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研究生:蔡東龍
研究生(外文):Tung-Lung Tsai
論文名稱:咽喉胃酸逆流症引發喉氣道過敏的神經與介質機轉
論文名稱(外文):The Neural and Mediators Mechanisms of Laryngeal Airway Hyperreactivity in Extraesophageal Reflux
指導教授:高毓儒張學逸何青吟吳肇卿
指導教授(外文):Yu Ru KouShyue-Yih ChangChing-Yin HoJaw-Ching Wu
學位類別:博士
校院名稱:國立陽明大學
系所名稱:臨床醫學研究所
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:2009
畢業學年度:97
語文別:英文
論文頁數:133
中文關鍵詞:反射反應增強喉部辣椒素敏感輸入神經纖維氫氧自由基食道胃酸外逆流症腺苷三磷酸活性氧
外文關鍵詞:enhanced reflex reactivitylaryngeal capsaicin-sensitive afferent fibershydroxyl radicalsextraesophageal refluxadenosine 5’-triphosphatereactive oxygen species
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食道外胃酸逆流(extraesophageal reflux, EER)被認為與喉氣道過度敏感(laryngeal airway hyper-reactivity, LAH)有關,但是兩者的因果關係與其中的致病機制尚未被闡明。我們以胃酸侵襲喉部建立增強喉部反射反應的大白鼠動物模式,以研究其中相關的神經與介質機轉。本研究共使用311隻大白鼠,在腹腔注射麻醉下保持自發性呼吸,以手術和插管方法將喉部區段隔離並維持其正常功能,將氨氣通過喉部引發呼吸暫停的反射反應大小當作喉部反應指標以進行實驗。在第一個研究中,我們發現以pH5胃蛋白酶侵襲喉部後此一反射反應約兩倍擴大(喉氣道過敏),但是以pH7.4, pH2胃蛋白酶和pH5-失活胃蛋白酶侵襲喉部後並無反射反應擴大現象。組織局學檢查發現pH5胃蛋白酶侵襲組呈現有限的喉部發炎與表皮受損,但pH2胃蛋白酶侵襲喉部造成最嚴重的傷害現象。在以pH5胃蛋白酶侵襲喉部的大白鼠,氨氣通過喉部所引發的呼吸暫停的反射和喉氣道過敏在上喉神經被切斷或是被神經旁辣椒素處理(perineural capsaicin treatment , PCT:可選擇性阻斷辣椒素敏感性傳入神經纖維)後會被消除,但是不受假性神經旁辣椒素處理所影響。這樣的喉氣道過敏可因喉部預先給予dimethylthiourea(DMTU, 氫氧自由機清除劑)或deferoxamine(DEF, 抗氧化劑)而預防其發生,但是不受到DMTU的載體或是鐵飽和DEF(失效DEF)預處理影響其出現,而且當PCT、DMTU或是DEF預處理的效果消除後,喉氣道過敏會再度出現。從第一個研究的結果顯示:1)喉部受到弱酸性,而非強酸性,胃蛋白酶侵襲才可引發喉氣道過敏,2)這樣的喉氣道過敏可能是經由位於上喉神經中的辣椒素敏感性傳入神經纖維的傳導,而此神經被氫氧自由基敏感化所造成。
氫氧自由基是一種活性氧(reactive oxygen species, ROS)的形式,可由超氧陰離子機(superoxide anion radical)和雙氧水(H2O2)的反應而形成。過去已知過度產生活性氧是組織發炎常見的後果,而活性氧可以促進腺苷三磷酸(adenosine triphosphate, ATP)從細胞中釋出。因此,我們在第二個實驗進一步假設被胃酸或是H2O2侵襲後發炎的喉部,會因為活性氧的增加造成ATP的釋出以活化P2X嘌呤受體,而引發喉氣道過敏。我們發現H2O2侵襲喉部可引發與以pH5胃蛋白酶侵襲喉部相似的喉氣道過敏。H2O2侵襲喉部所引發的喉氣道過敏可被喉部DMTU預處理所預防,可見活性氧的重要角色。以pH5胃蛋白酶或是H2O2侵襲喉部所引發的喉氣道過敏可被喉部ATP清除劑(apyrase和adenosine deaminase混合物)或是P2X受體拮抗劑(iso-pyridoxalphosphate-6-azophenyl-2',5'-disulphonate)預處理所預防。當喉部直接給予P2X受體促效劑(alpha,beta-methylene-ATP)也可以引發喉氣道過敏。以pH5胃蛋白酶或是H2O2侵襲喉部都可以發現在喉部液體ATP濃度增加、喉部組織脂質過氧化(lipid peroxidation)產物的增加以及發炎的現象。從第二個研究的結果顯示:喉部被胃酸或是H2O2侵襲引發發炎反應且在大白鼠喉部產生過多活性氧,喉部過多的活性氧可能因此進一步促進ATP被釋放出來活化2X受體造成辣椒素敏感性傳入神經纖維敏感化而產生喉氣道過敏。
總而言之,我們的研究在食道外胃酸逆流的動物模式上,發現了牽涉喉氣道過敏致病機轉新的神經與介質機制。對此神經與介質機制有調控性物質,可能選擇做為治療食道外胃酸逆流引發喉氣道過敏病患潛在治療處方的標的。
Extraesophageal reflux (EER) is associated with laryngeal airway hyperreactivity (LAH), but neither the cause-effect relationship nor the underlying mechanism has been elucidated. Here we established a rat model with enhanced laryngeal reflex reactivity induced by laryngeal acid-pepsin insult and investigated the neural and mediator mechanisms involved. The laryngeal segments of 311 anesthetized rats were functionally isolated while animals breathed spontaneously. Ammonia vapor was delivered into the laryngeal segment to measure laryngeal reflex reactivity. In the first study, we found that the laryngeal pH5-pepsin treatment doubled the reflex apneic response to ammonia, whereas laryngeal pH7.4-pepsin, pH2-pepsin and pH5-denatured pepsin treatment had no effect. Histological examination revealed limited laryngeal inflammation and epithelial damage after pH5-pepsin treatment and more severe damage after pH2-pepsin treatment. In rats that had received the laryngeal pH5-pepsin treatment, the apneic response to ammonia was abolished by either denervation or perineural capsaicin treatment (PCT; a procedure selectively blocks capsaicin-sensitive afferent fibers) of the superior laryngeal nerves, but was unaffected by perineural sham treatment. LAH was prevented by laryngeal application of either dimethylthiourea [DMTU, a hydroxyl radical (•OH) scavenger] or deferoxamine (DEF, an antioxidant for •OH), but was unaltered by the DMTU vehicle or iron-saturated DEF (ineffective DEF). LAH reappeared after recovery from PCT, DMTU or DEF treatment. The results obtained from the first study suggest that 1) laryngeal insult by pepsin at a weakly acidic pH, but not at acidic pH, can produce LAH and 2) LAH is probably mediated through sensitization of the capsaicin-sensitive laryngeal afferent fibers by a •OH mechanism.
•OH are a major type of reactive oxygen species (ROS) that can be formed by the reaction involving superoxide anion radical and hydrogen peroxide (H2O2). It is known that excess production of ROS is one of the major consequences of tissue inflammation and that ROS may promote the release of ATP from cells. Accordingly, in the second study, we further hypothesized that activation of P2X purinoceptors by ATP subsequent to an increase in ROS induces LAH in an inflamed larynx that has been insulted by acid-pepsin or H2O2. We found that laryngeal insult with acid-pepsin or H2O2 produced LAH with similar characteristics. The H2O2-induced LAH was prevented by laryngeal pretreatment with dimethylthiourea (a •OH scavenger), suggesting a critical role for ROS. The LAH induced by both insults were completely prevented by ATP scavengers (a combination of apyrase and adenosine deaminase) or a P2X receptor antagonist (iso-pyridoxalphosphate-6-azophenyl-2',5'-disulphonate). Laryngeal application of a P2X receptor agonist (alpha,beta-methylene-ATP) also produced LAH. An insult with either acid-pepsin or H2O2 similarly promoted an increase in the levels of ATP, lipid peroxidation and inflammation in the larynx. The results of the second study suggest that laryngeal insult with acid-pepsin or H2O2 induces inflammation and produces excess ROS in the rat's larynx. The latter may in turn promote the release of ATP to activate P2X receptors resulting in sensitization of capsaicin-sensitive laryngeal afferent fibers and LAH.
Collectively, our studies revealed novel neural and mediator mechanisms involved in the pathogenesis of LAH in an animal model of EER. Modulations of neural and mediator mechanisms thus are possible target choices for potential therapeutic regimes to treat LAH in EER patients.
English Abstract………………………………………………………i
Chinese Abstract………………………………………………………iv
List of Abbreviations ………………………………………………vi
Introduction……………………………………………………………1
1. Gastroesophageal reflux disease (GERD) and extraesophageal reflux(EER)
1-1 Etiology and prevalence of GERD………………………2
1-2 The classification of GERD……………………………3
1-3 The quality of life in GER and EER patients………4
1-4 Extraesophageal syndromes………………………………5
1-5 New technique and concepts in GERD…………………5
1-6 Controversies in EER’s pathophysiology and treatments……………………………………………………7
2 The laryngeal reflex and possible mechanism of Laryngeal airway hyerreactivity (LAH)
2-1 Laryngeal sensory innervation……………………………9
2-2 Airway and laryngeal reflex………………………………10
2-3 Capsaicin sensitive afferent fibers in the vagal airway afferent………………………………………………………12
2-4 Airway sensory hyperreactivity…………………………13
3 Current Animal model of EER…………………………………14
4 The physiology of reactive oxygen species (ROS) in inflammation……………………………………………………………15
5 The role of ROS and ATP in sensory sensitization……19
5-1 Vagal sensory fiber response to ROS and ATP…………19
5-2 Evidence of ROS and ATP sensitizing sensory nerve ending……………………………………………………………………20
6 Hypothesis ………………………………………………………21
Material and methods…………………………………………………23
Results…………………………………………………………………35
Discussions……………………………………………………………43
Conclusions……………………………………………………………52
Perspectives……………………………………………………………55
References………………………………………………………………59
Figures and Tables……………………………………………………73
Publications……………………………………………………………98
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