Background: Airway inflammation is the core pathological process of asthma, with the key inflammatory regulators incompletely defined. Recently, fibroblast growth factor 2 (FGF2) has been reported to be an inflammatory regulator; however, its role in asthma remains elusive. This study aimed to investigate the immunomodulatory role of FGF2 in asthma. Methods: First, FGF2 expression was characterised in clinical asthma samples and the house dust mite (HDM)-induced mouse chronic asthma model. Second, recombinant mouse FGF2 (rm-FGF2) protein was intranasally delivered to determine the effect of FGF2 on airway inflammatory cell infiltration. Third, human airway epithelium-derived A549 cells were stimulated with either HDM or recombinant human interleukin-1β (IL-1β) protein combined with or without recombinant human FGF2. IL-1β-induced IL-6 or IL-8 release levels were determined using enzyme-linked immunosorbent assay, and the involved signalling transduction was explored via Western blotting. Results: Compared with the control groups, the FGF2 protein levels were significantly upregulated in the bronchial epithelium and alveolar areas of clinical asthma samples [(6.70±1.79) vs. (16.32±2.40), P=0.0184; (11.20±2.11) vs. (21.00±3.00), P=0.033, respectively] and HDM-induced asthmatic mouse lung lysates [(1.00±0.15) vs. (5.14±0.42), P<0.001]. Moreover, FGF2 protein abundance was positively correlated with serum total and anti-HDM IgE levels in the HDM-induced chronic asthma model (R2=0.857 and 0.783, P=0.0008 and 0.0043, respectively). Elevated FGF2 protein was mainly expressed in asthmatic bronchial epithelium and alveolar areas and partly co-localised with infiltrated inflammatory cell populations in HDM-induced asthmatic mice. More importantly, intranasal instillation of rm-FGF2 aggravated airway inflammatory cell infiltration [(2.45±0.09) vs. (2.88±0.14), P=0.0288] and recruited more subepithelial neutrophils after HDM challenge [(110.20±29.43) cells/mm2 vs. (238.10±42.77) cells/mm2, P=0.0392] without affecting serum IgE levels and Th2 cytokine transcription. In A549 cells, FGF2 was upregulated through HDM stimulation and promoted IL-1β-induced IL-6 or IL-8 release levels [up to (1.41±0.12)- or (1.44±0.14)-fold change vs. IL-1β alone groups, P=0.001 or 0.0344, respectively]. The pro-inflammatory effect of FGF2 is likely mediated through the fibroblast growth factor receptor (FGFR)/mitogen-activated protein kinase (MAPK)/nuclear factor kappa B (NF-κB) pathway. Conclusions: Our findings suggest that FGF2 is a potential inflammatory modulator in asthma, which can be induced by HDM and acts through the FGFR/MAPK/NF-κB pathway in the airway epithelial cells.

Yuan-Yang Tan;Hui-Qin Zhou;Yu-Jing Lin;Liu-Tong Yi;Zhuang-Gui Chen;Qing-Dong Cao;Yan-Rong Guo;Zhao-Ni Wang;Shou-Deng Chen;Yang Li;De-Yun Wang;Yong-Kang Qiao;Yan Yan

Guangdong Provincial Key Laboratory of Biomedical Imaging and Guangdong Provincial Engineering Research Center,the Fifth Affiliated Hospital,Sun Yat-Sen University,Zhuhai 519000,Guangdong,China;Department of Pathology,the Fifth Affiliated Hospital,Sun Yat-Sen University,Zhuhai 519000,Guangdong,China;Department of Pediatrics,the Third Affiliated Hospital,Sun Yat-Sen University,Guangzhou 510630,China;Department of Cardiothoracic Surgery,the Fifth Affiliated Hospital,Sun Yat-Sen University,Zhuhai 519000,Guangdong,China;Department of Otolaryngology,Yong Loo Lin School of Medicine,National University Health System,National University of Singapore,Singapore 119228,Singapore;BGI-Shenzhen,Shenzhen 518083,Guangdong,China;Central Laboratory,the Fifth Affiliated Hospital,Sun Yat-Sen University,Zhuhai 519000,Guangdong,China

军事医学研究（英文）

[1]Yuan-Yang Tan;Hui-Qin Zhou;Yu-Jing Lin;Liu-Tong Yi;Zhuang-Gui Chen;Qing-Dong Cao;Yan-Rong Guo;Zhao-Ni Wang;Shou-Deng Chen;Yang Li;De-Yun Wang;Yong-Kang Qiao;Yan Yan-.FGF2 is overexpressed in asthma and promotes airway inflammation through the FGFR/MAPK/NF-κB pathway in airway epithelial cells)[J].军事医学研究（英文）,2022(06):639-654

FGF2,overexpressed,promotes,airway,inflammation,through,FGFR,MAPK,pathway,cells,Background,Airway,core,pathological,process,key,inflammatory,regulators,incompletely,defined,Recently,fibroblast,growth,has,been,reported,however,its,role,remains,elusive,This,study,aimed,investigate,immunomodulatory,Methods,First,expression,was,characterised,clinical,samples,house,dust,mite,HDM,induced,mouse,chronic,model,Second,recombinant,protein,intranasally,delivered,effect,infiltration,Third,human,epithelium,derived,A549,were,stimulated,either,interleukin,combined,without,release,levels,determined,using,enzyme,linked,immunosorbent,assay,involved,signalling,transduction,explored,via,blotting,Results,Compared,control,groups,significantly,upregulated,bronchial,alveolar,areas,respectively,asthmatic,lung,lysates,Moreover,abundance,positively,correlated,serum,total,anti,IgE,Elevated,mainly,partly,localised,infiltrated,populations,mice,importantly,instillation,aggravated,recruited,more,subepithelial,neutrophils,after,challenge,mm2,affecting,Th2,cytokine,transcription,In,stimulation,promoted,fold,change,alone,likely,mediated,receptor,mitogen,activated,kinase,nuclear,kappa,Conclusions,Our,findings,suggest,that,potential,which,by,acts

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