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研究生:李芷殷
研究生(外文):Chih-Yin Lee
論文名稱:天然複合物和Indomethacin對關節炎治療效果探討
論文名稱(外文):Combined Effects of Naturocetic Compounds and Indomethacin on the Therapy of Arthritis-in Vitro and in Vivo Studies
指導教授:陳建和陳建和引用關係梁有志
指導教授(外文):Chien-Ho Chen, Ph. D.Yu-Chih Liang, Ph. D.
學位類別:碩士
校院名稱:臺北醫學大學
系所名稱:醫學技術學系
學門:醫藥衛生學門
學類:醫學技術及檢驗學類
論文種類:學術論文
論文出版年:2005
畢業學年度:93
語文別:中文
論文頁數:102
中文關鍵詞:美洒辛玻尿酸軟骨硫素關節炎
外文關鍵詞:IndomethacinHyaluronanChondroitin sulfateArthritis
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PART1.
骨關節炎(OA)是關節炎中最常發生的疾病,主要的成因是長期的使用和年紀的增長等,並造成關節軟骨的物理性磨損和引起蛋白分解酵素降解軟骨組織,使得軟骨中的膠原蛋白纖維和醣蛋白降解,Matrix metalloproteinases(MMPs)被認為在骨關節炎中是降解軟骨組織過程中重要物質。近來報告指出,在OA 中表現的MMPs mRNA 主要有MMP-1, MMP-3, MMP-9, 和MMP-13 。在本實驗目的,證明Hyaluronan (HA), chondroitin sulfate A(CA)和indomethacin 可以抑制在interleukin-1β (IL-1β ) 刺激人類chondrosarcoma SW-1353細胞之下所產生的MMP-3。結果顯示,HA和 CA會隨著劑量的增加有效的抑制MMP-3產生;indomethacin可以有效抑制的MMP-3分泌,但不抑制細胞內的表現。此外,NO是軟骨細胞分化和細胞凋亡的重要調節因子之一,並且可經由前發炎激素像是IL-1β所活化產生。結果也顯示,HA和 CA 會隨著劑量的增加,明顯有效的抑制iNOS表現和 NO產生;HA和 CA只抑制NO產生但沒有抑制iNOS表現。結論, HA和 CA可以有效的阻止OA的發展 ,這可再次證明,目前臨床使用可以有效治療關節炎。Indomethacin不但減少MMP-3的分泌,也藉由抑制NO產生並能夠降低發炎現象,這都有助於治療OA。因此實驗結果提供新的證據印證HA、CA和 indomethacin可以有效幫助OA治療。

PART2.
本篇實驗的目的,研究經由玻尿酸(hyaluronan)和indomethacin共同作用治療抗原所引起的關節炎(antigen-induced arthritic ,AIA)兔子實驗動物模式。在玻尿酸和indomethacin注射關節中治療的期間,觀察兔子關節的腫脹,血清中C-reactive protein levels (CRP), 和prostaglandin E2 的變化,並且觀察血清中matrix metalloproteinases-3(MMP-3)活性、巨觀和微觀觀察關節的變化。玻尿酸和indomethacin會使CRP下降,低劑量的indomethacin結合玻尿酸一起治療(Low I-H 5.6 μM indomethacin and hyaluronan),比單獨玻尿酸治療更能降低局部的發炎反應。 對 prostaglandin E2 的抑制效果有隨著劑量的增高,在High I-H (High I-H560 μM indomethacin and hyaluronan) 的治療組最明顯。在Western blot analysis 中各組的 MMP-3 表現皆是持續增加的,而在血清中抑制MMP-3效果,在Low I-H的治療組最明顯。巨觀和病理切片觀察中,單獨玻尿酸、Low I-H 和High I-H 治療皆有相當的治療效果。 結論,此實驗證明在臨床前用玻尿酸結合 indomethacin 注射關節治療,比單獨服用indomethacin(或MMP inhibitors)治療類風濕性關節炎提供更好的臨床效果。
PART1.
Osteoarthritis (OA) is the most prevalent disease of articular joints and is the major cause of disability in the elderly. Pathophysiologic changes occur in OA cartilage due to the excessive expression of cartilage degrading proteinases, the resultant progressive breakdown of collagen fibers, and the degradation of proteoglycan, mainly aggrecan . Matrix metalloproteinases (MMPs)are considered to be important in the chondrolytic processes that contribute to the degenerative changes in OA cartilage. Recent studies have identified the mRNA for some MMPs, such as MMP-1, MMP-3, MMP-9, and MMP-13, in human OA cartilage. In this study, we investigated the inhibitory effects of hyaluronan (HA), chondroitin sulfate A(CA) and indomethacin on the interleukin-1β (IL- 1β)–stimulated expression of MMP-3 in human chondrosarcoma SW-1353. The results showed that HA and CA effectively inhibited MMP-3 expression.. Indomethacin decreased MMP-3 protein secretion, but not inhibited the intracelluar protein expression . Besides, NO is generally believed to be an important mediator of the dedifferentiation and apoptosis of articular chondrocytes by the action of proinflammatory cytokines, such as interleukin- 1β.The results showed that HA and CA significantly inhibited the iNOS expression and nitric oxide production by the dose-dependent mamer. Indomethacin only inhibited nitric oxide production, but not inhibited the iNOS expression. In conclusion, HA and CA could effectively inhibit OA, which supports the clinical use in the treatment. Indomethacin reduced MMP-3 secretion in the mediun and
decreased the inflammatory response by inhibition of nitric oxide production were helpful to cure OA. Therefore, our study provides new data on the mechanism of action of these drugs, which could help to explain their clinical efficacy in OA patients.

PART2.
The combined effect of hyaluronan and indomethacin in the treatment of arthritis using antigen-induced arthritic (AIA) rabbits as a model was evaluated in this study. AIA was monitored by assessing joint swelling, C-reactive protein levels (CRP), and prostaglandin E2 in New Zealand white rabbits for 40 days during the course of special interval treatment by intra-articular injections of hyaluronan and indomethacin. The contralateral knee joint that was not treated served as an internal control. End-point analyses included a matrix metalloproteinases-3 activity assay, and macroscopic and microscopic joint examinations. Hyaluronan (H) and indomethacin (I)-treated rabbits showed a reduction in serum CRP levels with respect to hyaluronan-treated ones. The results of although there was no significant therapeutic effect, an intra-articular injection of low I-H (5.6 μM indomethacin and hyaluronan) was a little more efficient than hyaluronan alone in reducing local inflammation in the knee joint. Clinical assessments of the drug treatments (4 intra-articular injections in the right knee joint) on AIA in rabbits, there were no statistically significant differenc of the experiment, but the effect of indomethacin and hyaluronan on serum CRP, PGE2, and MMP-3 were statistically significant difference. Statistically significant inhibition of serum CRP was only observed in the low I-H group. Inhibition of serum PGE2 was dose-dependent in the low I-H group (13.3% ± 2.9%) and high I-H group
(35.9% ± 3.3%). The order of serum MMP-3 inhibition was the low I-H group (-64.6% ± 12.0%) > high I-H group (-75.8% ± 5.0%) > hyaluronan group (-81.7% ± 26.7%). In Western blot analysis of MMP-3, there was a continual increase in serum pro-form MMP-3 protein in all treatment groups (immunization) from days 1 to 40. Macroscopic analysis and histological analysis of the joints, there were improved efficiency in the hyaluronan treatment group , in the low I-H group and high I-H group . Conclusion of this study provides preclinical support for the hypothesis that an intra-articular injection of hyaluronan in combination with indomethacin (and/or MMP inhibitors) might provide substantially greater clinical benefits to rheumatoid arthritis patients than indomethacin (and/or MMP inhibitors) alone at the systemic level than are achievable with current therapies.
PART1.
Abstract
中文摘要
TABLE of CONTENT:
Chapter 1 : INTRODUCTION
1、The summary of osteoarthritis (OA
2、The cytokine interleukin-1 (IL-1)
3、NO
4、Hyaluronic acid
5、Chondroitin sulfate
6、Non-steroidal anti-inflammatory drugs
7、The purpose of this study
Chapter 2:MATERIALS AND METHODS
1.、Materials
2、Methods
(1)Cell lines
(2)MTT assay for cell proliferation
(3)Nitric Oxide Colorimetric Assay
(4)SDS–PAGE and Western blot analysis
Chapter 3:RESULTS
1、Effects of IL-1β on MMP-3 expression in SW-1353
2、The extent of cell viability
3、Hyaluronic acid sodium salt(HA)inhibit IL-1β-induced MMP-3
4、 Hyaluronic Acid FCH sodium hyaluronate FCH200 inhibit IL-1β-induced MMP-3
5、Chondroitin sulfate A Sodium salt(CA)inhibit IL-1β-induced MMP-3
6、Indomethacin inhibit IL-1β-induced MMP-3
7、Inhibition of NO production in cultured medium
8、Effects of IL-1β induced iNOS expression
9、Inhibition effects of IL-1β induced iNOS expression
Chapter 4:DISCUSSION
Chapter 5:REFERNCES
Chapter 6:FIGURES

PART2.
Abstract
中文摘要
TABLE of CONTENT:
Chapter 1 : INTRODUCTION
1、The summary of arthritis.
2、The effect and function of Hyaluronan
3、Non-steroidal anti-inflammatory drugs
4、Antigen-induced arthritis (AIA) model
5、The index marker of arthritis
6、The purpose of this study
Chapter 2:MATERIALS AND METHODS
1.、Materials
2.、Methods
(1)Preparation of the hyaluronan and indomethacin intra-articular injection
(2)AIA animal model
(3)Clinical assessments of AIA
(4)CRP assay
(5)PGE2 assay
(6)Quantification of MMP-3
(7)Inhibition of therapeutic responses formula
(8)Western blot analysis
(9)Macroscopic analysis of the joints
Chapter 3:RESULTS
1、Development of arthritis
2、Weight of the rabbits
3、Effect of indomethacin and hyaluronan on joint swelling
4、Effect of indomethacin and hyaluronan on serum CRP, PGE2, and MMP-3
5、Inhibition of therapeutic responses
6、Western blot analysis of MMP-3
7、Macroscopic analysis of the joints
8、Histological analysis of the joints
Chapter 4:DISCUSSION
Chapter 5:REFERNCES
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