Objectives

Although mycophenolate mofetil-induced (MMF) effectively improves long-term graft survival, the gastrointestinal (GI) side effects due to MMF-induced GI barrier damage limit its use in clinic. Keratinocyte growth factor (KGF) plays a crucial role in the intestinal protection and repair process. This study is designed to investigate the protective effect of KGF on MMF-induced intestinal mucosal barrier disruption and the potential mechanism.

Methods

Thirty adult male C57BL/6 mice were assigned to one of the following groups: the MMF group, the MMF + KGF group, and the control group (n = 10 in each group). Animals in the MMF group received MMF (500 mg/kg) by gavage once daily for 15 consecutive days; animals in the MMF + KGF group received MMF (500 mg/kg) by gavage and KGF (5 mg/kg) by intraperitoneal injection once daily for 15 consecutive days; and control mice were given an equal volume of vehicle during the 15-day experimental period. In each group, intestinal paracellular permeability, histopathological changes and shifts in tight junction (TJ) protein were evaluated; further, proliferation and apoptosis of intestinal epithelial cells (IECs) were assessed, and intraepithelial lymphocytes (IELs) were isolated and analyzed by flow cytometry.

Results

MMF caused intestinal mucosal injury, increased intestinal mucosal permeability, and altered expression of TJ protein. Moreover, MMF treatment inhibited IEC proliferation and increased apoptosis. MMF treatment resulted in a lower proportion of γδ⁺ T cells in IELs (γδ⁺ IELs). Conversely, concurrent administration of KGF with MMF effectively alleviated MMF-induced intestinal mucosal disruption, inhibited the increase in intestinal permeability, and maintained TJ protein expression. KGF also reversed the MMF-mediated inhibition of proliferation and promotion of apoptosis in IECs. In addition, KGF significantly enhanced the proportion of γδ⁺ IELs.

Conclusion

Our findings suggest that MMF induces intestinal epithelial barrier disruption in mice. KGF may play a protective role to ameliorate the disruption and provide a therapeutic intervention for gastrointestinal disorders induced by MMF.

中文翻译：

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角质形成细胞生长因子改善了小鼠体内麦考酚酸酯引起的肠屏障破坏。

目标

尽管霉酚酸酯引起的移动性（MMF）有效地改善了长期移植物的存活率，但是由于MMF引起的胃肠道屏障受损而引起的胃肠道（GI）副作用限制了其在临床中的使用。角质形成细胞生长因子（KGF）在肠道保护和修复过程中起着至关重要的作用。本研究旨在探讨KGF对MMF诱导的肠粘膜屏障破坏的保护作用及其潜在机制。

方法

将三十只成年雄性C57BL / 6小鼠分配至以下组之一：MMF组，MMF + KGF组和对照组（每组n = 10）。MMF组的动物连续连续15天每天一次通过管饲接受MMF（500 mg / kg）。MMF + KGF组的动物每天进行一次连续15天的灌胃MMF（500 mg / kg）和腹腔注射KGF（5 mg / kg）；在15天的实验期内，对小鼠和对照组小鼠给予等量的媒介物。在每组中，评估肠副细胞的通透性，组织病理学变化和紧密连接（TJ）蛋白的变化。此外，评估肠上皮细胞（IEC）的增殖和凋亡，并分离上皮内淋巴细胞（IEL）并通过流式细胞术进行分析。

结果

MMF引起肠粘膜损伤，肠粘膜通透性增加和TJ蛋白表达改变。而且，MMF治疗抑制IEC增殖并增加凋亡。MMF治疗导致γ的比例较低δ ⁺ T细胞在IELs（γ δ ⁺ IELs）。相反，将KGF与MMF同时给药可有效缓解MMF引起的肠粘膜破坏，抑制肠通透性的增加，并维持TJ蛋白表达。KGF还逆转了MMF介导的IECs增殖抑制和细胞凋亡促进作用。此外，KGF显著增强γ的比例δ ⁺ IELs。

结论

我们的研究结果表明MMF诱导小鼠肠上皮屏障破坏。KGF可能起到保护作用，以改善干扰并为MMF引起的胃肠道疾病提供治疗干预。