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研究生：	吳乙柔 Wu, Yi-Rou
論文名稱：	介白素二十四在氣喘性呼吸道重塑過程中的調控角色 The role of interleukin-24 in asthmatic airway remodeling
指導教授：	許育祥 Hsu, Yu-Hsiang
學位類別：	碩士 Master
系所名稱：	醫學院 - 臨床醫學研究所 Institute of Clinical Medicine
論文出版年：	2021
畢業學年度：	109
語文別：	英文
論文頁數：	59
中文關鍵詞：	氣喘、介白素二十四、過敏性發炎反應、呼吸道重塑
外文關鍵詞：	Asthma, IL-24, Allergic inflammation, Airway remodeling
相關次數：	點閱：194 下載：0
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氣喘是一種影響所有年齡段人群的慢性呼吸道疾病。常見的病理變化包括免疫細胞浸潤造成過敏性發炎反應、呼吸道重塑以及支氣管過度收縮痙攣造成之呼吸不順暢、胸悶等臨床症狀。由於氣喘是一種具有高度異質性的疾病，目前的治療方式無法有效地治療全部氣喘患者，因此仍然需要研究潛在致病機制並研發新的治療標的。介白素二十四為具有調節免疫功能的細胞激素，過去文獻證實介白素二十四參與在多種自體免疫病與傷口修復的過程中。近來有臨床研究發現，從氣喘患者的痰液中可以偵測到高量的介白素二十四，然而它在氣喘病程發展中的確切功能仍然是尚未釐清的。因此我的研究目的將探討介白素二十四在過敏性氣喘中的角色以及探討介白素二十四如何調控免疫反應以及呼吸道重塑。首先我利用卵白蛋白作為過敏原來建立氣喘小鼠模式，並且觀察介白素二十四的表現情形。此外我們也利用介白素二十四基因剔除小鼠與野生型小鼠來誘發氣喘小鼠模式，並且藉由分析氣喘症狀與表徵來評估並比較兩者之疾病嚴重程度。利用小鼠的氣管細胞群和人的肺纖維母細胞株來進一步探討介白素二十四的作用與功能。我們研究發現，在小鼠誘發氣喘後，介白素二十四表現量有大幅增加的現象。此外與野生型小鼠相比較下，介白素二十四剔除小鼠在外來過敏原刺激後，其發炎反應是較為輕微的，疾病嚴重程度也趨於和緩。在細胞實驗的部分，介白素二十四透過降低上皮細胞中 ZO-1、claudin 和 occludin 的表達來破壞氣管的緊密連接完整性。介白素二十四促進IL-13 和 Muc5ac 的表達來促進粘液產生。綜合目前的結果，我們證實介白素二十四具有破壞氣管表皮細胞結構以及促進肺纖維母細胞纖維化的功能。這將有助於了解導致過敏性哮喘的潛在機制，並可能為未來治療氣喘提供新的治療靶點。

Asthma is a chronic respiratory disease affecting people of all ages. It is characterized by allergic inflammation, airway remodeling, and hyperresponsiveness. As a highly heterogeneous disease, some patients are refractory to current therapies. Therefore, there are still unmet needs for novel therapeutic agents for treating asthma. Interleukin-24 (IL-24) is an immunoregulatory cytokine that has been proved to be involved in the process of wound healing and several autoimmune disorders. A recent study indicated that IL-24 level was elevated in sputum of asthmatic patients. However, the function of IL-24 in asthma remains unclear. In this study, we aimed to investigate how IL-24 regulates inflammatory cascades and tissue remodeling processes in the pathogenesis of allergic asthma. We established ovalbumin (OVA)-induced asthmatic mouse model. Clinical features and endotypes of asthma were analyzed to evaluate the severity of disease progression between wild type (WT) and IL-24 knockout (KO) mice in OVA-induced asthma model. Our results showed that IL-24 expression was increased in OVA-induced asthmatic mouse model. The level of OVA-specific IgE in serum and airway inflammation were significantly reduced in IL-24 KO mice compared with WT mice in OVA-induced asthmatic model. Ex vivo, IL-24 destructed tight junction integrity of trachea by reducing ZO-1, claudin, and occludin expression in primary tracheal epithelial cells. Additionally, IL-24 also promoted mucus production from trachea epithelial cells by upregulating IL-13 and Muc5ac expression. In vitro, IL-24 exerted a profibrotic effects on lung fibroblasts. Taken together, these findings provide new evidence that IL-24 is involved in the development of allergen-induced airway remodeling and inflammation. Our findings will help us to understand the potential mechanisms leading to the allergic asthma and may provide a novel therapeutic target for treating asthma.

Ⅰ. 中文摘要 I
Ⅱ. Abstract II
Ⅲ. Acknowledgement III
Ⅳ. Abbreviation IV
Ⅴ. Content VI
Ⅵ. Introduction 1
1.Asthma 1
2.Airway inflammation in asthma 2
3.Airway remodeling in asthma 3
4.Monoclonal antibody therapy for asthma 5
5.Cytokine 6
6.IL-24 6
7.Roles of IL-10 family in asthma 9
8.Ovalbumin (OVA)-induced allergic asthma mouse model 10
Ⅶ. Research motivation 11
Ⅷ. Hypothesis and Study design 12
Ⅸ. Materials and Methods 13
1.Animals 13
2.Ovalbumin-induced allergic asthma mouse model 13
3.Blood collection and analysis 13
4.Bronchoalveolar lavage fluid collection and analysis 14
5.Fluorescence-activated cell sorting (FACS) analysis 14
6.Lung tissue collection 14
7.Histology staining and analysis 15
8.Lung tissue homogenates 15
9.Enzyme-linked immunosorbent assay (ELISA) 15
10.RNA isolation and reverse transcription-polymerase chain reaction (RT-PCR) 15
11.Quantification real time polymerase chain reaction (RT-qPCR) 16
12.Western blot 16
13.Physiological evaluation 17
14.Transfection of mouse IL-24-pCMV3-C-His tag into mammalian cells 17
15.Purification of recombinant mouse IL-24 from mammalian cells 18
16.Isolation and primary culture of mouse trachea epithelial cells 18
17.Permeability assay 19
18.Immunofluorescence staining 19
19.Statistical analysis 19
Ⅹ. Results 21
1.OVA induced allergic inflammation and airway remodeling in C57BL/6 mice 21
2.IL-24 expression was increased in OVA-induced asthmatic mouse model 21
3.IL-24 deficiency attenuated OVA-induced allergic airway inflammation 22
4.IL-24 affected the production of IgE in sensitization phase 23
5.Construction and Purification of mouse IL-24 protein 24
6.IL-24 impaired epithelial tight junction integrity of trachea ex vivo 24
7.IL-24 promoted mucus production in tracheal epithelial cells ex vivo 25
8.IL-24 had a profibrotic effect on lung fibroblasts 25
ⅩⅠ. Discussion 27
ⅩⅡ. Tables 33
Table 1. Mouse primer sequences used for RT-qPCR 33
Table 2. Human primer sequences used for RT-qPCR 35
ⅩⅢ. Figures and figure legends 36
Figure 1. OVA induced allergic inflammation and airway remodeling in C57BL/6 mice 37
Figure 2. IL-24 expression was increased in OVA-induced asthmatic mouse model 38
Figure 3. IL-24 deficiency attenuated OVA-induced allergic airway inflammation 41
Figure 4. IL-24 affected the production of IgE in sensitization stage 42
Figure 5. Construction and Purification of mouse IL-24 protein 43
Figure 6. IL-24 impaired epithelial tight junction integrity of trachea ex vivo	45
Figure 7. IL-24 promoted mucus production in tracheal epithelial cells ex vivo 46
Figure 8. IL-24 had a profibrotic effect on lung fibroblasts 47
Figure 9. Working model of IL-24 in allergic asthma 48
ⅩⅣ. References 49
                                    

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