臺灣博碩士論文加值系統

臨床上，對麻醉醫師而言，處理氣喘患者的氣道是一項挑戰。這類患者對於喉鏡，氣管插管以及手術中的種種刺激相當敏感而且容易引起氣道阻塞。因此，為了避免氣道阻塞，選擇擁有氣管平滑肌鬆弛而且不會刺激迷走神經等藥理功能的麻醉藥進行麻醉誘導及維持麻醉就顯得相當重要。Propofol是一種靜脈注射的麻醉劑，臨床的報告指出它可能可以抑制氣道平滑肌的收縮。另外，在血管平滑肌上，propofol可以抑制由endothelin-1及arginine vasopressin所引發IP3生成的作用。這些報告增加“ propofol 經由抑制Gq-coupling receptor活化後的訊息傳遞路徑而抑制氣道平滑肌收縮 ”假說成立的可能性。因此，我們試圖檢驗此假說。實驗結果顯示propofol前處理使carbachol誘發氣道平滑肌收縮的濃度反應曲線顯著的往右側移動。而propofol不僅可以減少carbachol誘發Ca2+的釋放，亦可抑制calcium influx。另外，propofol也會抑制carbachol誘發的inositol phosphates accumulation。至於氣道平滑肌細胞膜上muscarinic receptors的密度(Bmax) 並不會受到propofol的改變；雖然100 mM propofol不會影響解離常數，然而300 mM propofol則顯著的使KD增加。我們的結論是propofol 抑制犬氣道平滑肌收縮，而其作用機轉是抑制mAChR活化後的訊息傳遞路徑。
了解氣喘的病理生理學有助於麻醉藥物的選擇。氣喘的特性包括氣道發炎與氣道狹窄，而後者的部分原因是氣道平滑肌細胞的增生與肥大。臨床的實驗顯示，在氣喘病人的氣道分泌物中，thrombin 的生成有增加的現象。在許多不同種類的細胞中，thrombin可以刺激細胞增生。目前有越來越多的證據顯示生長因子與G protein-coupled recptors 經由活化許多的訊息傳遞路徑包括mitogen-activated protein kinase (MAPK) 而刺激細胞增生。因此，在氣道平滑肌細胞上，thrombin有可能經由活化MAPK路徑而刺激細胞增生。實驗的結果顯示隨著濃度的增加thrombin可以活化p42/p44 MAPK，AP-1以及刺激[3H]thymidine incorporation。而氣道平滑肌細胞以pertussis toxin (PTX) 前處理顯著的抑制thrombin所誘發的p42/p44 MAPK 以及[3H]thymidine incorporation。而這些反應也可以被tyrosine kinase抑制劑genistein與herbimycin A、phosphatidyl inositide (PI)-phospholipase C (PLC) 抑制劑U73122、protein kinase C (PKC) 抑制劑GF109203X、PI3K抑制劑wortmannin與LY294002、以及加入BAPTA/AM plus EGTA以移除Ca2+等所減緩。另外，thrombin所誘發的p42/p44 MAPK，AP-1的活化以及刺激[3H]thymidine incorporation的作用可以被MEK1/2的抑制劑PD98059所抑制，顯示活化的過程需要MEK1/2。而藉由H-Ras-15A與Raf-N4這兩個dominant negative mutant的過度表現可以顯著的抑制thrombin與PDGF-BB所誘發的反應，顯示Ras與Raf是活化p42/p44 MAPK所必須。綜合以上的結論是在犬氣道平滑肌細胞上，thrombin誘發細胞增生是經由活化Ras/Raf/MEK/MAPK的訊息傳遞路徑所造成；而其活化p42/p44 MAPK導致細胞增生則受到PI-PLC、Ca2+、PKC、tyrosine kinase與PI3K的調控。

In clinics, it is a challenge for an anesthesiologist to manage the airway of patients with asthma. These patients are vulnerable to the stimulation of laryngoscope, endotracheal intubation and surgical stimulation. Therefore, choice of anesthetics with characteristics of airway smooth muscle relaxation and without vagal stimulation is crucial for the avoidance of airway obstruction. Propofol (2,6-di-isopropylphenol), a popular intravenous anesthetic, was reported to interfere with the contraction of airway smooth muscle. In addition, in vascular smooth muscle, propofol has been shown to inhibit the IP3 production induced by endothelin-1 and arginine vasopressin. These reports raise the hypothesis that propofol might attenuate contraction of airway smooth muscle via the inhibition of receptors-mediated signal transduction pathway. Therefore, we try to test this hypothesis. The experimental results showed that pretreatment with propofol shifts the concentration-response curves of carbachol-induced smooth muscle contraction to the right. Propofol not only decreased the release of Ca2+ from internal stores but also inhibited the calcium influx induced by carbachol. In addition, carbachol-induced IPs accumulation was attenuated by propofol. Moreover, propofol did not alter the density of muscarinic receptors (Bmax). The dissociation constant (KD) value was not altered by pretreatment with 100 mM propofol, but was significantly increased by 300 mM. These results conclude that propofol attenuates the muscarinic-receptor-mediated airway muscle contraction. The mechanism underlying these effects was due to attenuation of IPs generation and inhibition of Ca2+ mobilization through the inhibition of receptor-coupled signal transduction pathway.
The understanding of the pathophysiology of asthma is required for the selection of anesthetics. Asthma is characterized by airway inflammation and narrowing. The latter is attributed in part to the hyperplasia and hypertrophy of airway myocytes. It has been demonstrated that elevation of thrombin is detected in the airway fluids of asthmatic patients. In a variety of cell types, thrombin has been shown to stimulate cell proliferation. Several lines of evidence have shown that growth factors and G protein-coupled recptors activate various signal transduction pathways include mitogen-activated protein kinase (MAPK) associated with cell proliferation. Therefore, it is likely that the stimulation of the MAPK pathway by thrombin links to cell proliferation in TSMCs. This study was designed to test this hypothesis, and experimental results showed that thrombin stimulated [3H]thymidine incorporation and p42/p44 MAPK phosphorylation in a time- and concentration-dependent manner in canine TSMCs. Pretreatment of TSMCs with pertussis toxin (PTX) significantly inhibited [3H]thymidine incorporation and phosphorylation of MAPK induced by thrombin. These responses were attenuated by tyrosine kinase inhibitors genistein and herbimycin A, phosphatidyl inositide (PI)-phospholipase C (PLC) inhibitor U73122, protein kinase C (PKC) inhibitor GF109203X, removal of Ca2+ by addition of BAPTA/AM plus EGTA, and PI3K inhibitors wortmannin and LY294002. In addition, thrombin-induced [3H]-thymidine incorporation, p42/p44 MAPK phosphorylation and AP-1 activation was inhibited by PD98059 (an inhibitor of MEK1/2), indicating that activation of MEK1/2 was required for these responses. Furthermore, overexpression of dominant negative mutants, H-Ras-15A and Raf-N4, significantly suppressed p42/p44 MAPK activation induced by thrombin and PDGF-BB, indicating that Ras and Raf may be required for activation of these kinases. These results conclude that the mitogenic effect of thrombin was mediated through the activation of Ras/Raf/MEK/MAPK pathway. Thrombin-mediated MAPK activation was modulated by PI-PLC, Ca2+ , PKC, tyrosine kinase, and PI3K associated with cell proliferation in cultured canine TSMCs.

縮寫表 (Abbreviations) …………………………………………………vii
Effects of pharmacological inhibitors ………………….……………x
中文摘要 (Abstract in Chinese) ………………………………………xi
英文摘要 (Abstract in English) ……………………………………xiii
PART I. PROPOFOL-REGULATED MUSCARINIC
RESPONSES IN AIRWAY SMOOTH MUSCLE………………………………………1
緒論………………………………………………………………2
實驗材料及方法…………………………………………………8
實驗結果…………………………………………………………14
討論………………………………………………………………18
圖表………………………………………………………………23
PART II. THROMBIN-REGULATED AIRWAY SMOOTH
MUSCLE CELL PROLIFERATION……………………………………………39
緒論……………………………………………………………………………40
實驗材料及方法…………………………………………………50
實驗結果…………………………………………………………57
討論………………………………………………………………63
圖表………………………………………………………………72
參考文獻………………………………………………………………………99
附錄一………………………………………………………………………118
附錄二………………………………………………………………………124

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