Studies on the regulatory mechanism of immuno-inflammatory responses by the euroendocrine system in the gastrointestinal mucosa, and the mucosal injury by the failure of this regulatory function.

本课题组对粘膜免疫系统与神经内分泌系统的关系进行了研究，并报道了几项重要的前沿研究工作。在本研究项目中，我们旨在从两个系统之间密切联系的观点出发，对肠粘膜防御和吸收功能中的调节机制进行分类，并从细胞或组织学和分子或遗传水平上探讨这种调节机制紊乱引起的免疫炎症疾病的病理生理机制。在胃肠粘膜中，前膜巨噬细胞在摄取和递送腔内抗原方面发挥着重要作用。促肾上腺皮质激素释放因子(CRF)神经肽家族的哺乳动物成员Urocortin和CRF受体及其mRNA在出生后3个月龄的固有层巨噬细胞中被检测到。促肾上腺皮质激素释放激素受体…固有层单核细胞的分布也较多。Urocortin在固有层巨噬细胞局部合成，与来自下丘脑的CRF一起，作为粘膜免疫系统的自分泌/旁分泌调节作用于固有层炎症细胞。此外，已知由心理应激和CRF感染引起的肠易激综合征患者的结肠粘膜，粘膜表面上皮层的巨噬细胞缺失或明显减少，聚集在粘膜底部。固有层中的嗜酸性粒细胞增多(将在2001年美国DDW杂志上发表)。结肠粘膜中的血管肠肽和11β-羟基类固醇脱氢酶(11βHSD)在水和电子的吸收中起着至关重要的作用。目前的研究发现，血管活性肠肽直接调节上皮细胞的功能，25周龄的人结肠上皮细胞也表达11βHSD，与人结肠上皮细胞的分化或成熟有关。有趣的是，溃疡性结肠炎患者的结肠上皮细胞缺乏这些酶。这些发现表明，免疫炎症功能，除了流产和胃肠粘膜的运动外，还受到神经内分泌系统的巧妙调节，这种调节的失败可能会导致包括免疫炎性疾病在内的各种胃肠道疾病。较少

Our research group has studied the relationship between mucosal immune system and neuroendocrine system, and reported several important and leading research works. In the present research project, we aimed to clanify the regulatory mechanism in the intestinal mucosal defense and absorption functions from our idea for the close relationship between two systems, and the pathophysiological mechanism for the immuno-inflammatory disorders caused by the disturbance of this regulatory mechanism at the cellular or histological and molecular or genetical levels.In the gastrointestinal mucosa, macrophages in the lamina prepria play an important roled for uptaking and presenting intraluminal antigens. Urocortin, a mamarian member of the corticotropin-releasing factor (CRF) neuropeptide family and CRF receptor and their mRNA were detected in lamina propria macrophages from as early as three months of age at the time of the exposure to dietary intake and luminal bacteria after birth. CRF receptors … More werel also found in lamina propria mononuclear cells. Urocortin locally synthesized in lamina propria macrophages, together with CRF from hypothalamus, my act on lamina propria inflammatory cells as an autocrine/paracrine regulator of the mucosal immne system. In addition, the colonic mucosa from patients with irritable bowel syndrome, which is known to induced by psychological stress and also CRF infection, macrophages beneathe the mucosal surface epithelial layer were absent or much decreased and aggregated at the base of the mucosa. Eosinophils in the lamina propria increased (to be presented in DDW 2001 in US). Vasoatice intestinal peptide (VIP) and 11 β-hydroxysteroid dehydrogenases (11 βHSD) in the colonic mucosal play a cruicial roles in water and elecrolyte absorption. The present investigation found that VIP modulate directly the epithelial cell functions and 11 β HSD is also expressed by the colonic epithelia from 25 weeks gestion associated with differentiation or maturation in human colonic epithelia. Interestingly colonic epithelia in the ulcerative colitis patients lacked in these enzymes.These findings imply that immuno-inflammatory functions, in addition to aborption and movement of the gastrointestinal mucosa are ingeniously regulated by the neuro-endocrine system, and the failure of this regulation may cause various disorders of the gastrointestinal tract including immuno-inflammatory diseases. Less