ABSTRACT
BACKGROUND:Transfusion of bone marrow mesenchymal stem cells may become a novel and effective biological therapy for inflammatory bowel disease in clinical practice. Nevertheless, the oncological safety of the treatment is worrisome, and is a key to determine whether mesenchymal stem cells can be widely used in treatment of inflammatory bowel disease, and deserves further investigation. OBJECTIVE:To evaluate the therapeutic effect of bone marrow mesenchymal stem celltransfusion against inflammatory bowel disease in mouse models, and to clarify the effects of mesenchymal stem cells on tumorigenesis of inflammatory bowel disease. METHODS:Mouse model of colitis was established using Balb/c (H-2d) mice exposed to dextran sulfate sodium. Syngeneic bone marrow mesenchymal stem cells were transfused into mouse model through caudal vein. The therapeutic effect of mesenchymal stem cells was compared and observed, and pathological remission of colitis was evaluated. Mouse model of colitis-driven colon carcinogenesis was established using Balb/c (H-2d) mice exposed to dextran sulfate sodium and azoxymethane. Tumor formation within the murine colon was compared and observed after transfusion of mesenchymal stem cells. RESULTS AND CONCLUSION:In models of dextran sulfate sodium-induced colitis, weight loss and fecal occult blood were lessened in the bone marrow mesenchymal stem cellgroup compared with the phosphate buffered saline group. Histological damage score of colitis was less in the bone marrow mesenchymal stem cellgroup:mucosal structure of distal colon was almost intact under microscope, and there was smal area of epithelial defects and cryptal defects. Inflammatory cellinfiltration, proliferation of capil ary and smal vessels could be observed in mucosa and submucosa. Homing and colonization of mesenchymal stem cells in submucosa of inflamed colon could also be observed by in vivo tracing. In the dextran sulfate sodium/azoxymethane model of colitis-driven colon carcinogenesis, the number of intestinal tumors and tumor load were obviously less in the bone marrow mesenchymal stem cellgroup than in the control group. Results indicated that transfusion of bone marrow mesenchymal stem cells can apparently improve colitis lesions of mice with inflammatory bowel disease and inhibit carcinogenesis of colitis, which may provide theoretical support for the biological safety of mesenchymal stem cells transplantation for inflammatory bowel disease.
ABSTRACT
<p><b>OBJECTIVE</b>To confirm that the severity of inflammation can promote the colitis-associated colorectal cancer(CAC) and explore the function of STAT3 signal pathway in CAC.</p><p><b>METHODS</b>Mutagenic agent azoxymethane(AOM) and pro-inflammatory agent dextran sodium sulfate salt (DSS) were used to develop a mouse model of CAC. By changing the concentration of DSS (0, 1% and 2% respectively), the mouse model with different extent of severity of inflammation was developed and the risk of carcinogenesis among these groups was compared. The expression of STAT3 signal pathway was detected by immunohistochemistry staining.</p><p><b>RESULTS</b>In the evaluation of inflammatory severity, disease activity index, histopathological inflammation scores and the expression of pro-inflammation chemokines such as TNF-α, IL-6 and IL-12 in the higher inflammatory response group were higher than that in the lower inflammatory response group. The incidence of colorectal tumor was 100%(12/12) in the higher inflammatory response group and the incidence of colorectal tumor was 58.3%(7/12) in the lower inflammatory response group, and the difference between these two group was statistically significant (P<0.05). The multiplicity(number of tumors/colon) was 12.5±0.5 in the higher inflammatory response group and the multiplicity was 6.6±1.0 in the lower inflammatory response group, and the difference between these two groups was statistically significant (P<0.001). The tumor load(sum of tumor diameters per mouse) in the higher inflammatory response group was 44.2±2.4 mm and that in the lower inflammatory response group was only 18.7±2.7 mm, and the difference between these two groups was statistically significant (P<0.0001). Moreover, the expression of p-STAT3 (Tyr705) was higher in colitis tissue of the higher inflammatory response group than that of the lower inflammatory response group.</p><p><b>CONCLUSIONS</b>Inflammation can promote the colitis-associated CAC. And the activation of STAT3 signal pathway may promote the development of CAC.</p>
Subject(s)
Animals , Mice , Azoxymethane , Colitis , Colonic Neoplasms , Colorectal Neoplasms , Pathology , Dextran Sulfate , Disease Models, Animal , Immunohistochemistry , Inflammation , Interleukin-6 , Mice, Inbred C57BL , STAT3 Transcription Factor , Signal Transduction , Tumor Necrosis Factor-alphaABSTRACT
Objective: Effects of cholesterol oxides (Ch-Ox) on plasma prostacyclin (PGI 2) and endothelin (ET) levels of rats in different selenium (Se) status were investigated. Methods: Weaning male Wistar rats were fed Se deficient diet (containing Se 0.038 mg/kg) and stock diet (Se 0.326 mg/kg, control group) respectively, for 13 weeks. One of Ch-Ox, cholestane-3 beta, 5 alpha, 6 beta-triol (3-triol) was injected into the rats through tail vein.24 h after treatment, the plasma PGI 2, thromboxane A 2 (TXA 2) and ET of animals were determined by radioimmunoassay. Results: Blood Se content, glutathione peroxidase activity and plasma PGI 2 levels of Se deficient rats were significantly lower than that of the control group (P