急性痛風發作是尿酸結晶沈積於關節所造成的發炎性反應，到目前為止治療痛風關節炎的藥物都各有不同的副作用，因此尋求一種安全有效的藥物是大家努力的方向。穗花珊瑚醇(lemnalol)是一種分離自台灣軟珊瑚的海洋天然物。我們利用注射尿酸結晶到大鼠的關節，建立痛風的動物模型，同時評估給予穗花珊瑚醇的療效。結果發現，穗花珊瑚醇可改善疼痛、足部水腫和膝關節腫脹。在組織型態學和免疫組織化學實驗分析發現，穂花珊瑚醇可減少發炎細胞的浸潤以、c-Fos、誘導型一氧化氮合成酶和第二型環氧酶的蛋白質表現。另外我們也探討穗花珊瑚醇在痛風模式中對於肥胖細胞及蝕骨細胞之影響。實驗結果發現痛風結晶注入大鼠踝關節會造成肥胖細胞的浸潤與脫粒以及蝕骨細胞相關蛋白TGF-beta1，MMP-9，Cathepsin K 和TRAP 蛋白質表現量增加。我們總結發現，穗花珊瑚醇可改善痛風關節炎的症狀與徴候，並且對於尿酸結晶所引起的發炎反應包含嗜中性白血球及肥胖細胞的浸潤，抑制肥胖細胞脫粒也可以壓抑蝕骨細胞的活性。因此我們認為他對痛風關節炎或其他發炎性闗節炎的藥物開發具有相當大的潛力。

An acute gout attack manifests in the joint as dramatic inflammation. To date, the clinical use of medicinal agents has typically led to undesirable side effects. Numerous efforts have failed to create an effective and safe agent for the treatment of gout. Lemnalol—an extract from Formosan soft coral—has documented anti-inflammatory and anti-nociceptive properties. We attempt to examine the therapeutic effects of lemnalol on intra-articular monosodium urate (MSU)-induced gouty arthritis in rats and found that treatment with lemnalol (intramuscular [im]) significantly attenuated MUS-induced mechanical allodynia, paw edema, and knee swelling. Histomorphometric and immunohistochemistry analysis revealed that MSU-induced inflammatory cell infiltration as well as the elevated expression of c-Fos and pro-inflammatory proteins (inducible nitric oxide synthase and cyclooxygenase-2) observed in synovial tissue were significantly inhibited by treatment with lemnalol. Moreover, we also investigated the effects of lemnalol, on mast cells function and osteoclast activities in gout arthritis. We found that both infiltration and degranulation of mast cells increased at 24 h after MSU injection in the ankle joint. Immunohistochemical analysis showed that MSU induced upregulation of TGF-β1 and MMP-9 and the osteoclast markers cathepsin K and TRAP in ankle tissues. We conclude that lemnalol treatment may be beneficial for improving gouty arthritis symptoms and signs, and attenuation the inflammatory reaction including neutrophils, mast cells infiltration and mast cell degranulation and for suppressing osteoclast activation in gouty arthritis. Lemnalol may be a promising candidate for the development of a new treatment for gout and other acute inflammatory arthritis diseases.

Table of Contents
論文審定書……………………………………………………….. i
誌謝……………………………………………………………….. ii
中文摘要………………………………………………………….. xii
Abstract……………………………………………………….….. Xiii
1. General Introduction………………………………………….. 1
1.1 History of gout……………………………………………..... 2
1.2 Epidemiology of gout……………………………………….. 2
1.3 Diagnosis of gout……………………………………..…….. 4
1.4 Pain in gouty arthritis………………………………………. 5
1.4.1 Nociception and pain……………………………………... 5
1.4.2 Inflammation and pain……………………………………. 6
1.4.3 Animal models to test mechanical allodynia……………… 6
1.5 Pathogenesis of gout………………………………………… 7
1.5.1 Local factors……………………………………………… 8
1.5.2 Cells in gouty arthritis……………………………………. 9
1.5.2.1 Neutrophils……………………………………………. 9
1.5.2.2 Mast cells……………………………………………… 9
1.5.2.3 Macrophages………………………………………….. 10
1.5.3 Inflammatory mediators involved in gout………………… 11
1.5.3.1 Cytokine………………………………………………. 11
1.5.3.2 Chemokines…………………………………………… 12
1.5.3.3 Arachidonic acid (AA) ……………………………….. 12
1.5.3.4 Reactive oxygen species and nitric oxide……………… 15
1.5.3.5 Interaction between nitric oxide and prostaglandin biosynthesis…………………………………………………....
16
1.5.3.6 Vasoactive amines and proteases……………………… 17
1.5.3.7 Complement system…………………………………... 17
1.5.3.8 Neuropeptides……………………………………..….. 18
1.6 The role of osteoclasts in gouty arthritis…………………… 18
1.6.1 Osteoclast maturation and differentiation………………... 18
1.6.2 Cross talk between osteoblasts and osteoclasts…………… 19
1.6.3 Osteoclastogenesis and gout……………………………… 20
1.7 Current treatments for gout……………………………….. 21
1.7.1 Colchicine………………………………………………… 22
1.7.2 NSAIDs…………………………………………………… 23
1.7.3 Corticosteroids…………………………………………… 23
1.8 Marine compounds in drug discovery……………………... 24
1.9 Anti-inflammatory marine compounds…………………… 26
1.10 The history and previous studies of lemnalol…………….. 27
1.11 Specific aims……………………………………………….. 28
2. General Materials and Methods……………………………… 29
2.1 Animals……………………………………………………… 30
2.2 MSU preparation and the gout animal model……………... 31
2.3 Experimental design behavior study and synovial inflammation……………………………………………………
31
2.4 Experimental design for study of mast cell activation and osteoclastogenesis……………………………………………….
31
2.5 Measurement of nociceptive behavior (mechanical allodynia) ………………………………………………………..
33
2.6 Measurement of knee width and ankle edema…………….. 33
2.7 Histopathological examination…………………………….. 33
2.8 Immunohistochemistry for iNOS, COX2, c-Fos, CD117, MMP-9, TGF-β1, Cathepsin K and TRAP…………………….
34
2.9 Histology and MCs counting……………………………….. 36
2.10 Statistical analysis…………………………………………. 37
3. Part I. The effects of lemnalol on leukocyte infiltration and iNOS, COX-2, and c-Fos protein expression in gouty arthritis model. ……………………………………………………………..

38
3.1 Introduction………………………………………………… 38
3.2 Results………………………………………………………..
41
3.2.1 The effects of lemnalol on the inflammation induced by MSU…………………………………………………………….
41
3.2.2 Histomorphometric analysis of the effect of lemnalol on MSU-induced WBC infiltration………………………………….
42
3.2.3 Effects of lemnalol on iNOS, COX-2 and c-Fos protein expression in ankle synovium……………………………………
42
3.3 Discussion…………………………………………………… 44
3.3.1 Summary………………………………………………….. 44
3.3.2 Lemnalol attenuates MSU-induced inflammation………… 44
3.3.3 Effects of lemnalol on iNOS and COX-2 in MSU-induced gouty arthritis……………………………………………………
45
3.3.4 The effect of lemnalol on c-Fos in MSU-induced gouty arthritis………………………………………………………….
46
3.3.5 Colchicine and lemnalol dosages in the present study…..... 47
3.4 Conclusion…………………………………………………… 48
4. Part II. The effects of lemnalol on mast cell activation and osteoclast protein expression in gouty arthritis model………….
56
4.1 Introduction…………..…………………………………….. 57
4.2 Results…………………………………...………………….. 60
4.2.1 Effect of lemnalol on MSU-induced ankle edema…………. 60
4.2.2 Effects of lemnalol on MC infiltration and degranulation in synovial tissue…………………………………………………... 60
4.2.3 Effect of lemnalol on synovial TGF-β1 in MSU-injected rats. …………………………………………………………….. 61
4.2.4 Effect of lemnalol on MMP-9 in MSU-injected rats………. 61
4.2.5 Effect of lemnalol on cathepsin K in MSU-injected rats…... 62
4.2.6 Effect of lemnalol on TRAP in MSU-injected rats………… 62
4.3 Discussion…………………………………………………… 64
4.3.1 Gout and osteoclastogenesis……………………………… 64
4.3.2 Effects of lemnalol on MC infiltration and degranulation… 65
4.3.3 Effect of lemnalol on TGF-β1 and MMP-9………………. 66
4.3.4 Effects of lemnalol on the osteoclast markers TRAP and cathepsin K……………………………………………………… 67
4.4 Conclusions…………………………………………………. 69
5.Summary……………………………………………………….. 83
6.Reference……………………………………………………….. 86
7. Appendix………………………………………………………. 99
7.1 Curriculum vitae……………………………………………. 100
7.2 Published paper…………………………………………….. 103

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