Epithelial expression and release of FGF-2 from heparan sulphate binding sites in bronchial tissue in asthma

Shute, Janis K.; Solic, Nicola; Shimizu, Judith A.; McConnell, W.T.; Redington, Anthony E.; Howarth, Peter H.

doi:10.1136/thx.2002.002626

Cited by 58 publications

(56 citation statements)

References 31 publications

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“…We have also found expression of Fgf2 mRNA in both mouse and human lung epithelial cells and inflammatory cells, but not in fibroblasts, which is consistent with prior reports (20,(22)(23)(24)(25)(26)(27)(28)(29)(30). Our data support a model in which FGF2 expression is increased primarily in inflammatory cells, thus facilitating its delivery to areas of injury.…”

Section: Fgf2 and Pulmonary Fibrosissupporting

confidence: 82%

“…Other studies have shown FGF2 staining in IPF lungs localized to the endothelium and areas of angiogenesis (21). In response to bleomycin, immunohistochemical staining of mouse lungs localized FGF2 to inflammatory cells, including macrophages (22,23) and mast cells (20,(24)(25)(26), as well as airway epithelial cells (27)(28)(29)(30). Recent studies describe decreased levels of Fgf2 mRNA in lungs from a large cohort of patients with IPF (31), but the temporal and spatial pattern of Fgf2 expression and signaling remains unclear in early versus late stages of disease.…”

Section: Clinical Relevancementioning

confidence: 99%

See 1 more Smart Citation

Fibroblast Growth Factor 2 Is Required for Epithelial Recovery, but Not for Pulmonary Fibrosis, in Response to Bleomycin

Guzy

Stoilov

Elton³

et al. 2015

Am J Respir Cell Mol Biol

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The pathogenesis of pulmonary fibrosis involves lung epithelial injury and aberrant proliferation of fibroblasts, and results in progressive pulmonary scarring and declining lung function. In vitro, fibroblast growth factor (FGF) 2 promotes myofibroblast differentiation and proliferation in cooperation with the profibrotic growth factor, transforming growth factor-b1, but the in vivo requirement for FGF2 in the development of pulmonary fibrosis is not known. The bleomycin model of lung injury and pulmonary fibrosis was applied to Fgf2 knockout (Fgf2 2/2) and littermate control mice. Weight loss, mortality, pulmonary fibrosis, and histology were analyzed after a single intranasal dose of bleomycin. Inflammation was evaluated in bronchoalveolar lavage (BAL) fluid, and epithelial barrier integrity was assessed by measuring BAL protein and Evans Blue dye permeability. Fgf2 is expressed in mouse and human lung epithelial and inflammatory cells, and, in response to bleomycin, Fgf2 2/2 mice have significantly increased mortality and weight loss. Analysis of BAL fluid and histology show that pulmonary fibrosis is unaltered, but Fgf2 2/2 mice fail to efficiently resolve inflammation, have increased BAL cellularity, and, importantly, deficient recovery of epithelial integrity. Fgf2 2/2 mice similarly have deficient recovery of club cell secretory protein 1 bronchial epithelium in response to naphthalene. We conclude that FGF2 is not required for bleomycin-induced pulmonary fibrosis, but rather is essential for epithelial repair and maintaining epithelial integrity after bleomycin-induced lung injury in mice. These data identify that FGF2 acts as a protective growth factor after lung epithelial injury, and call into question the role of FGF2 as a profibrotic growth factor in vivo.Keywords: fibroblast growth factor 2; bleomycin; pulmonary fibrosis; lung injury; alveolar epithelial repair Clinical RelevanceFibroblast growth factors (FGFs) and, in particular, FGF2, are implicated in the pathogenesis of pulmonary fibrosis and recovery from airway epithelial cell (AEC) injury; however, the in vivo requirement for FGF2 in the development of pulmonary fibrosis is not known. In this study, we have found that mice lacking FGF2 do not show altered levels of fibrosis in response to bleomycin, indicating that FGF2 is dispensable for the generation of bleomycin-induced pulmonary fibrosis. In addition, we show that FGF2 knockout mice have increased mortality and weight loss in response to bleomycin, accompanied by deficient recovery of mature alveolar epithelium and epithelial barrier function. These findings suggest that FGF2 is required for lung epithelial recovery, that pharmacological inhibition of FGF signaling could impair the response to lung injury, and that FGF2 administration or augmentation may have therapeutic benefit for lung injury.Lung alveolar epithelial cell (AEC) injury can be caused by a variety of insults, including infection, trauma, aspiration, and sepsis. Chronic AEC injury of unknown origin is central to ...

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Section: Fgf2 and Pulmonary Fibrosissupporting

confidence: 82%

Section: Clinical Relevancementioning

confidence: 99%

Fibroblast Growth Factor 2 Is Required for Epithelial Recovery, but Not for Pulmonary Fibrosis, in Response to Bleomycin

Guzy

Stoilov

Elton³

et al. 2015

Am J Respir Cell Mol Biol

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“…The threshold concentration for the effect of FGF-2 on TGF-b-stimulated contractile protein gene expression in our cell model was about 10-100 picomolar, depending on the gene and the concentration of TGF-b. Whether such concentrations of FGF-2 are physiologically (and pathophysiologically) relevant remains unknown, because concentrations of FGF-2 in asthmatic airways have been assessed primarily by immunohistochemistry (14). FGF-2 is largely associated with heparin as an inactive complex.…”

Section: Discussionmentioning

confidence: 99%

“…FGF-2 has potential relevance in asthma, because concentrations of FGF-2 are higher in the airway submucosa and bronchoalveolar lavage fluid of patients with asthma, and increase further after exposure to allergen (13,14). In the airways, FGF-2 is predominantly expressed by epithelial cells, and is also detected in the ECM of the epithelial basement membrane, primarily bound to heparin, an important determinant of FGF-2 activity (14,15). FGF-2 is a potent mitogen of ASM cells in vitro (16), and is thought to play a role in AWR by contributing to ASM-cell hyperplasia.…”

mentioning

confidence: 99%

Transforming Growth Factor–β–Induced Differentiation of Airway Smooth Muscle Cells Is Inhibited by Fibroblast Growth Factor–2

Schuliga¹,

Javeed

Harris³

et al. 2013

Am J Respir Cell Mol Biol

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In asthma, basic fibroblast growth factor (FGF-2) plays an important (patho)physiological role. This study examines the effects of FGF-2 on the transforming growth factor-b (TGF-b)-stimulated differentiation of airway smooth muscle (ASM) cells in vitro. The differentiation of human ASM cells after incubation with TGF-b (100 pM) and/ or FGF-2 (300 pM) for 48 hours was assessed by increases in contractile protein expression, actin-cytoskeleton reorganization, enhancements in cell stiffness, and collagen remodeling. FGF-2 inhibited TGF-b-stimulated increases in transgelin (SM22) and calponin gene expression (n ¼ 15, P , 0.01) in an extracellular signal-regulated kinase 1/2 (ERK1/2) signal transduction-dependent manner. The abundance of ordered a-smooth muscle actin (a-SMA) filaments formed in the presence of TGF-b were also reduced by FGF-2, as was the ratio of F-actin to G-actin (n ¼ 8, P , 0.01). Furthermore, FGF-2 attenuated TGF-b-stimulated increases in ASM cell stiffness and the ASM-mediated contraction of lattices, composed of collagen fibrils (n ¼ 5, P , 0.01). However, the TGF-b-stimulated production of IL-6 was not influenced by FGF-2 (n ¼ 4, P . 0.05), suggesting that FGF-2 antagonism is selective for the regulation of ASM cell contractile protein expression, organization, and function. Another mitogen, thrombin (0.3 U ml 21), exerted no effect on TGF-b-regulated contractile protein expression (n ¼ 8, P . 0.05), a-SMA organization, or the ratio of F-actin to G-actin (n ¼ 4, P . 0.05), suggesting that the inhibitory effect of FGF-2 is dissociated from its mitogenic actions. The addition of FGF-2, 24 hours after TGF-b treatment, still reduced contractile protein expression, even when the TGF-b-receptor kinase inhibitor, SB431542 (10 mM), was added 1 hour before FGF-2. We conclude that the ASM cell differentiation promoted by TGF-b is antagonized by FGF-2. A better understanding of the mechanism of action for FGF-2 is necessary to develop a strategy for therapeutic exploitation in the treatment of asthma.Keywords: airway wall remodeling; a-smooth muscle actin; asthma; cytoskeleton; transgelin Airway wall remodeling (AWR) contributes to airway dysfunction in asthma. AWR comprises an array of persistent tissue structural changes that are thought to occur through a process of injury and dysregulated repair, linked to chronic airway inflammation. Features of AWR include the increased deposition of extracellular matrix (ECM), airway smooth muscle (ASM) hyperplasia and hypertrophy, mucous cell metaplasia, and angiogenesis (1). The deposition of collagens I and III in the subepithelial layer and within smooth muscle bundles by airway mesenchyma increases airway wall thickness and reduces airway wall distensibility (2, 3). An effective anti-remodeling treatment is expected to reduce airway reactivity and symptoms in asthma (4, 5).Transforming growth factor-b (TGF-b) is an important mediator of AWR in asthma. TGF-b stimulates ASM cells to differentiate into a more contractile and hypertrophic phenotype (6, 7). TGF-b ...

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“…In the lung, bFGF has been shown to be involved in several inflammatory diseases. An increased expression of bFGF has been found in the bronchoalveolar lavage and lung tissue of subjects with bronchial asthma and pulmonary fibrosis [10][11][12]19]. Moreover, bFGF has been implicated in the pathogenesis of sarcoidosis [10] and post-transplant obliterative bronchiolitis [20].…”

mentioning

confidence: 99%

Upregulation of basic fibroblast growth factor in smokers with chronic bronchitis

Guddo¹,

Vignola²,

Saetta³

et al. 2006

Eur Respir J

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The aim of the study was to investigate the expression of basic fibroblast growth factor (bFGF) and its receptor, fibroblast growth factor receptor (FGFR)-1, in the central airways of smokers with chronic bronchitis.The lobar bronchi from 17 subjects undergoing thoracotomy for solitary nodules were examined. All had a history of cigarette smoking, nine had symptoms of chronic bronchitis and airflow limitation, and eight were asymptomatic with normal lung function. Using immunohistochemical methods, bFGF and FGFR-1 expression in the total airway wall and the different airway compartments, i.e. bronchial glands, submucosal vessels and smooth muscle, was quantified. Moreover, to investigate the role of bFGF in angiogenesis, the number of submucosal vessels was quantified.Smokers with chronic bronchitis had an increased bFGF expression in the total airway wall compared with asymptomatic smokers, which was mainly due to bFGF upregulation in bronchial glands. By contrast, the expression of FGFR-1 and the number of submucosal vessels was similar in the two groups of subjects examined.In conclusion, smokers with chronic bronchitis have an increased expression of basic fibroblast growth factor in the central airways, which is mainly due to an increased expression in bronchial glands, suggesting the involvement of this growth factor in the pathogenesis of chronic bronchitis.

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Epithelial expression and release of FGF-2 from heparan sulphate binding sites in bronchial tissue in asthma

Cited by 58 publications

References 31 publications

Fibroblast Growth Factor 2 Is Required for Epithelial Recovery, but Not for Pulmonary Fibrosis, in Response to Bleomycin

Fibroblast Growth Factor 2 Is Required for Epithelial Recovery, but Not for Pulmonary Fibrosis, in Response to Bleomycin

Transforming Growth Factor–β–Induced Differentiation of Airway Smooth Muscle Cells Is Inhibited by Fibroblast Growth Factor–2

Upregulation of basic fibroblast growth factor in smokers with chronic bronchitis

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