臺灣博碩士論文加值系統

長期處於間歇性低氧狀態下，如同阻塞型睡眠呼吸中止症之發生，可能引發系
統性發炎反應。肺C 纖維為肺迷走感覺神經接受器主要的類型，目前已知對化學性
介質具有高敏感性。間歇性低氧能導致各種化學性介質之釋放增加，這些化學性介
質已被發現能導致肺C 纖維之刺激及敏感化，進而引發肺化學反射 (如呼吸中止、
心跳減緩及血壓下降)。Transient receptor potential (TRP) A1 接受器是屬於一種陽離
子通道位在痛覺神經元上，包括了對辣椒素敏感的肺C 纖維都有此接受器的分布，
可受到不同的發炎物質而活化。根據本實驗室先前的研究結果顯示，十個週期之急
性間歇性低氧能引發大鼠肺C 纖維之刺激作用與高敏感化之反應。因此本實驗使用
電生理之技術探討(1) 給予急性間歇性低氧，是否擴大辣椒素引發膈神經放電間距
延長 (視為呼氣時間延長之指標) 之呼吸反射。若可以造成其影響，則探討(2)
TRPA1 接受器是否參與急性間歇性低氧刺激後，辣椒素增強膈神經之呼吸反射反應
與肺C 纖維敏感化之過程；(3) TRPA1 接受器是否參與間歇性低氧引發肺C 纖維的
刺激之過程。本實驗之動物於麻醉開胸後，透過呼吸器以人工方式轉動三向閥，交
替給予動物三十秒氮氣伴隨三十秒空氣，共十個週期。在實驗組別中，分別記錄給
予間歇性低氧之前後，膈神經對於靜脈注射辣椒素所引起之呼吸反射反應與肺C 纖
維對於辣椒素之敏感化反應。本實驗結果發現，於間歇性低氧暴露後，可擴大膈神
經對辣椒素所引發放電間距延長；且將頸部雙側迷走神經切除後，則消除此反應。
事前給予藥物HC030031 之處理，為一種TRPA1 接受器拮抗劑，可明顯減弱間歇性
低氧造成膈神經對辣椒素所引發呼吸延長反應和抑制肺C纖維對辣椒素之敏感化反
應。同樣地，事前給予藥物HC030031 處理，亦可完全抑制間歇性低氧所造成肺C
纖維之刺激作用。根據以上實驗結果可知，間歇性低氧可導致肺C 纖維之刺激反應
與高敏感化反應，並且TRPA1 接受器之活化皆參與上述反應過程中。

Long-term exposure to intermittent hypoxia (IH), such as that occurring in
association with obstructive sleep apnea, may generate systemic inflammation. Pulmonary C-fiber afferents (PCFs), a major type of lung vagal sensory receptors, are known to be sensitive to chemical stimuli. Additionally, IH can cause increased release of various chemical mediators, which have been shown to be able to stimulate or sensitize PCFs and further eliciting pulmonary chemoreflex (e.g. apnea, bradycardiac, and hypotension). Transient receptor potential (TRP) A1 channel is a cation channel found preferentially on
nociceptive sensory neurons, including capsaicin-sensitive PCFs, and is activated by various inflammatory mediators. Our laboratory previously demonstrated that ten episodes of acute IH produced a stimulation and hypersensitivity of PCFs in rats. In this study, we carried out using the electrophysiological technique 1) to investigate whether capsaicin-induced phrenic apnea is enhanced by IH challenge, and if so 2) to investigate
the role of TRPA1 receptors in augmented phrenic apnea and PCF sensitivity to capsaicin injection, 3) to determine whether TRPA1 receptors are involved in PCFs stimulation by IH. Ten episodes (30 s of N2 + 30 s of 21% O2) of IH or room air (RA) were delivered via the respirator into the lungs, and activities of PN and PCFs were recorded in anesthetized, paralyzed, and artificially ventilated rats. In a separate group, we measured phrenic apnea to chemical (capsaicin injection) stimuli before and after IH/RA challenge. We found that phrenic apnea to injection of capsaicin was largely prolonged after IH challenge, but it was totally eliminated by bilateral vagotomy. Pretreatment with HC-030031, a TRPA1 selective antagonist, attenuated the IH enhanced phrenic apnea and PCF hypersensitivity to capsaicin injection. Similarly, pretreatment with HC030031 totally abolished IH-induced PCF stimulation. These results suggest that ten cycles of IH challenge evoked stimulation and hypersensitivity of PCFs, all of which are mediated at least partly through
activation of TRPA1 receptors.

目錄.......................................................................I
中文摘要...................................................................III
英文摘要...................................................................V
壹、文獻回顧及研究目的.....................................................1
緒言......................................................................1
背景知識..................................................................4
一、間歇性低氧 :.........................................................4
二、間歇性低氧對生理之影響...............................................5
三、間歇性低氧引發反應性氧衍生物之產生...................................6
四、間歇性低氧引發發炎反應...............................................8
五、肺迷走感覺神經.......................................................9
六、肺C 纖維神經之特性...................................................11
七、TRPA1 接受器參與肺C 纖維神經可塑性之可能機轉.........................13
八、間歇性低氧引發肺C 纖維之神經可塑性之機轉.............................14
九、研究目的.............................................................16
貳、實驗材料方法...........................................................17
一、實驗動物.............................................................17
二、一般手術.............................................................17
三、間歇性低氧模式.......................................................20
四、膈神經分離與記錄.....................................................20
五、單根神經分離與記錄...................................................21
六、肺C 纖維感覺神經鑑定.................................................23
七、藥品.................................................................24
八、實驗執行步驟.........................................................25
九、統計分析.............................................................28
�礡B實驗結果...............................................................29
一、藥物HC030031 前處理對於間歇性低氧刺激後膈神經對化學性刺激放電間距延長
之反應...................................................................29
二、藥物HC030031 前處理對於間歇性低氧造成肺C 纖維產生敏感化反應之影響....33
三、藥物HC030031 前處理對於間歇性低氧刺激肺C 纖維之影響..................37
四、藥物HC030031 前處理對於間歇性低氧引發肺C 纖維刺激作用之影響..........38
肆、討論...................................................................39
結論.....................................................................46
伍、圖表與說明.............................................................47
陸、參考文獻...............................................................65

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