FGF2 is overexpressed in asthma and promotes airway inflammation through the FGFR/MAPK/NF-κB pathway in airway epithelial cells.
FGF2 is overexpressed in asthma and promotes airway inflammation through the FGFR/MAPK/NF-κB pathway in airway epithelial cells.
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FGF2 在哮喘中过度表达，并通过气道上皮细胞中的 FGFR/MAPK/NF-κB 通路促进气道炎症
DOI：
10.1186/s40779-022-00366-3
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发表时间：
2022-01-29
影响因子：
21.1
通讯作者：
Yan Y
中科院分区：
文献类型：
--
作者：
Tan YY;Zhou HQ;Lin YJ;Yi LT;Chen ZG;Cao QD;Guo YR;Wang ZN;Chen SD;Li Y;Wang DY;Qiao YK;Yan Y
气道炎症是哮喘的核心病理过程，但其关键的炎症调节因子尚不完全清楚。最近，成纤维细胞生长因子2（FGF 2）已被报道是一种炎症调节因子，然而，它在哮喘中的作用仍然难以捉摸。本研究旨在探讨成纤维细胞生长因子2在哮喘中的免疫调节作用。首先，在临床哮喘样品和屋尘螨（HDM）诱导的小鼠慢性哮喘模型中表征FGF 2表达。第二，鼻内递送重组小鼠FGF 2（rm-FGF 2）蛋白以确定FGF 2对气道炎性细胞浸润的影响。第三，用HDM或重组人白细胞介素-1 β（IL-1β）蛋白与或不与重组人FGF 2组合刺激人气道上皮来源的A549细胞。采用酶联免疫吸附试验测定IL-1β诱导的IL-6或IL-8释放水平，并通过Western blotting检测所涉及的信号转导。与对照组相比，哮喘患者支气管上皮和肺泡区的FGF 2蛋白水平显著上调（6.70 ± 1.79 vs. 16.32 ± 2.40，P = 0.0184; 11.20 ± 2.11 vs. 21.00 ± 3.00，P = 0.033）和HDM诱导的哮喘小鼠肺裂解物（1.00 ± 0.15 vs. 5.14 ± 0.42，P < 0.001）。此外，在HDM诱导的慢性哮喘模型中，FGF 2蛋白丰度与血清总IgE和抗HDM IgE水平呈正相关（R2分别为0.857和0.783，P = 0.0008和0.0043）。在HDM诱导的哮喘小鼠中，升高的FGF 2蛋白主要表达于支气管上皮和肺泡区域，并且部分与浸润的炎性细胞群共定位。更重要的是，rm-FGF 2鼻内滴注加重了气道炎症细胞浸润（2.45 ± 0.09 vs. 2.88 ± 0.14，P = 0.0288），并在HDM激发后招募更多的上皮下中性粒细胞[（110.20 ± 29.43）个细胞/mm 2与（238.10 ± 42.77）个细胞/mm 2，P = 0.0392]不影响血清IgE水平和Th 2细胞因子转录。在A549细胞中，FGF 2通过HDM刺激上调，并促进IL-1β诱导的IL-6或IL-8释放水平（与单独IL-1β组相比，变化高达1.41 ± 0.12或1.44 ± 0.14倍，P = 0.001或0.0344）。FGF 2的促炎作用可能通过成纤维细胞生长因子受体（FGFR）/促分裂原活化蛋白激酶（MAPK）/核因子κ B（NF-κB）途径介导。本研究结果提示，FGF 2是一种潜在的哮喘炎症调节因子，HDM可诱导FGF 2表达，并通过FGFR/MAPK/NF-κB通路在气道上皮细胞中发挥作用。在线版本包含补充材料，可通过10.1186/s40779-022-00366-3获得。
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. 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. 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. 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. The online version contains supplementary material available at 10.1186/s40779-022-00366-3.
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影响因子：
6.1
作者：
da Silva, J.;Hilzendeger, C.;Louis, R.
通讯作者：
Louis, R.
影响因子：
24.3
作者：
Hinks, Timothy S. C.;Levine, Stewart J.;Brusselle, Guy G.
通讯作者：
Brusselle, Guy G.
影响因子：
14.2
作者：
Moore, Wendy C.;Hastie, Annette T.;Li, Xingnan;Li, Huashi;Busse, William W.;Jarjour, Nizar N.;Wenzel, Sally E.;Peters, Stephen P.;Meyers, Deborah A.;Bleecker, Eugene R.
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Bleecker, Eugene R.
DOI：
10.1164/rccm.200308-1094oc
发表时间：
2004-02-01
影响因子：
24.7
作者：
Johnson, JR;Wiley, RE;Jordana, M
通讯作者：
Jordana, M
影响因子：
14.2
作者：
Djukanovic, R
通讯作者：
Djukanovic, R