The Role Of The MTORC1 Signaling Pathway In The Gastric Mucosa Injury In Mice Caused By Chemotherapy

Objective:To explore the role of m TORC1 signaling pathway in the gastric mucosa injury by chemotherapy drugs busulfan(BU)and Cyclophosphamide(CY).Methods:The 8 week SPF male C57BL/6 mice were randomly divided into four groups(n=15),namely the control group,BU+CY group,Rapamycin group,BU+CY+Rapamycin group.The mice in each group were executed respectively on Day 2,Day 6 and Day 14 after the modeling.Two hours before the mice were sacrificed at each observation time point,BrdU(120mg / kg body weight)was injected intraperitoneally.After the mice were sacrificed,the gastric body mucosa was taken,fixed in 4% paraformaldehyde solution at 4 ℃ for 15 h,and embedded in paraffin.Serial sections of 5μm thickness were prepared and adjacent sections were taken for routine aematoxylin and eosin(HE)staining,TUNEL assay and immunohistochemical assay.The pathological changes of gastric mucosa was observed by using HE staining;BrdU positive cells and PS6 positive protein of gastric mucosa were detected by the two–step immunohistochemical method;apoptosis was detected using TUNEL method;stereological measurement was done by using image analyzer.Results:1.Through HE staining,obvious damage of gastric mucosa,exfoliation of mucosal epithelial cells,irregular arrangement of gastric fundic glands and a large number of inflammatory cells were observed in the mice of the BU+CY group,while the damage of gastric mucosa reduced significantly in the BU+CY+Rapamycin group.2.Compared with normal group,the number density of BrdU positive cells in gastric mucosa was decreased significantly in the BU+CY group(P<0.01),whilethat in the BU+CY+Rapamycin group was almost recovered to normal.3.Compared with normal group,the number of gastric mucosal apoptosis cells were increased significantly in the BU+CY group(P<0.01),while obvious recovery was observed in the BU+CY+Rapamycin group,with no statistic deference.4.Compared with normal group,the integral optical density of PS6 was significantly higher in the BU+CY group(P<0.05),indicating that the m TORC1 pathway was activated strongly,while it was significantly reduced in the BU+CY+Rapamycin group,indicating that the mTORC1 pathway was restrained.5.Decrease of the number density of BrdU positive cells and increase of apoptosis cells could be observed in the Rapamycin group.Conclusion:Chemotherapy drugs BU+CY can activate the m TORC1 signaling pathway,inhibit the epithelial cell proliferation of gastric mucosa,and promote the epithelial cell apoptosis of gastric mucosa,resulting in gastric mucosa injury,which can be reversed by Rapamycin.