Zhao Jingsong, de Vera Josephine, Narushima Seiko, Beck Eric X, Palencia Servando, Shinkawa Pauline, Kim Kyung-Ah, Liu Yi, Levy Michael D, Berg Daniel J, Abo Arie, Funk Walter D
Department of Research, Nuvelo, Inc, San Carlos, California, USA.
Gastroenterology. 2007 Apr;132(4):1331-43. doi: 10.1053/j.gastro.2007.02.001. Epub 2007 Feb 6.
BACKGROUND & AIMS: R-spondin 1 (Rspo1) is a novel epithelial mitogen that stimulates the growth of mucosa in both the small and large intestine.
We investigated the therapeutic potential of Rspo1 in ameliorating experimental colitis induced by dextran sulfate sodium (DSS) or trinitrobenzene sulfonic acid (TNBS) as well as nonsteroidal anti-inflammatory drug-induced colitis in interleukin (IL)-10-deficient mice.
Therapeutic administration of recombinant Rspo1 protein reduced the loss of body weight, diarrhea, and rectal bleeding in a mouse model of acute or chronic DSS-induced colitis. Histologic evaluation revealed that Rspo1 improved mucosal integrity in both villus and/or crypt compartments in the small intestine and colon by stimulating crypt cell growth and mucosal regeneration in DSS-treated mice. Moreover, Rspo1 significantly reduced DSS-induced myeloperoxidase activity and inhibited the overproduction of proinflammatory cytokines, including tumor necrosis factor-alpha, IL-1alpha, IL-6, interferon-gamma, and granulocyte-macrophage colony-stimulating factor, in mouse intestinal tissue, indicating that Rspo1 may reduce DSS-induced inflammation by preserving the mucosal barrier function. Likewise, Rspo1 therapy also alleviated TNBS-induced interstitial inflammation and mucosal erosion in the mouse colon. Furthermore, Rspo1 substantially decreased the histopathologic severity of chronic enterocolitis by repairing crypt epithelium and simultaneously suppressing inflammatory infiltration in piroxicam-exposed IL-10(-/-) mice. Endogenous Rspo1 protein was localized to villus epithelium and crypt Paneth cells in mouse small intestine.
Our results show that Rspo1 may be clinically useful in the therapeutic treatment of inflammatory bowel disease by stimulating crypt cell growth, accelerating mucosal regeneration, and restoring intestinal architecture.
R-spondin 1（Rspo1）是一种新型上皮有丝分裂原，可刺激小肠和大肠黏膜生长。
我们研究了Rspo1在改善由葡聚糖硫酸钠（DSS）或三硝基苯磺酸（TNBS）诱导的实验性结肠炎以及白细胞介素（IL）-10缺陷小鼠中由非甾体抗炎药诱导的结肠炎方面的治疗潜力。
重组Rspo1蛋白的治疗性给药减轻了急性或慢性DSS诱导的结肠炎小鼠模型中的体重减轻、腹泻和直肠出血。组织学评估显示，Rspo1通过刺激DSS处理小鼠的隐窝细胞生长和黏膜再生，改善了小肠和结肠绒毛和/或隐窝区的黏膜完整性。此外，Rspo1显著降低了DSS诱导的小鼠肠道组织中的髓过氧化物酶活性，并抑制了促炎细胞因子的过度产生，包括肿瘤坏死因子-α、IL-1α、IL-6、干扰素-γ和粒细胞-巨噬细胞集落刺激因子，表明Rspo1可能通过维持黏膜屏障功能来减轻DSS诱导的炎症。同样，Rspo1治疗也减轻了TNBS诱导的小鼠结肠间质炎症和黏膜糜烂。此外，Rspo1通过修复隐窝上皮并同时抑制吡罗昔康暴露的IL-10（-/-）小鼠中的炎症浸润，显著降低了慢性小肠结肠炎的组织病理学严重程度。内源性Rspo1蛋白定位于小鼠小肠的绒毛上皮和隐窝潘氏细胞。
我们的结果表明，Rspo1可能通过刺激隐窝细胞生长、加速黏膜再生和恢复肠道结构，在炎症性肠病的治疗中具有临床应用价值。
