臺灣博碩士論文加值系統

一氧化氮（nitric oxide，NO）是細胞內與細胞間訊息傳遞的一個重要分子，和體內很多功能的調控有關，因此提供了一個嶄新的治療方向，相對的也使得NO相關物質的藥理研究越來越蓬勃發展。Soluble guanylyl cyclase （sGC）藉由合成cyclic GMP的功能媒介了許多NO的作用，包括正常的生理功能與不正常的病理反應。可惜，有關NO/sGC/cyclic GMP系統在呼吸道疾病的角色至今仍未完全明瞭。所以，徹底了解此一訊息傳遞路線在呼吸道的重要性，將有助於設計和發展治療呼吸道疾病的藥物，如氣喘。最近，有兩個和此訊息傳遞路線有關的藥物相繼被發現：一個是sGC活化劑YC-1 （3-(5''-hydroxymethyl-2''-furyl)-1-benzyl -indazole），另一個則是sGC抑制劑ODQ（1H[1,2,4]oxadiazolo- [4,3,-a]quinoxalin-1-one）。本論文的主要目標就是要運用這兩個藥物的特性來研究cyclic GMP在呼吸道的角色。
首先，我們利用ODQ與先前廣泛使用的sGC抑制劑methylene blue來釐清sGC/cyclic GMP在sodium nitroprusside（SNP）誘發氣管鬆弛作用中所扮演的角色。天竺鼠離體氣管先以carbachol引起收縮，再加入SNP造成劑量相依性的鬆弛作用。前處理methylene blue（10，30和100 mM）僅能些微但有劑量相關的抑制SNP的鬆弛作用。相對的，給予ODQ （3-10 mM）能劑量相關性的抑制SNP的反應，並且在10 mM時可以達到完全抑制的作用。此外，進一步的實驗更証實了ODQ在氣管平滑肌對sGC的抑制作用比methylene blue強。ODQ （10 mM）可以完全抑制SNP提昇cyclic GMP含量的反應，而methylene blue即使在濃度高達100 mM也僅能部份降低SNP的作用。另一方面，我們也證實經由methylene blue所引起的氣管收縮現象和乙醯膽鹼系統有關，而非經由抑制cyclic GMP生成而來。因為 ODQ和NO合成抑制劑L-NAME並不會改變氣管的張力，而atropine（無選擇性毒蕈鹼受體拮抗劑）及4-DAMP（選擇性M3毒蕈鹼受體拮抗劑）可抑制其收縮現象。總結上述，目前的研究證實，SNP所誘導的天竺鼠氣管擴張反應，完全是經由cyclic GMP-dependent的調控機轉。Methylene blue是一個作用相當微弱的sGC抑制劑，並另外具有調控乙醯膽鹼系統的作用；反之，ODQ則為一強效、具特異性的sGC抑制劑。因此，在研究NO作用的調控機轉時，ODQ將有助於釐清是經由cyclic GMP-dependent或-independent的作用。
論文的第二部份則是探討YC-1對天竺鼠氣管張力反應與cyclic GMP及cyclic AMP含量的影響。同時，我們也特別研究合併YC-1和外生性或內生性NO對這些參數的反應。YC-1在濃度3 or 10 mM時，雖然本身並不影響氣管的鬆弛作用，卻可以濃度相關性的方式來加強SNP所誘發的氣管鬆弛現象。SNP的鬆弛反應及YC-1的加強現象，都可以被sGC抑制劑ODQ所恢復。而在indomethacin，atropine，guanethidine，a-chymotrypsin和histamine存在下，電場刺激（electric field stimulation）造成的鬆弛反應也會被YC-1 （10 mM）顯著加強。而這個作用會在L-NAME或ODQ前處理下被阻斷。此外，在IBMX存在下，合併YC-1和SNP可以顯著提昇cyclic GMP的含量；相反的，卻不會影響cyclic AMP的含量。另一方面，在人類的血小板YC-1也影響了phosphodiesterase 5（PDE5）的活性。而在xanthine/xanthine oxidase產生superoxide anion（O2-）的實驗，YC-1並不影響O2-的含量，也不會抑制superoxide dismutase的活性。綜合以上結果，雖然YC-1本身對氣管張力並沒有影響，但卻以活化sGC與抑制PDE5的雙重作用來提昇cyclic GMP含量，達到加強外生性或內生性NO誘導氣管鬆弛作用。
肺泡巨噬細胞（alveolar macrophages）是肺部重要的免疫細胞之一，可以防禦和清除不當吸入性污染物或病原體。然而當肺泡巨噬細胞受到不當入侵物質過度刺激時，也會釋放許多和呼吸道疾病有關的有毒物質，而導致急性發炎或氣喘發作。在論文的前兩部份，我們已經證實了cyclic GMP在氣管擴張上扮演重要功能，而且YC-1可以經由加強NO，提昇cyclic GMP含量的作用，來促進其鬆弛反應。基於這些現象，在論文的第三部份我們將進一步探討YC-1在肺泡巨噬細胞的藥理功能與機轉，希望有助於釐清YC-1在治療呼吸道疾病的潛力。NR8383肺泡巨噬細胞在LPS/IFNg的刺激下，可呈現時間相關性的增加TNFa釋放。YC-1本身幾乎不會影響TNFa濃度，但可增加LPS/IFNg的作用，且呈現劑量與時間相關的方式。下列幾項證據顯示，YC-1加強LPS/IFNg誘導TNFa生成的作用不是經由cyclic GMP或cyclic AMP的系統而來。第一，YC-1的作用不會被sGC抑制劑ODQ與protein kinase G抑制劑KT 5823所降低。第二，cyclic GMP與cyclic AMP類似物的作用和YC-1不同，這些類似物是以濃度相關的方式明顯抑制LPS/IFNg所誘導的TNFa生成。第三，直接測量cyclic nucleotides的含量也證實，YC-1在LPS/IFNg存在下，並不會增加cyclic GMP與cyclic AMP的濃度。另一方面，為了探討YC-1在這個現象的作用機轉，我們進一步使用了和訊息傳遞有關的藥理抑制劑來研究。結果顯示，PD 098059，SB 203580與genistein並不影響YC-1促進LPS/IFNg誘發TNFa的生成。然而，有趣的是，Ro 31-8220與Go 6976反而更加強YC-1的促進作用。顯然地，傳統型protein kinase C和YC-1促進LPS/IFNg誘發TNFa產量的反應有交互作用。總結上述，在NR8383肺泡巨噬細胞，YC-1經由與cyclic GMP和cyclic AMP-independent的路徑加強LPS/IFNg誘導TNFa的生成，而且此路徑會受到PKC的調控。至於，YC-1的促進作用以及與PKC的關係則有待進一步研究釐清。

Soluble guanylyl cyclase (sGC) plays a pivotal role in the transduction of inter- and intracellular signals conveyed by nitric oxide (NO). Due to the ubiquitous nature of NO, signal transduction induced by sGC/cyclic GMP also has profound physiological as well as pathophysiological significance. However, the role of sGC/cyclic GMP pathway in the pathogenesis of airway function is currently unclear. Thus, it is crucial that elucidation of the NO/sGC/cyclic GMP may provide the greatest opportunity for the design and development of therapeutic agents for airway diseases. Recently, two interesting compounds in sGC activation are found: the activator YC-1 (3-(5''-hydroxymethyl-2''-furyl)-1-benzyl-indazole) and the inhibitor ODQ (1H-[1,2,4]oxadiazolo[4,3,-a]-quinoxalin-1- one). The goal of this thesis is to investigate the role of cyclic GMP in airway function, by using these two compounds.
Firstly, we compared the effects of ODQ and methylene blue to clarify the role of cyclic GMP in mediating the relaxant response in guinea-pig trachea induced by sodium nitroprusside (SNP). SNP evoked a concentration-dependent relaxation of guinea-pig isolated tracheas precontracted with carbachol. Preincubation with methylene blue (10, 30 and 100 mM) resulted in a slight but concentration-dependent prevention of the relaxant response to SNP. In contrast, the relaxation to SNP was extensively prevented by 3 mM ODQ and almost abolished by 10 mM ODQ. SNP (30 mM) induced a significant elevation of cyclic GMP accumulation, which was partially attenuated by 100 mM methylene blue, whereas completely abolished by 10 mM ODQ. Additionally, Methylene blue, but not ODQ and Nw-nitro-L-arginine methyl ester (L-NAME), caused a concentration-dependent contraction in the tracheal preparation. Moreover, atropine (non-selective muscarinic receptor antagonist) and the 4-DAMP (M3-selective antagonist) greatly inhibited the contractile effect evoked by methylene blue. In conclusion, this study provides substantial evidence that SNP-induced muscle relaxation in guinea-pig trachea is completely via a cyclic GMP-dependent mechanism. Methylene blue is a rather weak inhibitor of sGC and has additional effect of modulating the cholinergic system, while ODQ is a more potent and specific inhibitor of sGC than methylene blue in guinea-pig trachea. Thus, ODQ is an important tool in differentiating between cyclic GMP-dependent and -independent effects of NO.
Secondly, the effects of YC-1 on tension, levels of cyclic GMP and cyclic AMP were investigated in guinea-pig trachea. Especially, we studied the synergistic effect of YC-1 with exogenous or endogenous nitric oxide on these parameters. YC-1 at the concentration 3 or 10 mM, which caused only minor effect by itself, elicited concentration-dependent potentiation of sodium nitroprusside (SNP)-induced tracheal relaxation. This relaxation of YC-1 with SNP was reversed by ODQ. Relaxant responses to electric field stimulation (EFS) in the presence of indomethacin, atropine, guanethidine, α-chymotrypsin and histamine were also markedly increased by YC-1 (10 mM). In the presence of L-NAME or ODQ, the relaxant effects to EFS were attenuated and the following addition of YC-1 did not further enhance relaxation. YC-1 (10 mM) or SNP (0.3 mM) alone did not induce significant elevation of cyclic GMP levels in the presence of IBMX, whereas simultaneous application of both compounds markedly elevated the cyclic GMP accumulation. In contrast, the cyclic AMP levels were not altered even at the combination of YC-1 and SNP. Additionally, YC-1 also affected cyclic GMP metabolism, since it inhibited the activity of phosphodiesterase type V in human platelets. YC-1 (30 mM) did not scavenge superoxide anion and had no effect on the removal of superoxide anion by superoxide dismutase in a xanthine/xanthine oxidase system. In conclusion, these results indicate that although YC-1 elicits negligible relaxation of guinea-pig trachea by itself, it can potentiate the relaxant responses of exogenous or endogenous NO. This synergistic response of YC-1 is via the elevation of cyclic GMP contents.
Finally, since alveolar macrophages play a significant role in the pathogenesis of several lung diseases including asthma and acute inflammation due to inhaled bacterial particles and dusts. In this study, we investigate the action of YC-1 on TNFa production by activated alveolar macrophages. Activation of NR 8383 alveolar macrophages with LPS/IFNg elicited a time-dependent increase of TNFa formation. Although YC-1 itself did not significantly induce TNFa formation in activated macrophage, it potentiated TNFa expression in a concentration- and time-dependent manner. By measuring formation of cyclic GMP and cyclic AMP, in contrast to the expectation, YC-1 failed to enhance both cyclic nucleotides in activated macrophages. Moreover, pretreatment with sGC inhibitor ODQ did not alter the YC-1-potentiated TNFa production. On the other hand, both cyclic GMP analogues and cyclic AMP analogues concentration-dependently diminished TNFa release. These observations suggested that the up-regulation of TNFa production by YC-1 was not associated with cyclic GMP and cyclic AMP. Furthermore, we have examined the signaling pathways responsible for up-regulation of TNFa production by YC-1 using several pharmacological inhibitors. PD 098059, SB 203580, genistein, indomethacin, and NS 398 failed to alter the YC-1-potentiated TNFa formation. Interestingly, Ro 31-8220 and Go 6976 showed an increase rather than a decrease on the effect of YC-1. Taken together, these results indicated that classic protein kinase C is involved in the YC-1-elicited TNFa accumulation. In conclusion, the increase of TNFa production by YC-1 is via a cyclic GMP- and cyclic AMP-independent mechanism. The underling mechanism needs to be investigated further.

封面
目錄
縮寫表
中文摘要
英文摘要
第一章　緒論
１－１　研究動機與目的
１－２　文獻回顧
第二章　Soluble guanylyl cyclase 在一氧化氮引起氣管擴張作用的角色
緒言
材料與方法
結果
討論
第三章　YC-1 促進一氧化氮所引起的氣管擴張作用
緒言
材料與方法
結果
討論
第四章　YC-1 在肺泡巨噬細胞的藥理作用與機轉
緒言
材料與方法
結果
討論
第五章　結論與展望
參考文獻
著作

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