臺灣博碩士論文加值系統

氣喘是一種非常複雜的氣道發炎病症，通常認為是由輔助型第二型T細胞誘發抗原特異性IgE及eosinophils大量增加所造成的。然而最近研究在一些類固醇頑固型的慢性氣喘病患中不只eosinophils高且neutrophils也高。然而這類病患可能與輔助型Th17細胞所分泌的IL-17為主，導致neutrophils的發炎。先前的研究發現金針菇免疫調節蛋白FIP-fve會誘使細胞傾向Th1進而減緩OVA所誘發食物過敏與塵蟎所誘發的呼吸道過敏。
本研究以BALB/c小鼠建立由OVA誘導的急慢性氣喘動物模式，並利用所收集肺泡沖洗液經Liu’s染色確定其發炎細胞浸潤的狀況。且進一步探討急慢性動物致敏模式的差異與評估金針菇免疫調節蛋白是否能治療此種慢性氣喘。研究中亦檢測FIP-fve對IL-17上下游相關路徑所誘發eosinophils發炎的影響,並確定FIP-fve或類固醇在慢性氣喘中氣道重塑相關的MMPs、膠原蛋白及黏素等相關導致肺纖維化前趨物質的變化。
藉由研究結果顯示，FIP-fve能顯著改善急慢性期的呼吸道發炎，且FIP-fve不僅是對於IL-4、IL-5、IL-13具有抑制作用其對於Th17與Th22也具有一定的調節。FIP-fve可能透過升高IL-22且同時減少IL-17的方式來改善慢性期呼吸道重塑的狀況。
FIP-fve具有抗發炎的效果且能反轉呼吸道重塑的問題，因此FIP-fve在未來可能可以開發作為過敏疾病的一種輔助藥物。

Asthma is a heterogeneous inflammatory disorder of the airway. Th2 response is usually contributed to high levels of allergen-specific IgE and eosinophilic airway inflammation. Recently, several findings demonstrated that neutrophils, not eosinophils, are the major inflammatory cells in chronic asthma patients with steroid-resistant.FIP-fve is a fungal immunomodulatory protein (FIP) isolated from the fungus Flammulina velutipes that exhibits anti-inflammatory properties on OVA-induced acute food allergy and HDMs-induced airway inflammation. The proposal will focus on the mechanisms of IL-17 axis and their immune-microenvironment in chronic asthma with corticosteroid-resistant.
The first of the study, we will have established the acute asthma model and chronic asthma model with corticosteroid-resistant with female Balb/c mice. We will evaluate the potential therapeutic role of FIP-fve and corticosteroid in an acute or chronic asthma mouse model characterized by increased neutrophils rather than eosinophils using Liu’s staining and BALF cell counts. Moreover, we will confirm that FIP-fve or corticosteroid effect on MMPs, collagen and mucus secretion for airway remodeling in chronic asthma.
According to our results, FIP-fve could improve airway inflammation not only in acute asthma, but also in chronic. FIP-fve could significantly decrease Th2 cytokines (IL-4, IL-5 and IL-13), and regulated Th17 and Th22. FIP-fve may play a role in decrease IL-17 and increase IL-22. Moreover, FIP-fve could also reversed airway remodeling in chronic asthma model.
FIP-fve had anti-inflammatory effects on OVA-induced airway inflammation and an effect to inhibited Th17 cells to reduced airway remodeling and collagen expression. FIP-fve might be a potential alternative therapy for allergic airway diseases.

目錄
謝誌----------------------------------------------------------------------------------I
中文摘要--------------------------------------------------------------------------III
Abstract---------------------------------------------------------------------------IV
第一章 緒論
1.1 氣喘------------------------------------------------------------------------1
1.2 氣喘的現況---------------------------------------------------------------5
1.3 氣喘的特徵---------------------------------------------------------------6
1.4 金針菇免疫調節蛋白---------------------------------------------------7
第二章 研究動機
2.1研究動機與目的---------------------------------------------------------9
第三章 材料與方法
3.1 金針菇免疫調節蛋白FIP-fve的純化
3.1.1 金針菇免疫調節蛋白的萃取與純化----------------------10
3.1.2 SDS-聚丙烯醯銨電泳法(SDS-polyacrylamide slab gel electrophoresis) ----------------------------------------------11
3.2 實驗動物---------------------------------------------------------------13
3.3 OVA雞卵蛋白致敏模式
3.3.1 急性期致敏動物模式----------------------------------------14
3.3.2 慢性期致敏模式的起頭104天與分組--------------------15
3.3.3 76天慢性期致敏模式的確立與分組----------------------16
3.4 實驗動物脾臟細胞的取得與培養---------------------------------17
3.5 血清中IgE、IgG2a測定---------------------------------------------17
3.6 肺泡沖洗液中血球的分類計數------------------------------------19
3.7 脾臟細胞、血清與細胞沖洗液中各種細胞激素的測定-- ----20
3.8 MMP家族之檢測------------------------------------------------------21
3. 9 肺部組織病理切片--------------------------------------------------21
3.10 統計分析-------------------------------------------------------------21
第四章 結果
4.1 FIP-fve 純化結果-----------------------------------------------------23
4.2急性期OVA致敏動物模式的建立與FIP-fve在急性期的療效
評估及實驗分組-------------------------------------------------------24
4.2.1 FIP-fve對於急性期OVA致敏鼠在呼吸道過度反應上的
影響---------------------------------------------------------------25
4.2.2 FIP-fve對於急性期OVA致敏鼠在血清中OVA-specific
antibodies的表現----------------------------------------------25
4.2.3 FIP-fve對於急性期OVA致敏鼠在呼吸道發炎細胞浸潤
上的影響---------------------------------------------------------26

4.2.4 FIP-fve對於急性期OVA致敏鼠在肺泡沖洗液中Th2細
胞激素的影響---------------------------------------------------26
4.2.5 FIP-fve對於急性期OVA致敏鼠在肺泡沖洗液中Th1細
胞激素的影響--------------------------------------------------27
4.2.6 FIP-fve對於急性期OVA致敏鼠在肺泡沖洗液中TGF-
β的影響---------------------------------------------------------27
4.2.7 FIP-fve對於急性期OVA致敏鼠在呼吸道發炎上的影響
---------------------------------------------------------------------27
4.3 慢性期致敏模式的建立與分組------------------------------------29
4.4 76天與104天兩種慢性致敏模式的比較----------------------30
4.4.1 76天與104天兩種慢性致敏模式在AHR上的表現---30
4.4.2 76天與104天兩種慢性致敏模式在血清中IgE與IgG1上的表現-------------------------------------------------------30
4.4.3 76天與104天兩種慢性致敏模式在呼吸道發炎細胞浸潤上的表現量-------------------------------------------------31
4.4.4 76天與104天兩種慢性致敏模式在BALF中各種細胞激素上的表現-------------------------------------------------31
4.5急性期動物模式與慢性期模式的差異----------------------------32
4.5.1急性期與慢性期致敏模式在AHR上的表現-------------33
4.5.2 急性期與慢性期致敏模式在血清中IgE與IgG1的表現
--------------------------------------------------------------------33
4.5.3 急性期與慢性期致敏模式在血清中IgE的time course表現-------------------------------------------------------------34
4.5.4 急性期與慢性期致敏模式在呼吸道細胞浸潤的表現-34
4.5.5 急性期與慢性期致敏模式在BALF中各種細胞激素的表現--------------------------------------------------------------35
4.6急性期與慢性期致敏模式在加入FIP-fve後的表現------------36
4.6.1 FIP-fve對於急性期與慢性期致敏模式在血清中IFN-r的劑量反應效應----------------------------------------------37
4.6.2 FIP-fve對於急性期與慢性期致敏模式在AHR上的影響-------------------------------------------------------------------37
4.6.3 FIP-fve對於急性期與慢性期致敏模式在血清中IgE與IgG2a的表現--------------------------------------------------38
4.6.4 FIP-fve對於急性期與慢性期致敏模式在呼吸道細胞浸潤的影響-------------------------------------------------------38
4.6.5 FIP-fve對於急性期與慢性期致敏模式在BALF中各種細胞激素的影響----------------------------------------------39
4.6.6 FIP-fve對於急性期與慢性期致敏模式在BALF中各種細胞激素的表現(cytokine array的分析) ---------------40
4.7 FIP-fve與corticosteroid對於慢性期致敏鼠呼吸道發炎與呼吸道重塑的影響-----------------------------------------------------41
4.7.1 FIP-fve與corticosteroid對於慢性期致敏鼠在呼吸道過度反應上的影響----------------------------------------------42
4.7.2 FIP-fve與corticosteroid對於慢性期致敏鼠在血清中IgE與IgG2a的影響-------------------------------------------42
4.7.3 FIP-fve與corticosteroid能有效改善慢性期致敏鼠呼吸道中的細胞浸潤----------------------------------------------43
4.7.4 FIP-fve與corticosteroid對於慢性期致敏鼠肺泡沖洗液中Th1/Th2/Treg細胞激素表現的影響------------------43
4.7.5 FIP-fve與corticosteroid對於慢性期致敏鼠在血清或肺泡沖洗液中IL-17, IL-22及MMP9表現的影響---------44
4.7.6 FIP-fve與corticosteroid對於慢性期致敏鼠在脾臟細胞之各種細胞激素的表現-------------------------------------45
4.7.7 FIP-fve與corticosteroid對於慢性致敏鼠在呼吸道發炎現象的影響----------------------------------------------------45
4.7.8 FIP-fve與corticosteroid對於慢性致敏鼠在呼吸道重塑上的影響-------------------------------------------------------46

第五章 討論---------------------------------------------------------------------48
第六章 縮寫表------------------------------------------------------------------57
參考文獻-------------------------------------------------------------------------59
圖表--------------------------------------------------------------------------------75
圖目錄
Figure 1---------------------------------------------------------------------------75
Figure 2---------------------------------------------------------------------------76
Figure 3---------------------------------------------------------------------------78
Figure 4---------------------------------------------------------------------------80
Figure 5---------------------------------------------------------------------------81
Figure 6---------------------------------------------------------------------------82
Figure 7---------------------------------------------------------------------------83
Figure 8---------------------------------------------------------------------------84
Figure 9---------------------------------------------------------------------------85
Figure 10-------------------------------------------------------------------------86
Figure 11-------------------------------------------------------------------------87
Figure 12-------------------------------------------------------------------------88
Figure 13-------------------------------------------------------------------------89
Figure 14-------------------------------------------------------------------------90
Figure 15-------------------------------------------------------------------------91
Figure 16-------------------------------------------------------------------------92
Figure 17-------------------------------------------------------------------------93
Figure 18-------------------------------------------------------------------------94
Figure 19-------------------------------------------------------------------------95
Figure 20-------------------------------------------------------------------------96
Figure 21-------------------------------------------------------------------------97
Figure 22-------------------------------------------------------------------------98
Figure 23-------------------------------------------------------------------------99
Figure 24------------------------------------------------------------------------100
Figure 25------------------------------------------------------------------------101
Figure 26------------------------------------------------------------------------102
Figure 27------------------------------------------------------------------------103
Figure 28------------------------------------------------------------------------104
Figure 29------------------------------------------------------------------------105
Figure 30------------------------------------------------------------------------106
Figure 31------------------------------------------------------------------------107
Figure 32------------------------------------------------------------------------108
Figure 33------------------------------------------------------------------------109
Figure 34------------------------------------------------------------------------110
Figure 35------------------------------------------------------------------------111
Figure 36------------------------------------------------------------------------112
Figure 37------------------------------------------------------------------------113
Figure 38------------------------------------------------------------------------114
表目錄
Table 1---------------------------------------------------------------------------115
Table 2---------------------------------------------------------------------------116
Table 3---------------------------------------------------------------------------117

參考文獻
1.Ranabir Pal, Sanjay Dahal, Shrayan Pal. Prevalence of Bronchial Asthma in Indian Children. Indian J Community Med 2009; 34(4):310-316.
2.Bousquet J, Mantzouranis E, Cruz AA, Aït-Khaled N, Baena-Cagnani CE, Bleecker ER, et. al. Uniform definition of asthma severity, control, and exacerbations: document presented for the World Health Organization Consultation on Severe Asthma. J Allergy Clin Immunol 2010; 126(5):926-38.
3.Holgate ST, Polosa R: Treatment strategies for allergy and asthma. Nat Rev Immunol 2008, 8(3):218-230.

4.Pin I, Gibson PG, Kolendowicz R, Girgis-Gabardo A, Denburg JA, Hargreave FE, and Dolovich J. Use of induced sputum cell counts to investigate airway inflammation in asthma. Thorax. 1995; 47(1):25-29.
5.Sedgwick JB, Calhoun WJ, Gleich GJ, Kita H, Abrams JS, Schwartz LB, Volovitz B, Ben-Yaakov M, and Busse WW. Immediate and late airway response of allergic rhinitis patients to segmental antigen challenge. Characterization of eosinophil and mast cell mediators. Am Rev Respir Dis 1991; 144(6): 1274-1281.
6.Wills-Karp M. Immunologic basis of antigen-induced airway hyperresponsiveness. Annu Rev Immunol. 1999; 17:255-281.
7.Seder RA, Paul WE, Davis MM, and Fazekas de St Groth B. The presence of interleukin 4 during in vitro priming determines the lymphokine-producing potential of CD4+ T cells from T cell receptor transgenic mice. J Exp Med. 1992; 176(4): 1091-1098.
8.Busse WW, Lemanske RF Jr. Asthma. N Engl J Med. 2001; 344(5): 350-362.
9.Romagnani S. Regulation and deregulation of human IgE synthesis. Immunol Today. 1990; 11(9): 316-321.
10.Sutton BJ and Gould HJ. The human IgE network. Nature. 1993; 366(6454): 421-428.
11.Walker C, Bode E, Boer L, Hansel TT, Blaser K and Virchow JC Jr. Allergic and nonallergic asthmatics have distinct patterns of T-cell activation and cytokine production in peripheral blood and bronchoalveolar lavage. Am Rev Respir Dis. 1992; 146(1): 109-115.
12.Burrows B, Martinez FD, Halonen M, Barbee RA and Cline MG. Association of asthma with serum IgE levels and skin-test reactivity to allergens. N Engl J Med. 1989; 320(5):271-277.
13.Metcalfe DD, Baram D, and Mekori YA. Mast cells. Physiol Rev. 1997; 77(4):1033-1079.
14.Wardlaw AJ, Dunnette S, Gleich GJ, Collins JV and Kay AB. Eosinophils and mast cells in bronchoalveolar lavage in subjects with mild asthma. Relationship to bronchial hyperreactivity. Am Rev Respir Dis. 1988; 137(1): 62-69.
15.Wilson RH, Whitehead GS, Nakano H, Free ME, Kolls JK, Cook DN. Allergic sensitization through the airway primes Th17-dependent neutrophilia and airway hyperresponsiveness. Am J Respir Crit Care Med 2009; 180(8):720-30.
16.Steinman L. A brief history of T(H)17, the first major revision in the T(H)1/T(H)2 hypothesis of T cell-mediated tissue damage. Nat Med 2007; 13(2):139-45.
17.Kudo M, Melton AC, Chen C, Engler MB, Huang KE, Ren X, et. al. IL-17A produced by αβ T cells drives airway hyper-responsiveness in mice and enhances mouse and human airway smooth muscle contraction. Nat Med 2012; 18(4):547-54.
18.Zhao J, Lloyd CM, Noble A. Th17 responses in chronic allergic airway inflammation abrogate regulatory T-cell-mediated tolerance and contribute to airway remodeling. Mucosal Immunol 2013; 6(2):335-46.
19.Chung K., Wenzel SE, Brozek JL, Bush A, Castro, Sterk PJ, et. al. International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma. Eur Respir J 2014; 43(2):343-73.
20.Lipworth BJ. Archives of internal medicine., Systemic adverse effects of inhaled corticosteroid therapy: A systematic review and meta-analysis. Arch Intern Med 1999; 159(9):941-55.
21.Umetsu DT, DeKruyff RH. The regulation of allergy and asthma. Immunol Rev 2006; 212:238-55.
22.Koga H, Miyahara N, Fuchimoto Y, Ikeda G, Waseda K, Ono K, et. al. Inhibition of neutrophil elastase attenuates airway hyperresponsiveness and inflammation in a mouse model of secondary allergen challenge: neutrophil elastase inhibition attenuates allergic airway responses. Respir Res 2013; 14(1):8.
23.Chang YC, Chow YH, Sun HL, Liu YF, Lee YT, Lue KH, et. al. Alleviation of respiratory syncytial virus replication and inflammation by fungal immunomodulatory protein FIP-fve from Flammulina velutipes. Antiviral Res 2014; 110:124-31.
24.Chang YC, Hsiao YM, Hung SC, Chen YW, Ou CC, Chang WT, Lue KH, Ko JL. Alleviation of Dermatophagoides microceras-induced allergy by an immunomodulatory protein, FIP-fve, from Flammulina velutipes in mice. Biosci Biotechnol Biochem. 2015;79(1):88-96.
25.Hsieh KY, Hsu CI, Lin JY, Tsai CC, Lin RH. Oral administration of an edible-mushroom-derived protein inhibits the development of food-allergic reactions in mice. Clin Exp Allergy 2003; 33(11):1595-602.
26.衛生福利部網站https://www.mohw.gov.tw
27.Hwang CY, Chen YJ, Lin MW, et al. Prevalence of atopic dermatitis, allergic rhinitis and asthma in Taiwan: a national study 2000 to 2007. Acta Derm Venereol. 2010; 90:589–94.
28.Wu WF, Wan KS, Wang SJ, Yang W, Liu WL. Prevalence, severity, and time trends of allergic conditions in 6-to-7-year-old school children in Taipei. J Investig Allergol Clin Immunol. 2011; 21(7):556-62.
29.Busse WW, Lemanske RF, Jr. Asthma. N Engl J Med. Feb 1 2001; 344(5): 350-362.
30.Ulrik CS. Outcome of asthma: longitudinal changes in lung function. Eur Respir J. 1999; 13 (4): 904-918.
31.El Enshasy HA, Hatti-Kaul R. Mushroom immunomodulators: unique molecules with unlimited applications. Trends Biotechnol. 2013; 23: 668-77.
32.Ko JL, Hsu CI, Lin RH, Kao CL, Lin JY. (1995). Anew fungal immunomodulatory protein, FIP-fve isolated from the edible mushroom, Flammulina velutipes and its complete amino acid sequence. Eur. J. Biochem. 228：244-9.
33.Ou CC, Hsiao YM, Wu WJ, Tasy GJ, Ko JL, Lin MY. FIP-fve stimulates interferon-gamma production via modulation of calcium release and PKC-alpha activation. J Agric Food Chem. 2009; 57(22): 11008-13.
34.Oettgen HC, Geha RS. IgE in asthma and atopy: cellular and molecular connections. J Clin Invest 1999; 104:829-35.
35.Souza MPA, Lima FMDS, Muniz IP, Pereira ÍS, Sousa LRO, Galantini MPL, Santos DPD, Figueiredo TB, Silva RAAD. Ovariectomy Modifies TH2, and TH17 Balance in BALB/C Allergic Mice. Iran J Allergy Asthma Immunol. 2017 Dec;16(6):525-536.
36.Camargo Hizume-Kunzler D, Greiffo FR, Fortkamp B, Ribeiro Freitas G, Keller Nascimento J, Regina Bruggemann T, Melo Avila L, Perini A, Bobinski F, Duarte Silva M, Rocha Lapa F, Paula Vieira R, Vargas Horewicz V, Soares Dos Santos AR, Cattelan Bonorino K. Aerobic Exercise Decreases Lung Inflammation by IgE Decrement in an OVA Mice Model. Int J Sports Med. 2017 Jun;38(6):473-480.
37.Wu HM, Fang L, Shen QY, Liu RY. SP600125 promotes resolution of allergic airway inflammation via TLR9 in an OVA-induced murine acute asthma model. Mol Immunol. 2015; 6:311-6.
38.Ye L, Song D, Jin M, Wang X. Therapeutic roles of telocytes in OVA-induced acute asthma in mice. J Cell Mol Med. 2017 Nov;21(11):2863-2871.
39.Volkov A, Hagner S, Löser S, Alnahas S, Raifer H, Hellhund A, Garn H, Steinhoff U. β5i subunit deficiency of the immunoproteasome leads to reduced Th2 response in OVA induced acute asthma. PLoS One. 2013; 8(4):e60565.
40.He J, Lv L, Wang Z, Huo C, Zheng Z, Yin B, Jiang P, Yang Y, Li J, Gao Y, Xue J. Pulvis Fellis Suis extract attenuates ovalbumin-induced airway inflammation in murine model of asthma. J Ethnopharmacol. 2017 Jul 31;207:34-41.
41.Evelyn Santos Guerra, Chrono K. Lee, Charles A. Specht, Bhawna Yadav, Haibin Huang, Ali Akalin, Jun R. Huh, Christian Mueller, and Stuart M. Levitz. Central Role of IL-23 and IL-17 Producing Eosinophils as Immunomodulatory Effector Cells in Acute Pulmonary Aspergillosis and Allergic Asthma. PLoS Pathog. 2017 Jan; 13(1): e1006175.
42.-Yurany Blanquiceth, Ana Lucia Rodríguez-Perea, Jorge H. Tabares Guevara, Luis Alfonso Correa, María Dulfary Sánchez, José Robinson Ramírez-Pineda, Paula Andrea Velilla. Increase of Frequency and Modulation of Phenotype of Regulatory T Cells by Atorvastatin Is Associated with Decreased Lung Inflammatory Cell Infiltration in a Murine Model of Acute Allergic Asthma. Front Immunol. 2016; 7: 620
43.Henderson WR Jr, Chiang GK, Tien YT, Chi EY. Reversal of allergen-induced airway remodeling by CysLT1 receptor blockade. Am J Respir Crit Care Med. 2006; 173(7):718-28.
44.Ly P. Ngoc, Diane R. Gold, Arthur O. Tzianabos, Scott T. Weiss, Juan C. Celedo´n. Cytokines, allergy, and asthma. Allergy and Clinical Immunology 2005, 5:161–166
45.Nelms K, Keegan AD, Zamorano J, Ryan JJ, P.aul WE. The IL-4 receptor: signaling mechanisms and biologic functions. Annu Rev Immunol 1999; 17:701-38.
46.Barnes, P.J. et al Drugs for asthma. Br J Pharmacol (2006)147 Suppl 1, S297-303.
47.Qian J, Xu Y, Yu Z. Budesonide and Calcitriol Synergistically Inhibit Airway Remodeling in Asthmatic Mice. Can Respir J. 2018.
48.Bunting MM, Shadie AM, Flesher RP, Nikiforova V, Garthwaite L, Tedla N, Herbert C, Kumar RK. Interleukin-33 drives activation of alveolar macrophages and airway inflammation in a mouse model of acute exacerbation of chronic asthma. Biomed Res Int. 2013;2013:250938.
49.Kao ST, Liu CJ, Yeh CC. Protective and immunomodulatory effect of flos Lonicerae japonicae by augmenting IL-10 expression in a murine model of acute lung inflammation. J Ethnopharmacol. 2015;168:108-15.
50.Lin CH, Yeh CH, Lin LJ, Wang JS, Wang SD, Kao ST. The Chinese Herbal Medicine Formula Sheng-Fei-Yu-Chuan-Tang Suppresses Th2 Responses and Increases IFN γ in Dermatophagoides pteronyssinus Induced Chronic Asthmatic Mice. Evid Based Complement Alternat Med. 2013; 2013:984121.
51.Tang X, Nian H, Li X, Yang Y, Wang X, Xu L, Shi H, Yang X, Liu R. Effects of the combined extracts of Herba Epimedii and Fructus Ligustrilucidi on airway remodeling in the asthmatic rats with the treatment of budesonide. 2017; 17(1):380.
52.Alrifai M, Marsh LM, Dicke T, Kılıç A, Conrad ML, Renz H, Garn H. Compartmental and temporal dynamics of chronic inflammation and airway remodelling in a chronic asthma mouse model. PLoS One. 2014 Jan 21;9(1):e85839.
53.Di Meglio P, Perera GK, Nestle FO. The multitasking organ: recent insights into skin immune function. Immunity 2011; 35:857-69.
54.Larche M, Robinson DS, Kay AB. The role of T lymphocytes in the pathogenesis of asthma. J Allergy Clin Immunol 2003; 111(3):450-63.
55.Pennino D, Bhavsar PK, Effner R, Avitabile S, Venn P, Quaranta M, et. al. IL-22 suppresses IFN-γ-mediated lung inflammation in asthmatic patients. J Allergy Clin 2013; 131(2):562-70.
56.Besnard AG, Sabat R, Dumoutier L, Renauld JC, Willart M, Lambrecht B, et. al. Dual Role of IL-22 in allergic airway inflammation and its cross-talk with IL-17A. Am J Respir Crit Care Med 2011; 183(9):1153-63.
57.Sonnenberg GF, Nair MG, Kirn TJ, Zaph C, Fouser LA, Artis D. Pathological versus protective functions of IL-22 in airway inflammation are regulated by IL-17A. J Exp Med 2010; 207(6):1293-305.
58.Takahashi K, Hirose K, Kawashima S, Niwa Y, Wakashin H, Iwata A, et al. IL-22 attenuates IL-25 production by lung epithelial cells and inhibits antigen-induced eosinophilic airway inflammation. J Allergy Clin Immunol. 2011; 128(5):1067-76.
59.Taube C, Tertilt C, Gyülveszi G, Dehzad N, Kreymborg K, Schneeweiss K, et. al. IL-22 is produced by innate lymphoid cells and limits inflammation in allergic airway disease. PLoS One. 2011; 6(7):e21799. 
60.Besnard AG, Sabat R, Dumoutier L, Renauld JC, Willart M, Lambrecht B, et al. Dual Role of IL-22 in allergic airway inflammation and its cross-talk with IL-17A. Am J Respir Crit Care Med. 2011; 183(9):1153-63.
61.Zhao Y, Yang J, Gao YD, Guo W. Th17 immunity in patients with allergic asthma. Int Arch Allergy Immunol 2010; 151(4):297-307.
62.Chang Y, Al-Alwan L, Risse PA, Roussel L, Rousseau S, Halayko AJ, TH17 cytokines induce human airway smooth muscle cell migration. J Allergy Clin Immunol. 2011; 127(4):1046-53.
63.Adan Chari Jirmo, Kathleen Daluege, Christine Happle, Melanie Albrecht, Anna-Maria Dittrich, Mandy Busse, Anika Habener,Jelena Skuljec, Gesine Hansen. IL-27 Is Essential for Suppression of Experimental Allergic Asthma by the TLR7/8 Agonist R848 (Resiquimod). J Immunol. 2016; 197(11): 4219–4227.
64.Xiaoqiong Su, Jue Pan, Fengxi Bai, Honglei Yuan, Nian Dong, Dandan Li, Xiangdong Wang, Zhihong Chen. IL-27 attenuates airway inflammation in a mouse asthma model via the STAT1 and GADD45γ/p38 MAPK pathways. J Transl Med. 2016; 14: 283.
65.Xie M, Mustovich AT, Jiang Y, Trudeau JB, Ray A, Ray P, Hu H, Holguin F, Freeman B, Wenzel SE. IL-27 and type 2 immunity in asthmatic patients: association with severity, CXCL9, and signal transducer and activator of transcription signaling. J Allergy Clin Immunol. 2015;135(2):386-94.
66.Rabih Halwani, Saleh Al-Muhsen, Al-Jahdali H, Hamid Q. Role of Transforming Growth Factor–b in Airway Remodeling in Asthma. Am J Respir Cell Mol Biol 2011; 44(2):127–33.
67.Al-Alawi M, Hassan T, Chotirmall SH. Transforming growth factor b and severe asthma: A perfect storm. Respir Med 2014; 108(10):1409-23.
68.W. Manuyakorn, “Airway remodelling in asthma: role for mechanical forces,” Asia Pacific Allergy, vol. 4, no. 1, pp. 19–24, 2014.
69.B. N. Davis, A. C. Hilyard, G. Lagna, and A. Hata, “SMAD proteins control DROSHA-mediated microRNA matura- tion,” Nature, vol. 454, no. 7200, pp. 56–61, 2008.
70.R. J. Homer and J. A. Elias, “Airway remodeling in asthma: therapeutic implications of mechanisms,” Physiology, vol. 20, no. 1, pp. 28–35, 2005.
71.Nakawah MO, Hawkins C, Barbandi F. Asthma, chronic obstructive pulmonary disease (COPD), and the overlap syndrome. J Am Board Fam Med. 2013; 26(4):470-7.
72.Atkinson, J.J. and Senior, R.M. Matrix metalloproteinase-9 in lung remodeling. Am J Respir Cell Mol Biol. 2003; 28: 12–24.
73.Lin, C.H., Hsiao, Y.M., Ou, C.C., Lin, Y.W., Chiu, Y.L., Lue, K.H. et al. GMI, a Ganoderma immunomodulatory protein, down-regulates tumor necrosis factor alpha-induced expression of matrix metalloproteinase 9 via NF-kappaB pathway in human alveolar epithelial A549 cells. J Agric Food Chem. 2010; 58: 12014–12021.
74.Chen JC, Tsai CC, Hsieh CC, Lan A, Huang CC, Leu SF. Multispecies probiotics combination prevents ovalbumin-induced airway hyperreactivity in mice. Allergol Immunopathol (Madr). 2018.
75.Holt PG. A potential vaccine strategy for asthma and allied atopic diseases during early childhood. Lancet 1994; 344:456–8.
76.Roy K, Mao HQ, Huang SK, Leong KW. Oral gene delivery with chitosan–DNA nanoparticles generates immunologic protection in a murine model of peanut allergy. Nat Med 1999; 5:387–91.