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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 蘇銘嘉(Ming-Jai Su) | |
| dc.contributor.author | Ching-I Wang | en |
| dc.contributor.author | 王靜宜 | zh_TW |
| dc.date.accessioned | 2021-06-08T00:04:31Z | - |
| dc.date.copyright | 2013-09-24 | |
| dc.date.issued | 2013 | |
| dc.date.submitted | 2013-08-14 | |
| dc.identifier.citation | 1. G.S. Martin, D.M. Mannino, S. Eaton, et al., The epidemiology of sepsis in the United States from 1979 through 2000. N Engl J Med, 2003. 348(16): p. 1546-54.
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/17277 | - |
| dc.description.abstract | CYY054c已知是可減少內毒素引發小鼠死亡的化合物，本實驗研究目的為探討此化合物在LPS刺激下，對RAW264.7細胞株反應之影響，並評估CYY054c對盲腸結紮穿刺手術(cecal ligation and puncture, CLP)誘導之敗血症病鼠心臟功能是否有保護作用。
LPS (100 ng/ml)處理下，誘導RAW264.7細胞株產生ROS、IL-1β、IL-6、IL-10和TNF-α。LPS同樣也使細胞產生COX-2與iNOS蛋白，並造成ERK-1/2磷酸化增加。低劑量serotonin (0.03 μM)可抑制LPS引起之IL-1β分泌，對其他LPS誘導產生的cytokine則沒有顯著影響。低濃度serotonin減少LPS誘導之IL-1β生成的情況，在提高serotonin濃度至0.1、0.3 及1 μM後會消失，而仍然不影響其他原先不受serotonin調控的cytokine之生成量。0.1 μM 5-HT7 受體拮抗劑sb269970存在下會減少LPS誘導之IL-1β 與TNF-α生成，然而sb269970卻會增強LPS誘導之IL-10的生成量。此外，CYY054c在0.03和0.3 μ M濃度下也可產生與sb269970類似的結果，即分別降低LPS刺激下所引起TNF-α與 IL-1β的分泌，並增加LPS誘導之IL-10生成。同時0.03 μM CYY054c 可抑制LPS所誘發COX-2和iNOS表現及ROS製造。為了探討5-HT7 受體，在LPS刺激下對RAW264.7 細胞株產生調控反應的角色為何，以西方墨點法得知，不論是serotonin (1 μM) , sb269970 (0.1 μM), 或CYY054c (0.03 μM)單獨存在均不會影響5-HT7 受體表現，在與LPS合併給予時亦不會影響LPS減少5-HT7 受體之作用。 另一方面，敗血性休克的高死亡率可能與心臟功能受損有關，先前研究中，在以靜脈注射內毒素誘導敗血症之大鼠中，CYY054c可以減少血漿中乳酸堆積，並且可降低發炎性細胞激素的產生。為了進一步模擬臨床上因感染而演變成敗血症的情況，本實驗所使用之敗血性休克動物模式為利用盲腸結紮穿刺手術，使動物因多重菌種感染而引發腹膜炎。實驗將Sprague-Dawley大鼠分為三種組別，分別為sham、CLP、與CLP+CYY054c (300 μg/kg/hr, i.p)組，至手術後六小時期間，藉由頸動脈插管記錄大鼠血壓及心跳速率，之後利用pressure-volume (PV) Loop導管監測心室功能相關參數。CLP手術組造成明顯低血壓、對phenylephrine (15 μg/kg ,i.v.)血管收縮劑反應性減少、高血糖、血漿blood urea nitrogen (BUN) 及creatinine濃度上升的情形。此外，CLP手術組之left ventricular developed pressure (LVDP) 、maximal rise/fall velocity of ventricular pressure [dp/dt(max)、dp/dt(min)]、stroke work和 storke volume明顯減少，顯示在敗血症初期心臟功能已經受損。給予CYY054c治療可以降低敗血症病鼠死亡率，並改善dp/dt(max)及心臟收縮功能指標-壓力與心臟體積關係圖之斜率(end systolic pressure – volume relationship , ESPVR)。因此CYY054c提高敗血症病鼠存活率的原因可能藉由減少敗血症過度的發炎反應，因而改善心臟收縮功能而來，然而關於CYY054c影響敗血症動物的詳盡機轉仍然需要進一步的研究。 | zh_TW |
| dc.description.abstract | CYY054c was a synthetic compound known to ameliorate endotoxin-induced mortality in mice. The aim of the study was to examine the effect of the compound on LPS-induced response in RAW264.7 cells, and to access whether CYY054c could improve cardiac function in cecal ligation and puncture induced endotoxemic rats.
In cultured RAW264.7 cells, LPS (100 ng/ml) treatment resulted in an increase of ROS, IL-1β, IL-6, IL-10, and TNF-α production. LPS also induced COX-2 and iNOS expression and ERK-1/2 phosphorylation. Low concentration of serotonin (0.03 μM) inhibit LPS-stimulated IL-1β secretion without significant effect on the other LPS-stimulated cytokine secretions. The inhibition of LPS-stimulated IL-1β secretion disappeared when serotonin concentration was increased to 0.1, 0.3, and1 μM. Other LPS-stimulated cytokine secretions, however, were unaffected by serotonin. LPS –stimulated IL-1β and TNF-α secretions were reduced by 0.1 μM sb269970 (5-HT7 receptor antagonist). LPS –stimulated IL-10 secretion, however, was enhanced by sb 269970. Similar to sb269970, CYY054c at 0.03, 0.3 μM was found to inhibit LPS-stimulated TNF-α and IL-1β secretion, and enhance LPS-stimulated IL-10 production. Besides, 0.03 μM CYY054c could attenuate LPS-induced expression of COX-2 and iNOS at protein levels and LPS-stimulated ROS production. To characterize the role of 5-HT7¬ receptor in the modulation of LPS –stimulated response in RAW264.7 cells, the present study found that treatment of the cells with serotonin (1 μM) , sb269970 (0.1 μM), or CYY054c (0.03 μM) affected neither basal expression of 5-HT7¬ receptor nor the LPS-induced reduction of 5-HT7¬ receptors. On the other hand, septic shock has a high mortality rate, partially related to myocardial dysfunction. Previous study showed CYY054c could reduce plasma lactate content and pro-inflammatory cytokine release in endotoxemia rats. To mimic clinical infection status, septic shock models were performed by cecal ligation and puncture (CLP) to induce polymicrobial peritonitis. Sprague-Dawley rats were divided into three groups, including sham operated, CLP, and CLP plus CYY054c (300 μg/kg/hr, i.p.) group. Blood pressure and heart rate measurement were obtained through carotid artery cannulation until six hours after surgery. Following the ventricular dynamic parameters were monitored using an invasive pressure-volume (PV) loop technique. CLP surgery induced significant hypotension, vassel hyporesponsiveness to phenylephrine (15 μg/kg ,i.v.), hyperglycemia, and increased plasma BUN and creatinine levels. Furthermore, early stage of sepsis induced by CLP animal model impaired cardiac function, as shown by decreased left ventricular developed pressure (LVDP), maximal rise/fall velocity of ventricular pressure [dp/dt(max)、dp/dt(min)], stroke work, and stroke volume. Co-treatment of CYY054c could decrease mortality of septic rats, restore maximal rise velocity of ventricular pressure and the slope of end systolic pressure – volume relationship (ESPVR), which is the load –independent myocardia contractility index. In conclusion, the protective effect of CYY054c on reduction of mortality in septic rats might be attributed to the decreased inflammatory response, which thus preserves cardiovascular function. More detail mechanism of CYY054c on septic rats need to be further investigated. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-08T00:04:31Z (GMT). No. of bitstreams: 1 ntu-102-R00443009-1.pdf: 5335635 bytes, checksum: 416bbbbf4ff4f1eb1a2bd2476cb410bc (MD5) Previous issue date: 2013 | en |
| dc.description.tableofcontents | 口試委員會審定書 I
致謝………. II 中文摘要. III Abstract… V 縮寫對照表(Abbreviations) VII 目錄……. IX 第一章 緒論 1 第一節 敗血症之簡介 1 一、 定義與致病原 1 二、 敗血症病理機制 2 第二節 敗血症所引發之心臟功能不全 4 一、 myocardial depressor substance (MDS) 4 二、 Nitric Oxide (NO) 5 三、 Reactive oxygen species (ROS) 7 四、 其他機轉 9 第三節 敗血症治療策略 10 第四節 敗血症疾病動物模式 12 第五節 研究動機與目的 13 緒論附圖表 15 Table 1. Criteria for the diagnosis of SIRS, Sepsis, Shock, and organ dysfunction. 15 Table 2. Main pathogens in septic shock 16 Table 3. Pathways and Mediators of Sepsis, Potential Treatments, and Results of Randomized, Controlled Trials (RCTs). 17 Table 4. Inhibition constant (Ki) of CYY 054c 18 Figure 1. Schematic representation of the major elements of the progression of inflammation using remote interactions between immune effector cells and parenchymal cells as the model for remote organ-system dysfunction. 18 Figure 2. Excessive inflammatory mediator production during sepsis. 19 Figure 3. Potential mechanism for myocardial dysfunction during sepsis. 20 Figure 4. Autocrine and paracrine regulation of cardiomyocyte function by NO. 21 Figure 5. Force-NO relationship in the diseased heart. 22 Figure 6. Proposed mechanisms underlying structural changes of the heart during sepsis. 23 Figure 7. Chemical structure of thaliporphine (A) and CYY 054c (B) 24 Figure 8. Chemical structure of CYY 054c derivatives 25 第二章 實驗材料與方法 26 第一節 實驗試劑 26 第二節 細胞實驗 27 一、 老鼠巨噬細胞株(RAW 264.7)培養 27 二、 細胞實驗給藥方法 27 三、 Cytokine測定 28 四、 MTT 細胞存活檢測 29 五、 蛋白質萃取 29 六、 蛋白質定量 29 七、 西方墨點法(Western Blot) 30 八、 cAMP測定 31 九、 ROS測定 31 第三節 動物實驗 32 一、 動物來源及飼養條件 32 二、 大鼠組別與給藥方式 32 三、 血流動力學監測 32 四、 盲腸結紮穿刺手術(cecal ligation and puncture, CLP) 33 五、 樣本收集及處理 34 六、 大鼠實驗流程簡圖 34 七、 小鼠存活率試驗 35 八、 實驗數據分析與統計 35 第三章 實驗結果 36 第一節 serotonin及CYY054對RAW264.6細胞株存活率之影響 36 第二節 5-HT7 受體在RAW264.7細胞株的表現與功能性 36 第三節 serotonin對LPS誘導RAW264.7 細胞株生成細胞激素之影響 37 第四節 CYY054c對以LPS誘導RAW264.7 細胞株生成細胞激素之影響 38 第五節 CYY054c對以LPS誘導RAW264.7 細胞株生成ROS之影響 40 第六節 CYY054c對LPS所誘導COX-2及iNOS的影響 40 第七節 CYY054c對LPS所誘導ERK磷酸化的影響 41 第八節 CYY054c對盲腸結紮穿刺手術誘導敗血症動物實驗之血行力學參數的影響…. 41 第九節 大鼠盲腸結紮穿刺手術，術後同時腹腔注射300 μg/kg CYY054c對心臟功能參數的影響 43 第十節 CYY054c衍生物對以內毒素誘導敗血症病鼠存活率之影響 44 第四章 數據圖表與表格 47 Figure 1. Effects of serotonin and CYY054c on cell viability of RAW 264.7 cells. 47 Figure 2. Effects of CYY054c, sb269970, 5-HT,and LPS on RAW 264.7 cells. 49 Figure 3. Effect of 5-HT7 activation on LPS- induced cytokine production in RAW 264.7 cells. 50 Figure 4. Effects of CYY054c pretreatment on LPS- induced cytokines production in RAW 264.7 cells. 51 Figure 5. Effect of different reagents on LPS-induced ROS production in RAW 264.7 cells. 53 Figure 6. Effects of CYY054c on COX-2 and iNOS expression in RAW264.7 cells. 55 Figure 7. Effects of CYY054c on LPS-induced phosphorylation of ERK-1/2 in RAW 264.7 cells. 57 Figure 8. Hemodynamic parameters of CLP induced septic rats. 59 Figure 9. Biochemical parameters of rats subjected to CLP surgery. 60 Figure 10. Pressure – volume loops of hearts in sham, and CLP groups of vehicle 61 Figure 11. Cardiac function of CLP -induced septic rats. 62 Figure 12A. Effects of CYY909-1 on 3-day survival rate of endotoxin challenged mice. 63 Figure 12B. Effects of CYY902 on 3-day survival rate of endotoxin challenged mice. 64 Figure 12C. Effects of CYY877-3 on 3-day survival rate of endotoxin challenged mice. 65 Figure 12D. Effects of CYY893-3 on 3-day survival rate of endotoxin challenged mice. 66 Figure 12E. Effects of CYY560 on 3-day survival rate of endotoxin challenged mice. 67 Figure 12F. Effects of CYY557 on 3-day survival rate of endotoxin challenged mice. 68 Figure 12G. Effects of sb269970 on 3-day survival rate of endotoxin challenged mice. 69 第五章 討論 70 第一節 細胞實驗 70 第二節 動物實驗 74 第六章 結論 80 第七章 參考文獻 81 | |
| dc.language.iso | zh-TW | |
| dc.title | CYY054c藥物及其衍生物對敗血症動物及發炎反應之研究 | zh_TW |
| dc.title | The effect of CYY054c and its derivatives on sepsis-induced inflammatory response | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 101-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 李安生(An-Sheng Lee),陳文彬(Wen-Pin Chen),顏茂雄(Mao-Hsiung YEN) | |
| dc.subject.keyword | 敗血症,盲腸結紮穿刺手術,CYY054c,5-HT7,sb269970, | zh_TW |
| dc.subject.keyword | sepsis,CLP,CYY054c,5-HT7,sb269970, | en |
| dc.relation.page | 89 | |
| dc.rights.note | 未授權 | |
| dc.date.accepted | 2013-08-14 | |
| dc.contributor.author-college | 醫學院 | zh_TW |
| dc.contributor.author-dept | 藥理學研究所 | zh_TW |
| 顯示於系所單位： | 藥理學科所 | |
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