2026-11-092026-11-09https://scholars.csmu.edu.tw/handle/123456789/38454Airway hyperreactivity (AHR), defined as exaggerated airway responses to various stimuli, is an important feature of asthma and chronic obstructive pulmonary disease. These lung inflammatory diseases cause pulmonary reactive oxygen species (ROS) excess and sensory hypersensitivity. In healthy lungs, lung vagal sensory receptors are primarily responsible for eliciting the defense reflexes in protecting the lungs against inhaled irritants and toxin. Stimulation of these afferents elicits extensive airway reflex responses such as cough, bronchoconstriction, hypersecretion of mucus. When these nerve endings become hypersensitive under pulmonary inflammation, these protective reflexes will become exacerbated and deleterious. Evidently, interfering with the mechanisms involving in this vagal sensory hypersensitivity is possible target choices for potential therapeutic regimes to suppress these exaggerated airway reflexes during lung inflammation. Recently, some studies showed that AHR can be depressed by treatment of antioxidants or reduced of lung sensory nerve function, suggests the involvement of ROS and hypersensitivity of lung vagal sensory receptors in these hyperreactivity. However, neither the ROS lead on AHR by sensitized lung vagal sensory receptors nor the mechanisms underlying this hypersensitivity of these sensory afferents remain to be explored. Among the lung vagal sensory receptors, a subpopulation of unmyelinated C-fibers and some myelinated Ad fibers termed as capsaicin-sensitive lung vagal afferent fibers (CSLAFs), are considered as nociceptive-like free nerve endings. Thus, AHR may develop when the sensitivity of these CSLAFs is enhanced under pathological conditions. It has been reported that various pharmacological receptors, including transient receptor potential vanilloid 1 (TRPV1) receptors and purinoceptors (P1 and P2 receptors), locate on the membrane of nerve terminals of CSLAFs. These pharmacological receptors respond to tussigenic stimuli and are therefore thought to provide the triggering mechanisms for the cough reflex. On the other hand, in inflamed airway tissues or under oxidative stress, various chemical mediators are released to amplify the inflammatory responses. Among them, ATP and its derivative adenosine, prostaglandins and leukotrienes are particular of interest because many lung cells release them under several pathological conditions and because they cause airway hyperreactivity. Indeed, these mediators have been largely implicated in the pathogenesis of asthma or allergic airway. Furthermore, these mediators are also candidates in the pathogenesis of neuropathic pain and other sensory hypersensitivity. We then propose a hypothesis to elucidate the possible neural and mediator mechanisms responsible for the pathogenesis of AHR induced by ROS insult. In this proposed study, we attempt to use a 3-year period to test this hypothesis. Our major goals are 1) to test whether H2O2 enhances the airway reflexes elicited by activation of CSLVAFs; if so, 2) to exam whether this H2O2-induced AHR is resulted from the elevation of the afferent excitability of CSLVAFs; 3) to determine whether this H2O2-induced AHR is specific to some airway stimuli; 4) to investigate and assess the relative contribution of possible TRPV1 receptors, P1 purinoceptors, and P2 purinoceptors to this AHR; 5) to study and assess the relative contribution of possible ATP, adenosine, cyclooxygenase metabolites, and lipoxygenase metabolites to this AHR; 6) to link the types of mediator involved with the types of pharmacological receptors involved in this AHR; 7) to test whether cigarette smoke (an common irritant that generates ROS) insult enhances the airway reflexes and induce sensory hypersensitivity, if so, to investigate whether this CS-induced AHR is through the same pathway with ROS-induced AHR; 8) to study whether endotoxin (an common inflammatory inducer) insult enhances the airway reflexes and induce sensory hypersensitivity, if so, to investigate whether this endotoxin-induced AHR is through the same pathway with ROS-induced AHR. Our preliminary results suggest that 1) H2O2 insult may sensitize CSLVAFs and promote AHR, and 2) hydroxyl radical is one part of the important mechanism responsible for H2O2 induced AHR. Our preliminary results thus suggest the feasibility of this proposal study. It is our hope that the result obtained from this proposed study may advance our knowledge regarding the pathogenetic mechanism of this reactive airway disease and provides potential therapeutic strategies.呼吸道過度反應是氣喘以及慢性阻塞性肺疾病的典型病症。這類病人的呼吸道受到刺激 時，會產生不正常的超大呼吸反應。此類呼吸道發炎的疾病常伴隨有肺中活性氧族群的過量產 生以及肺感覺敏感的現象。肺迷走感覺神經主要的功能是偵測肺中環境變化，以產生咳嗽、呼 吸道收縮、呼吸道黏液分泌等防禦性呼吸反射。然而肺發炎時會造成這些感覺神經變的過度敏 感，使的原本產生的這些保護反射反應被極度擴大，產生許多呼吸病症。因此瞭解肺迷走感覺 神經如何變的感覺敏感具有高度的臨床應用價值，試圖阻斷這類呼吸疾病造成肺迷走感覺神經 過度敏感的路徑或許可以用來減緩呼吸道過度反應。最近的實驗發現，抗氧化劑的處理或是阻 斷肺感覺神經的功能可以減緩肺發炎所產生的呼吸道過度反應，顯示活性氧族群以及肺感覺神 經在造成肺發炎時的呼吸道過度反應上扮演很重要的角色。然而目前仍不清楚是否活性氧族群 會使的肺感覺神經變的敏感，以及其中可能參與的神經與介質機轉為何。在肺中，有一群由C 纖維與少數Ad 纖維構成的肺迷走感覺神經對辣椒素特別地敏感，被稱做〝對辣椒素敏感的肺迷 走感覺神經纖維〞。這一類感覺神經纖維具有類似體表傷害性受器的特性，因此在病理情況下很 可能被感覺敏感化。文獻證實此類感覺神經纖維末稍上含有多種藥理受器，包括辣椒素受器、 嘌呤受器與腺.受器。這些藥理受器接受到刺激可能會引發咳嗽等喉反射。另一方面，在肺發 炎的情況下，組織會釋放出許多化學介質，比如腺嘌呤核.三磷酸與腺.酸、前列腺素與白三 烯素等。這些化學物質已知與氣喘、呼吸道過敏、神經性痛覺敏感等感覺過度疾病有關。綜合 以上原因，本計畫預計花費三年的時間來探討活性氧族群是否會使得肺感覺神經變的敏感而造 成呼吸道的過度反應。我們主要的研究目標是：(一) 觀察過氧化氫是否會使的刺激呼吸道產生 的呼吸反射反應更為擴大；如果會的話，我們將進一步：(二) 確認對辣椒素敏感的肺迷走感覺 神經纖維在過氧化氫造成呼吸道過度反應中的角色；(三) 評估辣椒素受器、嘌呤受器與腺.受 器是否牽涉在此過度反應中；(四) 分別探討腺嘌呤核.三磷酸與腺.酸、環氧化以及脂氧化脢 的代謝產物在這個過度反應中的重要性；(五) 釐清參與此過度反應的介質與受器關係，探討是 哪種化學介質作用哪種受器上。我們的初步結果顯示：(一) 過氧化氫造成呼吸反射反應的擴大 以及對辣椒素敏感的肺迷走感覺神經纖維的放電反應增強，(二) 氫氧自由基參與在此過氧化氫 造成的呼吸道過度反應中。我們的初步結果證實活性氧族群會使得對辣椒素敏感的肺迷走感覺 神經纖維變的敏感而造成呼吸道的過度反應的可能性。此計劃執行後所得的實驗結果，將有助 於我們對呼吸道過度反應疾病的病理成因能有更進一步的瞭解，而提供臨床上治療的參考。氧自由基呼吸道過度反應感覺敏感肺迷走感覺神經oxygen radicalsairway hyperreactivitysensory sensitizationlung vagal sensory receptorsProject