嗜中性白血球性氣喘中的釋網凋亡

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題名:	嗜中性白血球性氣喘中的釋網凋亡 NETosis in Neutrophilic Asthma
作者:	林欣樺 LIN, HSIN-HUA
貢獻者:	醫學科學研究所碩士班郭漢彬
關鍵詞:	嗜中性白血球;氣喘;釋網凋亡 NETosis;Neutrophil extracellular traps;IL-6;IL-6 trans-signaling;Neutrophilic asthma;Clarithromycin
日期:	2023-07-21
上傳時間:	2025-01-06 09:24:52 (UTC+8)
摘要:	氣喘是一個異質性的呼吸道慢性發炎疾病，根據主要參與發炎反應的免疫細胞可分為 type 2-high 和 type 2-low 型，其中 type 2-low 型包含嗜中性球性氣喘，臨床上這類型氣喘的病人通常表現較為嚴重的呼吸道症狀，且對於常規氣喘藥物及吸入型類固醇的治療效果較差。當嗜中性白血球被活化時可能會釋放出一種網狀結構-嗜中性細胞胞外誘捕網，此誘捕網透過細胞毒性酵素的顆粒釋放，破壞病原菌的構造與活性而達到免疫目的，先前文獻指出，許多疾病的嚴重程度和嗜中性細胞胞外誘捕網有關，例如嗜中性球性氣喘。目前的研究已有證據指出白細胞介素-8 會促使嗜中性白血球釋放嗜中性細胞胞外誘捕網，但關於白細胞介素-6 是否也會促使嗜中性細胞胞外誘捕網的產生，並使得嗜中性球性氣喘病人的呼吸道上皮屏障被破壞、症狀加劇，則還不清楚。大環內酯為抗生素的一種，除了作為對抗細菌的用藥之外，目前研究指出這類藥品也具有免疫調節的功能，可以用來治療一些肺部及呼吸道疾病，用於治療氣喘時則是針對非嗜酸性球性氣喘病人效果較佳，且治療後能降低病人體內的嗜中性細胞胞外誘捕網含量，然而目前並沒有證據指出嗜中性球性氣喘病人使用大環內酯類藥物治療是否能透過減少白細胞介素-6 所 2 誘導的嗜中性細胞胞外誘捕網，改善呼吸道上皮屏障的破壞。我們的研究結果指出，嚴重型嗜中性球性氣喘病人的痰液內有明顯較高的白細胞介素-6 受體、白細胞介素-6 和白細胞介素-8，以及嗜中性細胞胞外誘捕網，在使用開羅理黴素 (clarithromycin) 治療過後上述物質都有減少的趨勢，且病人的症狀有顯著的改善。我們也證實了，白細胞介素-6 確實能使嗜中性白血球釋放嗜中性細胞胞外誘捕網，且此誘捕網釋放出來的物質會導致呼吸道上皮細胞的屏障受損，而使用開羅理黴素可以抑制此現象發生。因此我們認為嗜中性球性氣喘病人使用大環內酯類藥物治療可以透過減少白細胞介素-6 所誘導的嗜中性細胞胞外誘捕網改善呼吸道上皮屏障的破壞已減緩症狀。 Asthma is a heterogeneous chronic inflammatory respiratory disease. According to the immune cells mainly involved in the inflammatory response, it can be divided into type 2-high asthma and type 2-low asthma. Type 2-low asthma includes neutrophilic asthma. Patients with neutrophilic asthma typically present with more severe respiratory symptoms and are less responsive to conventional asthma medications and inhaled corticosteroids. When neutrophils are activated, they may release a web-like structure which called neutrophil extracellular traps (NETs), which can destroy the structure and activity of pathogens through the release of cytotoxic enzyme particles. Previous researches showed that the severity of many diseases is related to NETs, such as neutrophilic asthma. Current studies have shown that interleukin (IL)-8 induces the production of NETs from neutrophils, but as to whether IL-6 also promotes the production of NETs and furthermore cause the epithelial barrier of patients with neutrophilic asthma destroyed and the symptoms aggravated is not clear. Macrolides are a type of antibiotics. In addition to being used as drugs against bacteria, current studies have demonstrated that macrolides also have immunomodulatory properties, and can be used to treat some 4 lung diseases. When used to treat asthma, they are aimed at patients with non-eosinophilic asthma have better outcomes, and the content of NETs of those patients can be reduced after treatment. However, there is currently no evidence shows that macrolides treatment could recover airway epithelial barrier disruption resulted from IL-6-induced NETosis on patients with neutrophilic asthma. Our results indicated that the sputum of severe neutrophilic asthmatics had significantly higher levels of IL-6 receptors (IL-6R), IL-6, IL-8, and NETs. These cytokines and NETs tended to decrease after treatment with clarithromycin, and the patients’symptoms were significantly improved. We also demonstrated that IL-6 can induce NETosis, and the NETs caused epithelial disruption, which could be inhibit by clarithromycin. Therefore, we speculate that macrolides decrease symptoms of severe neutrophilic asthmatics via inhibition of NETosis induced by IL-6.
描述:	碩士指導教授：郭漢彬口試委員：郭漢彬口試委員：李枝新口試委員：翁志銘
附註:	論文公開日期：2024-01-23
資料類型:	thesis
顯示於類別:	[醫學科學研究所] 博碩士論文

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