Fibroblast Growth Factor-2 in Remodeling of the Developing Basement Membrane Zone in the Trachea of Infant Rhesus Monkeys Sensitized and Challenged with Allergen

Evans, Michael J.; Winkle, Laura S. Van; Fanucchi, Michelle V.; Baker, Gregory L.; Murphy, April E.; Nishio, Susan J.; Schelegle, Edward S.; Gershwin, Laurel J.; Sannes, Philip L.; Plopper, Charles G.

doi:10.1097/01.lab.0000043911.94235.f3

Cited by 32 publications

(31 citation statements)

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“…Fibroblast growth factor receptor-1 (FGFR-1) was present in basal cells and the nuclei of columnar cells throughout this time period. In rhesus monkeys treated with house dust mite allergen (HDMA) during this period of development, we found significant thickening of the tracheal BMZ (12). Both perlecan and FGF-2 were evenly distributed throughout the thickened BMZ.…”

mentioning

confidence: 69%

Atypical development of the tracheal basement membrane zone of infant rhesus monkeys exposed to ozone and allergen

Evans¹,

Fanucchi²,

Baker³

et al. 2003

American Journal of Physiology-Lung Cellular and Molecular Phys

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The purpose of this study was to determine whether house dust mite allergen (HDMA) plus ozone altered this process. Rhesus monkeys were exposed to a regimen of HDMA and/or ozone or filtered air for 6 mo. To detect structural changes in the BMZ, we measured immunoreactivity of collagen I. To detect functional changes in the BMZ, we measured perlecan and fibroblast growth factor-2 (FGF-2). We also measured components of the FGF-2 ternary signaling complex [fibroblast growth factor receptor-1 (FGFR-1) and syndecan-4]. The width of the BMZ was irregular in the ozone groups, suggesting atypical development of the BMZ. Perlecan was also absent from the BMZ. In the absence of perlecan, FGF-2 was not bound to the BMZ. However, FGF-2 immunoreactivity was present in basal cells, the lateral intercellular space (LIS), and attenuated fibroblasts. FGFR-1 immunoreactivity was downregulated, and syndecan-4 immunoreactivity was upregulated in the basal cells. This suggests that FGF-2 in basal cells and LIS may be bound to the syndecan-4. We conclude that ozone and HDMA plus ozone effected incorporation of perlecan into the BMZ, resulting in atypical development of the BMZ. These changes are associated with specific alterations in the regulation of FGF-2, FGFR-1, and syndecan-4 in the airway epithelial-mesenchymal trophic unit, which may be associated with the developmental problems of lungs associated with exposure to ozone.perlecan; fibroblast growth factor-2; fibroblast growth factor receptor-1; syndecan-4; epithelial-mesenchymal trophic unit THE BASEMENT MEMBRANE ZONE (BMZ) is the central structure of the epithelial-mesenchymal trophic unit. The epithelial-mesenchymal trophic unit consists of opposing layers of epithelial and mesenchymal cells separated by the BMZ (11, 13, 17). The primary trophic unit consists of a layer of basal cells, the BMZ, and the attenuated fibroblast sheath. Recognition of the attenuated fibroblast sheath as a distinct layer of resident fibroblasts is key to the concept of an epithelial-mesenchymal trophic unit. The BMZ has a number of functions in the epithelial-mesenchymal trophic unit. It is specialized for attachment of epithelium with the extracellular matrix; it also serves as a barrier, binds specific growth factors, hormones, and ions, and is involved with electrical charge and cell-cell communication (1,8,40). Binding and storage of growth factors is an important function of the BMZ. The exchange of information between the epithelium and fibroblasts in the epithelial-mesenchymal trophic unit occurs via the BMZ.With transmission electron microscopy, the BMZ appears as three component layers: the lamina lucida, the lamina densa, and the lamina reticularis (LR). Together they make up the basal lamina. The LR is especially pronounced under the respiratory epithelium of large conducting airways, where it may be several micrometers thick. Collagen type I, III, and V form heterogeneous fibers that account for the thickness of the LR. The collagen fibers are arranged as a mat of large fibers orient...

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confidence: 69%

Atypical development of the tracheal basement membrane zone of infant rhesus monkeys exposed to ozone and allergen

Evans¹,

Fanucchi²,

Baker³

et al. 2003

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…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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“…For instance, the normal tracheal epithelium is separated from fibroblasts by a well-defined matrix that exhibits compositional and functional micro-heterogeneity (14,15,(96)(97)(98)(99)(100). Similarly, the term fibroblast does not indicate a single cell type.…”

Section: Comments On the Concepts That Guide Cell-based Therapy A Newmentioning

confidence: 99%

“…Herein, we focus only on the major epithelial cell types. For information on other tracheal cell types, the reader is referred to several excellent papers and reviews (14)(15)(16)(17)(18).…”

Section: Tracheobronchial Epithelial and Intraepithelial Cell Types Mmentioning

confidence: 99%

Lung Epithelial Healing: A Modified Seed and Soil Concept

Reynolds¹,

Brechbuhl²,

Smith³

et al. 2012

Proc Am Thorac Soc

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Airway epithelial healing is defined as restoration of health or soundness; to cure. Our research indicates that two types of progenitor cells participate in this process: the tissue-specific stem cell (TSC) and the facultative basal progenitor (FBP). The TSC restores the epithelium to its normal structure and function. Thus, the TSC regenerates the epithelium. In contrast, the FBP-derived epithelium is characterized by regions of cellular hyperplasia and hypoplasia. Since the FBP-derived epithelium deviates from normal, we term the FBP-mediated process repair. Our work indicates that the TSC responds to signals from other epithelial cells, including the FBP. These signals instruct the TSC to proliferate or to select one of several differentiation pathways. We interpret these data in the context of Stephen Padget's "seed and soil" paradigm. Therein, Padget explained that metastasis of a tumor, the seed, to a specific site, the soil, was determined by the growth and differentiation requirements of the tumor cell. By extending the seed and soil paradigm to airway epithelial healing, we suggest that proliferation and differentiation of the TSC, the seed, is determined by its interactions with other cell types, the soil. Based on this concept, we provide a set of suggestions for development of cell-based therapies that are directed toward chronic airways disease.

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Fibroblast Growth Factor-2 in Remodeling of the Developing Basement Membrane Zone in the Trachea of Infant Rhesus Monkeys Sensitized and Challenged with Allergen

Cited by 32 publications

References 33 publications

Atypical development of the tracheal basement membrane zone of infant rhesus monkeys exposed to ozone and allergen

Atypical development of the tracheal basement membrane zone of infant rhesus monkeys exposed to ozone and allergen

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

Lung Epithelial Healing: A Modified Seed and Soil Concept

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