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研究生:楊昌寰
研究生(外文):Chang-Huan Yang
論文名稱:間歇性低氧引發大鼠肺迷走 C 纖維神經敏感化之機轉
論文名稱(外文):Mechanisms underlying hypersensitivity of lung vagal C fibers induced by intermittent hypoxia in rats
指導教授:高毓儒
指導教授(外文):Yu Ru Kou
學位類別:博士
校院名稱:國立陽明大學
系所名稱:生理學研究所
學門:醫藥衛生學門
學類:醫學學類
論文種類:學術論文
論文出版年:2016
畢業學年度:104
語文別:中文
論文頁數:117
中文關鍵詞:間歇性低氧呼吸道敏感化肺迷走C纖維
外文關鍵詞:intermittent hypoxiaairway hypersensitivitylung vagal C fibers
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阻塞型睡眠呼吸中止,如同間歇性低氧之狀態,會於呼吸道產生大量反應性氧衍生物、造成呼吸道發炎和產生高反應性的呼吸道疾病,然而其中之致病機轉仍有待釐清。肺迷走C纖維 (lung vagal C fibers) 為主要的肺迷走感覺神經接受器,極易接受化學介質的刺激。呼吸道過度敏感,是因肺感覺神經,特別是肺迷走C纖維的敏感化,使得對於相同程度的化學刺激物,卻引發更強烈的感覺神經與反射反應,此現象也被認為與高反應性的呼吸道疾病之形成有關。事實上,收集相關文獻發現,間歇性低氧暴露後能造成NADPH oxidase活化,產生過量的反應性氧衍生物,進一步造成能量調節的酵素AMP-activated protein kinase (AMPK) 活化,而AMPK可促使肺組織發炎。另外,越來越多證據顯示大量的反應性氧衍生物和發炎物質,例如cyclooxygenase代謝產物,能夠敏感化肺迷走C纖維,最後導致呼吸道過度敏感之形成。根據上述之推測,間性低氧模式能夠造成過量反應性氧衍生物之產生、發炎物質之釋放和肺迷走C纖維敏感化,然而彼此之間的因果關係與相關機轉,仍有待進一步釐清。
本論文第一部份的研究,主要探討反應性氧衍生物敏感的AMPK之發炎過程,於24小時間歇性低氧藉由肺迷走C纖維參與而引發大鼠呼吸道過度敏感之角色。我們利用清醒大鼠分別暴露於持續24小時空氣或持續24小時間歇性低氧,另在間歇性低氧暴露前預處理N-acetyl-L-cysteine (NAC;一種抗氧化劑)、Compound C (一種AMPK抑制劑)、ibuprofen (一種cyclooxygenase抑制劑)或它們的溶劑。在暴露結束後立即進行實驗,我們發現持續24小時間歇性低氧暴露的大鼠相較於空氣暴露的大鼠,經由頸靜脈注射辣椒素 (capsaicin)、苯基二鳥胺酸 (phenylbiguanide) 或α,β亞甲基三磷酸腺苷 (α,β-methylene-ATP) 所引發的肺迷走C纖維參與之呼吸暫停反應和肺迷走C纖維的神經放電反應皆明顯增強。而此增強的反應在間歇性低氧暴露結束後的6小時開始遞減,並在結束後的12小時消失。此外,24小時間歇性低氧暴露後,增強化學刺激物引發的肺迷走C纖維參與的呼吸暫停反應和肺迷走C纖維神經活性之反應,可被預處理NAC、Compound C或ibuprofen顯著地減弱,但預處理溶劑則無此效果。再者,在生化檢驗數據方面,持續24小時間歇性低氧暴露後,代表氧化壓力的脂質過氧化作用、代表AMPK活化的AMPK磷酸化和一種cyclooxygenase的代謝產物-PGE2,皆比空氣暴露組顯著的增加。經由持續24小時間歇性低氧暴露後,肺組織脂質過氧化的增加可以經由預處理NAC而消除,但預處理Compound C或ibuprofen則無影響。24小時間歇性低氧暴露後可增加肺組織AMPK磷酸化,此作用可經由預處理NAC或Compound C而完全消除,但預處理ibuprofen則無明顯的作用。最後,經由持續24小時間歇性低氧暴露後,肺泡灌洗液內PGE2的增加,可以經由上述三種抑制劑的前處理而減少。此外,當預處理這些抑制劑的溶劑對於間歇性低氧暴露後所造成上述的結果,皆無顯著的影響。以上這些結果顯示,24小時間歇性低氧暴露後,可導致肺迷走C纖維敏感化,進而增強化學刺激物引發的呼吸暫停反應和肺迷走C纖維放電反應;而此作用是因呼吸道的一連串發炎反應,包括反應性氧衍生物的增加、AMPK的活化和cyclooxygenase代謝產物的釋放所導致。
本論文第二部份的研究,主要探討14天間歇性低氧暴露後是否可擴大化學刺激物引發肺迷走C纖維的反射反應與神經活性,並探討反應性氧衍生物與NADPH oxidase在此呼吸道過度敏感所扮演之角色。清醒大鼠分別暴露於14天空氣、14天間歇性低氧,另在有或無間歇性低氧暴露前每天預處理MnTMPyP (一種superoxide anion驅除劑)、apocynin (一種NADPH oxidase的抑制劑)或是溶劑。於第14天間歇性低氧暴露結束後的16小時,麻醉的大鼠經由頸靜脈注射化學刺激物,辣椒素 (capsaicin)、腺苷酸 (adenosine) 或α,β亞甲基三磷酸腺苷 (α,β-methylene-ATP) 誘發的呼吸暫停反應相較於空氣暴露組更為增強。此增強的反應可以藉由雙側迷走神經截斷或神經周圍辣椒素處理法 (可選擇性阻斷肺迷走C纖維神經的傳導)而消除;另外,14天間歇性低氧暴露後引發的呼吸暫停反應增強,可以藉由每天間歇性低氧暴露前預處理MnTMPyP或apocynin而避免,然而每天預處理抑制劑的溶劑則無此影響。而在電生理實驗中可以看到,14天間歇性低氧暴露後16小時,大鼠麻醉後經由頸靜脈注射化學刺激物可導致肺迷走C纖維放電反應顯著增強,但此增強反應並沒有在7天間歇性低氧暴露後的大鼠觀察到。而若在14天間歇性低氧暴露前每天預處理MnTMPyP或apocynin,則可以有效地抑制經由間歇性低氧造成的肺迷走C纖維放電反應增強的情形。最後,生化檢驗數據的結果顯示,14天間歇性低氧暴露後,代表氧化壓力的脂質過氧化明顯增加,此外代表NADPH oxidase活化指標的細胞膜上p47phox的表現量也顯著的提高。而脂質過氧化增加可以經由預處理MnTMPyP或apocynin而減少;但是細胞膜上p47phox的表現量增加只可以藉由預處理apocynin而消除。綜合上述結果顯示,大鼠於14天間歇性低氧暴露後,可以導致肺迷走C纖維敏感化,進而造成化學刺激物引發的呼吸暫停反應和肺迷走C纖維放電反應增強,此敏感化現象主要是藉由NADPH oxidase活化產生反應性氧衍生物造成。
綜合兩個研究主題結果我們的結論為,間歇性低氧暴露後,經由頸靜脈注射化學刺激物,可導致肺迷走C纖維敏感化,進而擴大化學刺激物引發的呼吸暫停反應。此間歇性低氧引發的敏感化作用,可能是藉由呼吸道一連串發炎物質反應,包含:NADPH oxidase活化產生反應性氧衍生物、AMPK的活化和cyclooxygenase代謝產物的釋放。我們的發現,可進一步地了解阻塞型睡眠呼吸中止病患伴隨高反應性的呼吸道疾病的病理機轉和提供可能的治療方針。
Obstructive sleep apnea (OSA), manifested by airway exposure to intermittent hypoxia (IH), is associated with excess reactive oxygen species (ROS) production in airways, airway inflammation, and hyperreactive airway diseases; however, the cause-effect relationship for these events remains unclear. Lung vagal C fibers (LVCFs), a major type of lung vagal sensory receptors, are known to be sensitive to chemical stimuli. Airway hypersensitivity is characterized by augmented sensory and reflex responses to stimuli because of sensitization of lung afferents, particularly LVCFs, which have been implicated in the development of hyperreactive airway diseases. In fact, IH can cause excess ROS generation via activation of NADPH oxidase, which in turn activates AMP-activated protein kinase (AMPK), a critical regulator of energy, and these events ultimately may lead to promotion of lung inflammation. Accumulating evidence suggests that excess ROS and inflammatory mediators such as cyclooxygenase metabolites may sensitize LVCFs, which then leads to the development of airway hypersensitivity. Accordingly, an experimental model of IH that can induce a cascade of excess ROS, increased inflammatory mediators, and LVCF hypersensitivity is required to study the cause-effect relationship and the underlying mechanism.
Our first study investigated the inflammatory role of ROS-sensitive AMPK in IH-induced airway hypersensitivity mediated by LVCFs in rats. Conscious rats were exposed to room air (RA) or IH with or without treatment with N-acetyl-L-cysteine (NAC, an antioxidant), Compound C (an AMPK inhibitor), ibuprofen (a cyclooxygenase inhibitor), or their vehicles. Immediately after exposure, we found that intravenous capsaicin, phenylbiguanide, or α,β-methylene-ATP evoked augmented LVCF-mediated apneic responses and LVCF afferent responses in rats subjected to 24-h IH exposure in comparison with those in 24-h RA rats. The potentiating effect of IH on LVCF responses decreased at 6 h after and vanished at 12 h after the termination of IH exposure. The potentiating effect of 24-h IH on LVCF-mediated apneic and LVCF afferent responses to chemical stimulants was significantly attenuated by treatment with NAC, compound C, or ibuprofen, but not by their vehicles. Further biochemical analysis revealed that rats exposed to IH for 24 h displayed increased lung levels of lipid peroxidation (an index of oxidative stress), AMPK phosphorylation (an index of AMPK activation), and prostaglandin E2 (a cyclooxygenase metabolite), compared with those exposed to RA for 24 h. 24-h IH-induced increase in lipid peroxidation was considerably suppressed by treatment with NAC but not by compound C or ibuprofen. IH-induced increase in AMPK phosphorylation was totally abolished by NAC or compound C but not by ibuprofen. 24-h IH-induced increase in prostaglandin E2 was considerably prevented by any of these three inhibitor treatments. The vehicles of these inhibitors exerted no significant effect on the three IH-induced responses. These results suggest that 24-h IH exposure sensitizes LVCFs, leading to an exaggerated reflex and afferent responses to chemical stimulants in rats. Moreover, this 24-h IH-induced LVCF sensitization is mediated through a cascade of inflammatory responses in the airways involving increases in ROS, AMPK activation, and cyclooxygenase metabolite release.
Our second study investigated whether 14-day IH augments the reflex and afferent responses of LVCFs to chemical stimulants and the roles of ROS and NADPH oxidase in such airway hypersensitivity. Rats were exposed to room air (RA) or 14-day IH with/without daily treatment with MnTMPyP (a superoxide anion scavenger), apocynin (an NADPH oxidase inhibitor), or vehicle. At 16 h after their last exposure, intravenous capsaicin, adenosine, or α,β-methylene-ATP evoked an augmented apneic response in anesthetized rats with 14-day IH exposure, compared to anesthetized rats with 14-days RA exposure. The augmented apneic responses to these LVCF stimulants were abolished by bilateral vagotomy or perivagal capsaicin treatment, which block LVCFs neural conduction and were significantly suppressed by treatment with MnTMPyP or apocynin, but not vehicle. Electrophysiological studies revealed that 14-day IH exposure potentiated the responses of LVCFs to these stimulants. This effect was inhibited by treatment with MnTMPyP or apocynin treatment and was not seen in rats who received 7-days of IH exposure. Biochemical analysis indicated that 14-day IH exposure increased both lung lipid peroxidation, which is indicative of oxidative stress, and expression of the p47phox subunit in the membrane fraction of lung tissue, which is an index of NADPH oxidase activation. The former was prevented by treatment with either MnTMPyP or apocynin, while the later was prevented by treatment with apocynin only. These results suggest that 14-day IH exposure sensitizes LVCFs in rats, leading to an exaggerated reflex and afferent responses to stimulants and that this sensitization is mediated via ROS generated by NADPH oxidase.
In conclusion, IH exposure sensitizes LVCFs and augments reflex apneic responses to chemical stimulants of LVCFs. This sensitizing effect of IH appears to be mediated through a cascade of inflammatory responses involving action of ROS derived from NADPH oxidase, AMPK activation, and releases of cyclooxygenase metabolites in the airways. Our findings may provide novel information for better understanding of the pathogenic mechanisms of OSA-associated hyperreactive airway diseases and potential therapy.
目錄

中文摘要 i
英文摘要 iv
目錄 vii
圖目錄 xi
表目錄 xiii
壹、緒言 1
貮、文獻回顧及研究目的 4
一、本研究的重要性 4
二、間歇性低氧 5
三、間歇性低氧對生理之影響 6
四、肺迷走感覺神經-肺迷走C纖維 (Lung vagal C-fibers; LVCFs) 7
五、間歇性低氧暴露後引發反應性氧衍生物之產生 10
六、間歇性低氧暴露後引發的發炎物質 12
七、間歇性低氧暴露後引發肺迷走C纖維敏感化之可能機轉 15
八、研究目的 16
參、實驗材料與方法 18
一、第一部份實驗:間歇性低氧藉由反應性氧衍生物誘發肺迷走C纖維敏感化之機轉 18
1、間歇性低氧之暴露 18
2、動物麻醉和基本手術 18
3、呼吸參數之測量 19
4、迷走感覺神經周圍辣椒素處理法 (Perivagal Capsaicin Treatment, PCT) 19
5、單根神經分離與記錄 20
6、心房導管手術 21
7、肺組織脂質過氧化反應之測定 22
8、支氣管肺泡灌洗液 (Bronchoalveolar lavage fluid, BALF) 製備 22
9、酵素連結免疫吸附法 (Enzyme-linked immunosorbent assay, ELISA) 23
10、西方墨點法 (Western blot) 23
11、實驗藥物使用與製備 25
12、實驗設計與組別分配 26
13、數據分析與統計 28
二、第二部分實驗:14天間歇性低氧誘發反應性氧衍生物和造成肺迷走C纖維敏感化之機轉 29
1、間歇性低氧之暴露 29
2、動物麻醉和基本手術 29
3、呼吸參數之測量 30
4、迷走感覺神經周圍辣椒素處理法 (Perivagal Capsaicin Treatment, PCT) 30
5、單根神經分離與記錄 30
6、肺組織脂質過氧化反應之測定 30
7、西方墨點法 (Western blot) 30
8、實驗藥物使用與製備 32
9、實驗設計與組別分配 33
10、數據分析與統計 35
肆、實驗結果 36
一、第一部份實驗:間歇性低氧藉由反應性氧衍生物誘發肺迷走C纖維敏感化之機轉 36
1、基本生理參數 36
2、持續24小時間歇性低氧處理後,肺迷走C纖維在化學刺激物刺激呼吸暫停反應中的角色 36
3、持續24小時間歇性低氧處理後化學刺激物對於肺迷走C纖維反應的影響 37
4、反應性氧衍生物、AMPK和環氧合酶代謝產物在持續24小時間歇性低氧誘發呼吸暫停反應和肺迷走C纖維反應的角色 38
5、持續24小時間歇性低氧暴露後大鼠肺臟脂質過氧化、AMPK磷酸化和PGE2的表現 38
二、第二部分實驗:14天間歇性低氧誘發反應性氧衍生物和造成肺迷走C纖維敏感化之機轉 39
1、基本生理參數 39
2、14天間歇性低氧處理後,肺迷走C纖維在化學刺激物刺激呼吸暫停反應中的角色 40
3、14天間歇性低氧處理後化學刺激物對於肺迷走C纖維反應的影響 40
4、反應性氧衍生物和NADPH oxidase (NOX) 在14天間歇性低氧誘發呼吸暫停反應和肺迷走C纖維反應的角色 41
5、14天間歇性低氧暴露後大鼠肺臟脂質過氧化和p47phox在肺臟的表現 41
伍、討論 43
一、本研究的主要發現 43
二、間歇性低氧藉由反應性氧衍生物誘發肺迷走C纖維敏感化之機轉 45
三、14天間歇性低氧誘發反應性氧衍生物和造成肺迷走C纖維敏感化之機轉 48
四、本研究的生理意義及未來應用 50
五、結論 51
陸、圖表與說明 52
柒、參考文獻 74
捌、附錄 (研究成果) 95

圖目錄

圖一、間歇性低氧處理之氧氣濃度變化 53
圖二、右側頸部迷走神經的單根神經分離與記錄示意圖 54
圖三、實驗裝置及各項生理參數測量之示意圖 55
圖四、兩隻分別持續暴露24小時空氣 (RA) 或間歇性低氧 (IH) 之大鼠對於三種化學刺激物引發的呼吸暫停反應 57
圖五、肺迷走C纖維在間歇性低氧後三種化學刺激物誘發大鼠呼吸暫停反應所扮演的角色 58
圖六、兩隻分別持續暴露24小時空氣 (RA) 或間歇性低氧 (IH) 之大鼠對於三種化學刺激物引發的肺迷走C纖維反應 59
圖七、持續24小時間歇性低氧對肺迷走C纖維敏感化的影響 60
圖八、反應性氧衍生物、AMPK和環氧合酶代謝產物在持續24小時間歇性低氧暴露後三種化學刺激物誘發呼吸暫停反應和肺迷走C纖維反應的角色 61
圖九、持續24小時間歇性低氧暴露後大鼠肺臟脂質過氧化、AMPK磷酸化和PGE2的表現量 62
圖十、兩隻空氣 (RA) 或14天間歇性低氧暴露之大鼠對於三種化學刺激物引發的呼吸暫停反應 64
圖十一、肺迷走C纖維在14天間歇性低氧後三種化學刺激物誘發大鼠呼吸暫停反應所扮演的角色 66
圖十二、兩隻分別暴露空氣 (RA) 或14天間歇性低氧之大鼠對於三種化學刺激物誘發的肺迷走C纖維反應 67
圖十三、14天間歇性低氧對肺迷走C纖維敏感化的影響 68
圖十四、反應性氧衍生物和NADPH oxidase (NOX) 在14天間歇性低氧暴露後三種化學刺激物誘發呼吸暫停反應的角色 69
圖十五、反應性氧衍生物和NADPH oxidase (NOX) 在14天間歇性低氧處理後三種化學刺激物誘發肺迷走C纖維反應的角色 70
圖十六、大鼠肺臟脂質過氧化和p47phox的表現量 71

表目錄

表一、14天空氣或間歇性低氧暴露前與暴露後大鼠的體重變化 72
表二、肺迷走C纖維在不同組別的基礎神經反應 73


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