Dieckgraefe Brian K, Crimmins Dan L, Landt Vonnie, Houchen Courtney, Anant Shrikant, Porche-Sorbet Rhonda, Ladenson Jack H
Department of Medicine, Washington University School of Medicine, St Louis, MO 63110, USA.
J Investig Med. 2002 Nov;50(6):421-34. doi: 10.1136/jim-50-06-02.
The pathophysiology of inflammatory bowel disease (IBD) reflects a balance between mucosal injury related to an ongoing inflammatory process and mucosal reparative mechanisms. Proreparative mucosal factors may offer new therapeutic paradigms. Transcriptional profiling can be applied to identify candidate gene products involved in colonic mucosal regeneration.
Resection specimens from patients who underwent colonic resection for IBD or non-IBD indications were analyzed by performing Affymetrix GeneChip hybridization (Affymetrix, Inc., Santa Clara, Calif) and histopathologic scoring. Expression and physiologic processing of Reg Ialpha, the most highly expressed member of the regenerating (Reg) gene family, was further studied by performing specific immunohistochemistry, protein sequencing, and mass spectroscopy.
Foregut-derived tissues normally express human Reg proteins with minimal expression in the colon. In the setting of tissue injury associated with IBD, Reg Ialpha Reg Ibeta, and Reg III mRNA were highly expressed in colonic mucosa. Paired histopathologic scoring demonstrated that Reg expression was not related to the presence or the degree of mucosal inflammation. Studies of the Reg Ialpha protein revealed evidence of proteolytic cleavage at the N-terminus. In IBD, intact Reg Ialpha protein was expressed by the metaplastic Paneth granular cell population. Whereas Reg Ialpha cleaved at the N-terminus, it was also deposited throughout the lamina propria. Reg Ialpha treatment was shown to reduce epithelial apoptosis that occurred in response to treatment with hydrogen peroxide.
Ectopic expression, physiologic processing, and directed tissue deposition of Reg Ialpha are components of the colonic mucosal regenerative response in IBD. Reg Ialpha may serve to reduce epithelial apoptosis in inflammation.
炎症性肠病（IBD）的病理生理学反映了与持续炎症过程相关的黏膜损伤和黏膜修复机制之间的平衡。促修复性黏膜因子可能提供新的治疗模式。转录谱分析可用于识别参与结肠黏膜再生的候选基因产物。
对因IBD或非IBD指征接受结肠切除术患者的切除标本进行Affymetrix基因芯片杂交（Affymetrix公司，加利福尼亚州圣克拉拉）和组织病理学评分分析。通过特异性免疫组织化学、蛋白质测序和质谱法进一步研究再生（Reg）基因家族中表达最高的成员Reg Iα的表达和生理加工过程。
前肠来源的组织通常表达人Reg蛋白，在结肠中表达极少。在与IBD相关的组织损伤情况下，Reg Iα、Reg Iβ和Reg III mRNA在结肠黏膜中高表达。配对组织病理学评分显示，Reg表达与黏膜炎症的存在或程度无关。对Reg Iα蛋白的研究揭示了其N端存在蛋白水解切割的证据。在IBD中，化生的潘氏颗粒细胞群表达完整的Reg Iα蛋白。虽然Reg Iα在N端被切割，但它也沉积在整个固有层中。已证明Reg Iα治疗可减少过氧化氢处理后发生的上皮细胞凋亡。
Reg Iα的异位表达、生理加工和定向组织沉积是IBD中结肠黏膜再生反应的组成部分。Reg Iα可能有助于减少炎症中的上皮细胞凋亡。
