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研究生:黃天祐
研究生(外文):Tien-Yu Huang
論文名稱:Minocycline對於在小鼠引發之腸道發炎與腸道損傷之保護角色
論文名稱(外文):Protective Effects of Minocycline in Experimental Gut Inflammation and Injuries in Mouse Models
指導教授:廖經倫
指導教授(外文):Ching-Len Liao
學位類別:博士
校院名稱:國防醫學院
系所名稱:醫學科學研究所
學門:醫藥衛生學門
學類:醫學學類
論文種類:學術論文
論文出版年:2009
畢業學年度:98
語文別:中文
論文頁數:77
中文關鍵詞:敏諾塞克林大腸炎化療性腸炎
外文關鍵詞:minocyclinecolitischemotherapy-induced intestinal mucositis
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敏諾塞克林(minocycline)除了抗生素的角色以外,在許多發炎性疾病的動物及臨床實驗中,發現具有明顯抗發炎及抗細胞凋亡的特性。然而敏諾塞克林在腸道發炎或腸道損傷的病理機轉中,是否具有保護的角色,以往並沒有相關的文獻報告。所以我們利用小鼠的腸炎動物模式來探討敏諾塞克林對於腸道發炎與腸道損傷的影響,並進一步探討其可能的機轉。
我們利用dextran sulfate sodium (DSS) 及trinitrobenzene sulfonic acid (TNBS)來誘發小鼠的急性及慢性大腸炎,同時利用5-fluorouracil (5-FU)來引發小鼠的化療性腸炎,並進一步了解敏諾塞克林對於罹患腸炎的小鼠在臨床及組織病理上的影響。我們發現敏諾塞克林可以降低DSS誘發之急性腸炎所引起的死亡及腸道發炎的嚴重程度;同時也發現對於DSS誘發之慢性腸炎及TNBS誘發之急性腸炎也同樣具有保護能力。在機轉的探討上,發現敏諾塞克林可以抑制inducible nitric oxidase (iNOS)及nitric oxide (NO),發炎性細胞介質(proinflammatory cytokine),及matrix metalloproteinases (MMPs) mRNA的表現,同時會減少腸道上皮細胞的細胞凋亡。另一方面,在5-FU誘發之化療性腸炎模式中,藉由體重變化、腹瀉程度及腸道絨毛的變化,發現敏諾塞克林也具有一定的保護效果。在病理機轉上發現敏諾塞克林會抑制TNF-α及IL-1β的mRNA表現,減少腸道細胞的細胞凋亡,以及抑制poly(ADP-ribose) polymerase -1的活性;在小鼠腸道細胞的體外實驗中,也發現敏諾塞克林會抑制poly(ADP-ribose) polymerase -1的活性。除此之外,在小鼠異體移植的大腸腫瘤模式(CT26 xenograft model)中,敏諾塞克林有加強5-FU抗腫瘤的效果。
因此,從本實驗的研究發現,敏諾塞克林具有減緩腸道發炎及腸道損傷的效果,對於人類發炎性腸道疾病及化療性腸炎的治療,敏諾塞克林或許能提供治療或預防角色。
In addition to antimicrobial activity, minocycline exerts anti-inflammatory and antiapoptotic effects in several disease models. However, whether minocycline can affect the pathogenesis of gut inflammation or injuries has not been determined. Herein we investigated the effects of minocycline on experimental gut inflammation and injuries and studied the underlying mechanisms. Acute and chronic colitis in mice was induced by dextran sulfate sodium (DSS) or trinitrobenzene sulfonic acid (TNBS), and chemotherapy-induced intestinal mucositis in mice was triggered by 5-Fluorouracil (5-FU). The effects of minocycline on gut damage were assessed clinically and histologically. We found that minocycline treatment significantly diminished mortality rate and attenuated the severity of DSS-induced acute colitis, as well as DSS-induced chronic colitis and TNBS-induced colitis. Mechanistically, minocycline administration suppressed inducible nitric oxide (iNOS) expression and nitrotyrosine production, inhibited proinflammatory cytokine expression, blocked the up-regulated mRNA expression of matrix metalloproteinases and diminished the apoptotic index in colonic tissues from mice with DSS-induced colitis. In 5-FU-induced intestinal mucositis, body weight loss results, diarrhea scores, and villi measurements showed that minocycline attenuated the severity of intestinal mucositis induced by 5-fluorouracil (5-FU). Minocycline repressed the expression of TNF-α, IL-1β, and iNOS, decreased the apoptotic index, and inhibited poly(ADP-ribose) polymerase -1 (PARP-1) activity in the mouse small intestine. In vitro experiments showed that minocycline suppressed the upregulation of PARP-1 activity in enterocyte IEC-6 cells treated with 5-FU. In addition, minocycline treatment appeared to enhance the antitumor effects of 5-FU in tumor CT-26 xenograft mice. Our results indicate that minocycline protects mice from gut injury induced by 5-FU and enhances the antitumor effects of 5-FU in xenograft mice. These results demonstrate that minocycline protects mice against chemical-induced colitis and chemotherapy-induced intestinal mucositis, probably via its anti-inflammatory and antiapoptotic properties. Therefore, minocycline may be a potential medicine to treat human inflammatory bowel diseases or chemotherapy-induced intestinal mucositis.
CONTENTS
Contacts I
List of Tables IV
List of Figures V
List of Appendixes VII
Abstract in Chinese VIII Abstract in English X
Introduction 1
Materials and Methods
 Animals 6
 DSS-induced acute and chronic colitis 6
 TNBS-induced acute colitis 7
 Induction of intestinal mucositis by 5-FU and CPT-11 8
 Establishment of mice xenografted with CT-26 8
 Drugs administration 9
 Assessment of colitis and mucositis 10
 Assay of colonic myeloperoxidase activity 11
 Determination of serum nitric oxide levels 11
 Determination of proinflammatory gene expression in colonic and small intestinal tissues using the real-time reverse transcriptase–polymerase reaction 12
 Immunohistochemical staining and TUNEL assay of colon and small intestine sections 13
 Detection of proliferating enterocytes in the colon and small intestine 13
 Immunocytochemical staining of murine intestinal epithelial IEC-6 cells 13
 Statistical analysis 15
Results
 Minocycline treatment attenuates the severity of DSS-induced acute colitis
16
 Minocycline suppresses the expression of colonic proinflammatory cytokines and reduces nitrosative stress in mice with DSS-induced acute colitis 18
 Minocycline suppresses expression of MMPs in colonic tissues derived from mice with DSS-induced acute colitis 19
 Minocycline mitigates the apoptotic response in DSS-treated mice but does not restore the proliferative ability of colonic enterocytes 20
 Minocycline alleviates the severity of DSS-induced chronic colitis 21
 Protective effect of minocycline in TNBS-induced colitis 22
 Minocycline treatment attenuated the severity of intestinal mucositis induced by 5-FU or CPT-11 22
 Minocycline suppressed mRNA expression of certain proinflammatory cytokines and iNOS in small intestines of mice treated with 5-FU 23
 Minocycline inhibited PARP-1 activity induced by 5-FU in the small intestine of mice with intestinal mucositis 25
 Minocycline suppressed the upregulation of PARP-1 activity stimulated by 5-FU in murine intestinal epithelial IEC-6 cells 25
 Minocycline decreased apoptotic indexes and did not affect cell proliferation in the small intestine in response to 5-FU chemotherapy 26
 Minocycline enhanced the antitumor effects of 5-FU in mice with CT-26 xenograft 27
Discussion and Conclusions 28
Tables 41
Figures 43
References 60
Appendixes
List of Tables
 Table 1. Histologic Scoring System for DSS-induced colitis.
 Table 2. Primers for quantitative RT-PCR.

List of Figures
 Figure 1. The effect of minocycline dosage in DSS-induced acute colitis in C57BL/6J mice.
 Figure 2. Prophylactic and therapeutic treatment with minocycline protects C57BL/6J mice against DSS-induced acute colitis.
 Figure 3. Minocycline treatment preserves colon length and suppresses infiltration of inflammatory cells into colonic tissues of DSS-treated mice.
 Figure 4. Prophylactic minocycline treatment reduces the severity of DSS-induced acute colitis.
 Figure 5. Prophylactic minocycline treatment blocks expression of proinflammatory cytokines (A) and matrix metalloproteinases (B) in the distal colonic tissues of mice with DSS-induced acute colitis.
 Figure 6. Minocycline administration lowers the iNOS expression in colonic tissues and NO levels in sera of mice with DSS-induced acute colitis.
 Figure 7. Minocycline suppresses DSS-triggered apoptosis in colonic tissues.
 Figure 8. Minocycline attenuates the severity of DSS-induced chronic colitis.
 Figure 9. Effect of minocycline on TNBS-induced colitis in BALB/c mice.
 Figure 10. Minocycline attenuated the severity of intestinal mucositis induced in mice by 5-FU.
 Figure 11. Minocycline ameliorated the severity of intestinal mucositis induced in mice by CPT-11.
 Figure 12. Minocycline restored the lengths of jejuna and ilea villi in mice with 5-FU–induced intestinal mucositis.
 Figure 13. Minocycline suppressed proinflammatory cytokines and iNOS expression in small intestines of mice treated with 5-FU.
 Figure 14. Minocycline suppresses PARP-1 activity in vivo and in vitro.
 Figure 15. Effects of minocycline on proliferation and apoptosis of enterocytes in small intestines of mice with 5-FU–induced intestinal mucositis.
 Figure 16. Minocycline administration blocked 5-FU-induced apoptosis in enterocyte IEC-6 cells.
 Figure 17. The antitumor effects of minocycline alone or in combination with 5-FU in CT-26 xenograft mice.

List of Appendixes
Paper 1. Minocycline attenuates experimental colitis in mice by blocking expression of inducible nitric oxide synthase and matrix metalloproteinases
Paper 2. Minocycline attenuates 5-fluorouracil-induced small intestinal mucositis
in mouse model.
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