酐酶IV在Th2介导而非Th1介导的结肠炎的CEC中特异性下调。在功能上，抑制碳酸酐酶活性通过直接刺激CEC增殖导致DSS诱导的急性结肠炎恢复增强。在急性和慢性结肠炎的CEC中可检测到再生相关分子如再生基因IIIγ的表达增加，但在结肠炎恢复期未检测到。该分子的表达局限于表面上皮和隐窝上部而非隐窝下部。
这些研究表明，在慢性结肠炎期间，导致结肠炎加重或抑制的功能改变共存于CEC中。CEC功能可能在结肠炎的阶段和机制背景下受到不同调节。
