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Keratinocyte growth factor ameliorates mycophenolate mofetil-induced intestinal barrier disruption in mice
Yajun Song1, Wengang Hu2, Ya Xiao1
1Department of Urology, Xinqiao Hospital, the Third Military Medical University, NO.83 Xinqiao Street, Shapingba District, Chongqing, China.
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.
Insights
Mycophenolate mofetil (MMF) causes gastrointestinal barrier damage. Keratinocyte growth factor (KGF) protects against MMF-induced intestinal injury by improving barrier function and regulating cell proliferation and apoptosis.
Area of Science:
- Gastroenterology
- Immunology
- Pharmacology
Background:
- Mycophenolate mofetil (MMF) improves graft survival but causes gastrointestinal (GI) side effects due to GI barrier damage.
- Keratinocyte growth factor (KGF) is vital for intestinal protection and repair.
- Investigating KGF's protective effects against MMF-induced intestinal damage is crucial.
Purpose of the Study:
- To investigate the protective effect of KGF on MMF-induced intestinal mucosal barrier disruption.
- To elucidate the potential mechanisms underlying KGF's protective action.
Main Methods:
- Adult male C57BL/6 mice were divided into MMF, MMF + KGF, and control groups.
- MMF and KGF were administered daily for 15 days.
- Evaluated intestinal permeability, histopathology, tight junction (TJ) protein expression, intestinal epithelial cell (IEC) proliferation and apoptosis, and intraepithelial lymphocytes (IELs).
Main Results:
- MMF induced intestinal mucosal injury, increased permeability, and altered TJ protein expression.
- MMF inhibited IEC proliferation, increased apoptosis, and decreased γδ+ T cells in IELs.
- KGF administration alleviated MMF-induced damage, maintained TJ protein expression, reversed proliferation/apoptosis changes, and increased γδ+ IELs.
Conclusions:
- MMF induces intestinal epithelial barrier disruption in mice.
- KGF demonstrates a protective role in ameliorating MMF-induced GI damage.
- KGF may serve as a therapeutic intervention for MMF-related gastrointestinal disorders.
