Abstract
BackgroundAirway 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.MethodsFirst, 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.ResultsCompared 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.ConclusionOur 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.
Highlights
Airway inflammation is the core pathological process of asthma, with the key inflammatory regulators incompletely defined
Our findings suggest that fibroblast growth factor 2 (FGF2) is a potential inflammatory modulator in asthma, which can be induced by house dust mite (HDM) and acts through the FGF receptors (FGFRs)/mitogen-activated protein kinase (MAPK)/NF-κB pathway in the airway epithelial cells
FGF2 is overexpressed in asthmatic bronchial epithelium and alveolar areas To explore the expression pattern of FGF2 in asthmatic lungs, FGF2 expression in lung sections collected from asthmatic and non-asthmatic patients were compared by performing immunofluorescence staining
Summary
Airway inflammation is the core pathological process of asthma, with the key inflammatory regulators incompletely defined. Important is the participation of airway structural cells, that is, the airway epithelial cells (AECs) and airway smooth muscle cells (ASMs), which were initially considered passive responders, but were later considered to be the key immunoregulatory cells in asthma [3]. These resident airway cells are the targets and sources of various inflammatory mediators and crosstalk with immune cells in the perpetuation of chronic inflammation via autocrine or paracrine pathways. We provide evidence on the upregulation of fibroblast growth factor 2 (FGF2), known as basic fibroblast growth factor (bFGF), in both airway-resident cells and inflammatory cell populations in patients with asthma, which may shed light on the mechanisms of airway epithelium-driven inflammation
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