Fibroblast Growth Factor 2 and Transforming Growth Factor β1 Synergism in Human Bronchial Smooth Muscle Cell Proliferation

Bossé, Ynuk; Thompson, C. S.; Staňková, Jana; Rola‐Pleszczynski, Marek

doi:10.1165/rcmb.2005-0309oc

Cited by 69 publications

(78 citation statements)

References 38 publications

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“…Interactions between FGF-2 and TGF-b may also involve postreceptor signal transduction events. For example, the priming of ASM cells with TGF-b enhances the mitogenic effect of FGF-2, because both TGF-b and FGF-2 stimulate increases in the expression of the PDGF receptor and PDGF ligand, respectively (36). However, this type of coordinated response is unlikely to explain the antagonistic effects of FGF-2 on TGF-b-stimulated contractile expression reported here.…”

Section: Discussionmentioning

confidence: 74%

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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Section: Discussionmentioning

confidence: 74%

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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“…Against this beneficial effect on emphysema, however, FGF2 may be harmful through involvement in airway remodeling. FGF2 causes bronchial smooth muscle cell proliferation synergistically with TGF-␤ 1 (8) and bronchial expression, and FGF2 and FGF receptor 1 are enhanced in patients with COPD (24). Another potential adverse effect of FGF2 is pulmonary fibrosis (19).…”

Section: Discussionmentioning

confidence: 99%

Mesenchymal stem cell-conditioned media recovers lung fibroblasts from cigarette smoke-induced damage

Kim

Lee

Kim

et al. 2012

American Journal of Physiology-Lung Cellular and Molecular Phys

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Lee Y-S. Mesenchymal stem cell-conditioned media recovers lung fibroblasts from cigarette smoke-induced damage. Am J Physiol Lung Cell Mol Physiol 302: L891-L908, 2012. First published February 3, 2012 doi:10.1152/ajplung.00288.2011.-Cigarette smoking causes apoptotic death, senescence, and impairment of repair functions in lung fibroblasts, which maintain the integrity of alveolar structure by producing extracellular matrix (ECM) proteins. Therefore, recovery of lung fibroblasts from cigarette smoke-induced damage may be crucial in regeneration of emphysematous lung resulting from degradation of ECM proteins and subsequent loss of alveolar cells. Recently, we reported that bone marrow-derived mesenchymal stem cell-conditioned media (MSC-CM) led to angiogenesis and regeneration of lung damaged by cigarette smoke. In this study, to further investigate reparative mechanisms for MSC-CM-mediated lung repair, we attempted to determine whether MSC-CM can recover lung fibroblasts from cigarette smoke-induced damage. In lung fibroblasts exposed to cigarette smoke extract (CSE), MSC-CM, not only inhibited apoptotic death, but also induced cell proliferation and reversed CSE-induced changes in the levels of caspase-3, p53, p21, p27, Akt, and p-Akt. MSC-CM also restored expression of ECM proteins and collagen gel contraction while suppressing CSE-induced expression of cyclooxygenase-2 and microsomal PGE 2 synthase-2. The CSE-opposing effects of MSC-CM on cell fate, expression of ECM proteins, and collagen gel contraction were partially inhibited by LY294002, a phosphatidylinositol 3-kinase (PI3K) inhibitor. In rats, MSC-CM administration also resulted in elevation of p-Akt and restored proliferation of lung fibroblasts, which was suppressed by exposure to cigarette smoke. Taken together, these data suggest that MSC-CM may recover lung fibroblasts from cigarette smoke-induced damage, possibly through inhibition of apoptosis, induction of proliferation, and restoration of lung fibroblast repair function, which are mediated in part by the PI3K/Akt pathway. cigarette smoking; chronic obstructive pulmonary disease; emphysema CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD), a leading cause of death worldwide, is most often caused by cigarette smoking. COPD is characterized by expiratory airflow limitation that is not fully reversible, accompanying inflammation, and emphysematous destruction of the lung (39). Irrespective of the high incidence and mortality rates for COPD, most current therapies for this disease are supportive, and regenerative therapies to cure emphysema are not available.As a pathophysiological mechanism, proteolytic degradation of extracellular matrix (ECM) by protease activities overwhelming antiprotease activities has long been suspected to be responsible for the emphysematous change seen in patients with COPD (45). Lung fibroblasts are considered crucial for maintenance of the integrity of alveolar structure by producing ECM proteins, including collagen, elastin, and fibronectin, which are required for attach...

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“…Cells were subcultured into 96-well plates at 3,000 cells/well in a starvation medium, consisting of SmBM + 1% FBS, with or without the continued presence of FGF2 (2 ng/ml; unless otherwise specified) as previously described [10]. Cells were maintained in these conditions for 24 h before IL-4, IL-1β, TNFα (PeproTech Canada, Ottawa, Ont., Canada) or IL-13 (R&D, Minneapolis, Minn., USA) stimulations (10 ng/ml; unless otherwise specified).…”

Section: Methodsmentioning

confidence: 99%

“…Moreover, BALF concentrations of FGF2 are further increased following segmental allergen challenge in asthmatics [8], an effect occurring rapidly (10 min) and mediated by FGF2 desequestration from ECM constituents, mast cell degranulation or epithelial cell damage. In addition to its direct effect on BSMC proliferation, recent data from our laboratory have demonstrated that FGF2 pretreatment can confer to TGFβ1 a powerful mitogenic effect [10]. This later study suggested that an autocrine loop involving members of the platelet-derived growth factor (PDGF) family of growth factors and one of their receptor (PDGFRα) takes a significant part in mediating this FGF2-TGFβ1 proliferative synergism.…”

Section: Introductionmentioning

confidence: 99%

Interleukin-4 and Interleukin-13 Enhance Human Bronchial Smooth Muscle Cell Proliferation

Bossé¹,

Thompson²,

Audette³

et al. 2008

Int Arch Allergy Immunol

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Background: T_H2 inflammation and bronchial smooth muscle cell (BSMC) hyperplasia are characteristic features of asthma, but whether these phenomena are linked remains unknown. This study aims to define the effect of the T_H2 cytokines IL-4 and IL-13 on human BSMC proliferation when administered alone or in combination with the fibroblast growth factor 2 (FGF2) growth factor. In addition, the effects of the proinflammatory mediators TNFα and IL-1β and the involvement of members of the well-known family of platelet-derived growth factor (PDGF) mitogens were tested. Methods: BSMC proliferation was measured by crystal violet staining and PDGF and PDGF receptor (PDGFR) expression were determined by RT-PCR, immunocytochemistry, ELISA, flow cytometry and dot plot analysis. Results: Neither IL-4 nor IL-13 alone induced BSMC proliferation, despite both being potent inducers of PDGF-CC. However, following a pretreatment with FGF2, which increased PDGFR α chain expression, both IL-4 and IL-13 increased FGF2-induced BSMC proliferation in a time- and concentration-dependent manner. TNFα and IL-1β did not affect basal or FGF2-induced BSMC proliferation, but both proinflammatory mediators enhanced the proliferative synergism between FGF2 and the T_H2 cytokines. Conclusions: IL-4 and IL-13 potently induce FGF2-primed BSMC proliferation via an autocrine loop involving PDGFRα and PDGF-CC, and this proliferative synergism is amplified by proinflammatory cytokines.

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Fibroblast Growth Factor 2 and Transforming Growth Factor β1 Synergism in Human Bronchial Smooth Muscle Cell Proliferation

Cited by 69 publications

References 38 publications

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

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

Mesenchymal stem cell-conditioned media recovers lung fibroblasts from cigarette smoke-induced damage

Interleukin-4 and Interleukin-13 Enhance Human Bronchial Smooth Muscle Cell Proliferation

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