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研究生:阮婷
研究生(外文):Ting Ruan
論文名稱:活性氧族群於大白鼠肺中感覺訊息傳遞的機制
論文名稱(外文):Mechanisms Underlying the Sensory Transduction of Reactive Oxygen Species in the Rat Lung
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:2005
畢業學年度:94
語文別:中文
論文頁數:118
中文關鍵詞:氧自由基過氧化氫辣椒素受器第二型嘌呤X受器對辣椒素敏感的肺迷走感覺神經受器
外文關鍵詞:oxygen radicalshydrogen peroxideTRPV1 receptorsP2X receptorscapsaicin-sensitive lung vagal afferent fibers
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常見的活性氧族群包括超氧陰離子自由基、過氧化氫以及氫氧自由基。當吸入氧化性刺激物或是肺部處於病理的情況下,肺內的活性氧族群都可能會大量增加而造成肺組織的損傷。呼吸系統主要的感覺神經為肺迷走感覺神經受器,其負責偵測肺部病理與生理的變化,並將此感覺訊息傳遞到中樞,以適時引發保護與防禦性的呼吸反射。目前仍不清楚當肺中活性氧族群增加時,肺迷走感覺神經受器是否能立即偵測出並產生呼吸性防禦反射以減少活性氧族群對於組織的傷害。
肺迷走感覺神經受器依生理特性的不同,被區分成髓鞘神經纖維的慢適應受器、快適應受器以及無髓鞘神經纖維的 C-纖維神經末梢 (C-纖維)。其中,C-纖維與少數快適應受器對於辣椒素特別地敏感,被稱做“對辣椒素敏感的肺迷走感覺神經受器”。由於此類神經受器具有類似體表傷害性受器的特性,對於化學物質很敏感,所以在呼吸性防禦反射中的角色尤其重要。研究發現,此類神經纖維末梢上的辣椒素受器與第二型嘌呤 X 受器在其感覺訊息的轉換與傳遞上扮演重要的功能。本研究的目的是探討當肺中活性氧族群增加時,肺迷走感覺神經受器是否會被興奮並產生呼吸反射?而此感覺訊息傳遞的機轉為何? 為達成這些目的,我們利用呼吸反射與電生理的實驗探討大白鼠吸入霧化過氧化氫所引發呼吸反射的神經與活性氧族群機制,以及在過氧化氫造成對辣椒素敏感的肺迷走感覺神經受器的放電反應中,活性氧族群、辣椒素受器與第二型嘌呤 X 受器在此感覺訊息傳遞中扮演的角色。
我們在呼吸反射的實驗發現,動物吸入霧化的過氧化氫 (0.2 %) 會引發一複雜的呼吸反應,包括初期呼吸頻率減慢與其後產生的延遲性呼吸增快反應。通常呼吸增快反應中還會夾雜擴大吸氣的出現。前人證實,將頸部兩側迷走神經以高濃度辣椒素包圍或是將其冷卻至 7 oC,可以分別選擇地阻斷無髓鞘以及髓鞘迷走神經纖維的傳導。我們發現,給予過氧化氫前若先將迷走神經用辣椒素處理,則過氧化氫引發的初期呼吸減慢反應完全消失,而延遲性呼吸增快反應不但仍舊存在,還會提早顯現;相反的,當兩側迷走神經冷卻至 7 oC 時,過氧化氫造成延遲性呼吸變快與擴大吸氣反應沒有出現,而初期呼吸減慢反應依然存在,而且反應時間延長;在切除兩側迷走神經後,這兩種呼吸反應全部消失;假神經處理則不影響過氧化氫引發的反應。事先處理過氧化氫分解酶、氫氧自由基清除劑或是鐵離子螯合劑等手法,可以完全或部分抑制過氧化氫所引發的這些呼吸反射;然而前處理加熱去活化的過氧化氫分解酶、氫氧自由基清除劑溶劑或是鐵飽和的鐵離子螯合劑並不會影響過氧化氫所造成的呼吸型態改變。我們在電生理的實驗發現,過氧化氫會刺激對辣椒素敏感的肺迷走感覺神經受器,而且其興奮程度與給予過氧化氫的劑量 (0、0.2與0.4 %) 成正比。給予 0.4 % 過氧化氫引發這類感覺神經受器的興奮反應明顯地被事先給予氫氧自由基清除劑或鐵離子螯合劑減緩、被前處理過氧化氫分解酶完全預防,但不受前處理氫氧自由基清除劑的溶劑、鐵飽和的鐵離子螯合劑或是加熱去活化的過氧化氫分解酶影響。此神經放電反應,會被事先單獨給予辣椒素受器拮抗劑或是第二型嘌呤X受器拮抗劑部分減弱;可以被合併給予兩種受器拮抗劑大幅度抑制;但不受前處理這兩種受器拮抗劑的溶劑所影響。吸入香菸 (一種含有活性氧族群的刺激物) 所造成對辣椒素敏感的肺迷走感覺神經受器的興奮反應同樣可以被前處理氫氧自由基清除劑或是合併前處理辣椒素受器拮抗劑與第二型嘌呤X受器拮抗劑部分抑制。
根據以上這些實驗結果,我們推測:(1) 肺迷走無髓鞘與髓鞘感覺神經纖維都能夠偵測到肺中活性氧族群 (尤其是過氧化氫和氫氧自由基) 的過量產生,並引發呼吸性防禦反射。(2) 肺中活性氧族群 (特別是過氧化氫和氫氧自由基) 的增加會刺激對辣椒素敏感的肺迷走感覺神經受器。而此感覺訊息的傳遞是藉由其神經末梢上的辣椒素受器與第二型嘌呤X受器來達成。
Various lung diseases or inhalation of oxidant irritants may cause increased pulmonary production of reactive oxygen species (ROS). The major ROS are the superoxide anion radical, hydrogen peroxide (H2O2), and the hydroxyl radical (∙OH). Lung vagal sensory receptors are known to play an important role in detecting the onset of pathophysiological conditions and are responsible for triggering defensive or protective airway reflexes. Three major types of lung vagal sensory receptors have been classified: slowly adapting receptors, rapidly adapting receptors, and C-fiber nerve endings (C fibers). Afferent activity arising from the first two types is conducted by myelinated fibers, whereas activity from C fibers is conveyed by unmyelinated fibers. Particularly, a subgroup of lung vagal sensory receptors was termed as capsaicin-sensitive lung vagal afferent fibers. These afferent fibers, mainly C fibers and some rapidly adapting receptors, are sensitive to a variety of chemicals or irritants and are considered as nociceptive-like free nerve endings. Previous studies have suggested that the transient receptor potential vanilloid 1 (TRPV1) receptors and the P2X purinoceptors located on the nerve terminals play a role in sensory transduction functions of these afferent fibers. While abundant information suggests the importance of ROS in producing pulmonary pathophysiological consequences, the mechanism underlying the sensory transduction of ROS in the lung by vagal sensory receptors is still not known. Accordingly, the objective of the Study 1 was to delineate the neural and ROS mechanisms underlying the ventilatory responses to aerosolized H2O2 in rats using techniques of reflex investigation. The objective of the Study 2 was to assess the important role of ROS, TRPV1 and P2X receptors in H2O2-induced stimulation of capsaicin-sensitive lung vagal afferent fibers in rats using technique of electrophysiological investigation.
In the Study 1, we found that spontaneous inhalation of 0.2% aerosolized H2O2 acutely evoked initial bradypnea followed by delayed tachypnea which was frequently mixed with delayed augmented inspiration. The initial response was abolished after perivagal capsaicin treatment (PCT), but was prolonged during vagal cooling to 7 °C (VC); PCT and VC are known to differentially block the conduction of unmyelinated C and myelinated fibers, respectively. The delayed responses were eliminated during VC, but emerged earlier after PCT. Vagotomy, catalase (an antioxidant for H2O2), dimethylthiourea (an antioxidant for ∙OH), or deferoxamine (an antioxidant for ∙OH) largely or totally suppressed these reflexive responses, while sham nerve treatment, heat-inactivated catalase, saline vehicle, or iron-saturated deferoxamine failed to do so. In the Study 2, we found that airway challenge of aerosolized H2O2 (0, 0.2 and 0.4 %) produced a concentration-dependant stimulation of these fibers. The fiber responses to 0.4 % H2O2 were significantly attenuated by either dimethylthiourea or deferoxamine, were totally prevented by catalase and were unaffected by the vehicle for dimethylthiourea, iron-saturated deferoxamine or heat-inactivated catalase. The fiber responses to 0.4 % H2O2 were significantly attenuated by either capsazepine (a TRPV1 receptor antagonist) or iso-pyridoxalphosphate-6-azophenyl-2',5'-disulphonate (iso-PPADS, a P2X receptor antagonist), were further reduced by a combination of capsazepine and iso-PPADS, and were unaltered by their vehicles. The fiber responses to cigarette smoke (an irritant generating ROS) were attenuated by dimethylthiourea or capsazepine and iso-PPADS in combination.
Our results obtained from these two rat studies suggest that 1) both lung vagal unmyelinated C afferent fibers and myelinated afferent fibers serve as the sensory system to detect excess ROS, especially H2O2 and ∙OH in the lung and trigger defensive airway reflexes, and 2) ROS, especially H2O2 and ∙OH, may stimulate capsaicin-sensitive vagal lung afferent fibers and that this sensory transduction is mediated through both the TRPV1 and P2X receptors.
中文摘要 I
英文摘要 IV
一、緒言 1
二、文獻回顧及研究目的 5
2.1 本研究的重要性 5
2.2 呼吸反射防禦機轉 6
2.3 肺迷走感覺神經路徑及中樞投射處 7
2.4 肺迷走感覺神經受器與其生理特性 8
2.5 活性氧族群 14
2.6 活性氧族群影響肺迷走感覺神經受器活性之可能性 16
2.7 活性氧族群刺激肺迷走感覺神經受器之可能機制 17
2.8 研究目的 22
三、實驗材料與方法 24
3.1 研究一:呼吸反射實驗 24
3.1.1 動物的麻醉及一般手術 24
3.1.2 心肺生理參數的測量 24
3.1.3 藥物與溶液的製備 25
3.1.4 過氧化氫的遞送系統 26
3.1.5 選擇性阻斷迷走神經的傳導 27
3.1.6 抗氧化劑的前處理 28
3.1.7 實驗步驟 29
3.1.8 資料分析與統計 32
3.2 研究二:電生理實驗 33
3.2.1 動物的麻醉及一般手術 33
3.2.2 心肺生理參數的測量 34
3.2.3 單根神經的分離與記錄 34
3.2.4 肺迷走感覺神經受器的鑑定 35
3.2.5 藥物與溶液的製備 36
3.2.6 過氧化氫的遞送系統 34
3.2.7 煙的製備與遞送系統 37
3.2.8 前處理抗氧化劑 38
3.2.9 前處理受器拮抗劑 38
3.2.10 實驗步驟 39
3.2.11 資料分析與統計 42
四、實驗結果 44
4.1 研究一:呼吸反射實驗 44
4.1.1 過氧化氫引發的呼吸反應 44
4.1.2 迷走神經處理後過氧化氫引發的呼吸反應 45
4.1.3 抗氧化劑處理後過氧化氫引發的呼吸反應 46
4.1.4 過氧化氫引發的血壓變化 46
4.1.5 肺乾濕重與組織病理切片 47
4.2 研究二:電生理實驗 47
4.2.1 對辣椒素敏感的肺迷走感覺神經受器的生理特性 47
4.2.2 過氧化氫引發的神經放電反應 47
4.2.3 活性氧族群在過氧化氫引發神經放電反應中的角色 48
4.2.4 辣椒素受器與第二型嘌呤X類受器在過氧化氫引發神經放電反應中的角色 48
4.2.5 過氧化氫引發的心肺反應 49
4.2.6 活性氧族群、辣椒素受器與第二型嘌呤X類受器在煙引發神經放電反應中的角色 49
五、討論 51
5.1 本研究的主要發現 51
5.2 過氧化氫引發呼吸反射的生理機轉 52
5.3 過氧化氫引發神經放電的生理機轉 56
5.4 過氧化氫引發的心肺反應 57
5.5 本研究的生理意義 59
5.6 結論 59
六、圖表及說明 61
七、參考文獻 107
八、附錄
九、研究成果
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