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

2003 ◽  
Vol 285 (4) ◽  
pp. L931-L939 ◽  
Author(s):  
Michael J. Evans ◽  
Michelle V. Fanucchi ◽  
Gregory L. Baker ◽  
Laura S. Van Winkle ◽  
Lorraine M. Pantle ◽  
...  
Keyword(s):  
Growth Factor ◽  
Basement Membrane ◽  
Fibroblast Growth Factor ◽  
Rhesus Monkeys ◽  
Basement Membrane Zone ◽  
Fibroblast Growth ◽  
Basal Cells ◽  
Functional Changes ◽  
Developmental Problems ◽  
Atypical Development

Development of the basement membrane zone (BMZ) occurs postnatally in the rhesus monkey. 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.

Fibroblast growth factor-2 during postnatal development of the tracheal basement membrane zone

2002 ◽  
Vol 283 (6) ◽  
pp. L1263-L1270 ◽  
Author(s):  
Michael J. Evans ◽  
Michelle V. Fanucchi ◽  
Laura S. Van Winkle ◽  
Gregory L. Baker ◽  
April E. Murphy ◽  
...  
Keyword(s):  
Growth Factor ◽  
Basement Membrane ◽  
Fibroblast Growth Factor ◽  
Structural Changes ◽  
Growth Factor Receptor ◽  
Basement Membrane Zone ◽  
Fibroblast Growth Factor 2 ◽  
Fibroblast Growth ◽  
Basal Cells ◽  
Functional Components

Thickening of the basement membrane zone (BMZ) is a characteristic of several airway diseases; however, very little is known about how this process occurs. The purpose of this study was to define development of the BMZ in the trachea of growing rhesus monkeys at 1, 2, 3, and 6 mo of age. We measured immunoreactivity of collagen types I, III, and V to detect structural changes in the developing BMZ. To detect more dynamic, functional components of the epithelial-mesenchymal trophic unit, we evaluated the distribution of perlecan, fibroblast growth factor-2 (FGF-2), and fibroblast growth factor receptor-1 (FGFR-1). One-month-old monkeys had a mean collagen BMZ width of 1.5 ± 0.7 μm that increased to 4.4 ± 0.4 μm in 6-mo-old monkeys. Perlecan was localized in the BMZ of the epithelium at all ages. FGF-2 was strongly expressed in basal cells at 1–3 mo. At 6 mo, FGF-2 was expressed throughout the BMZ and weakly in basal cells. FGFR-1 immunoreactivity was expressed by basal cells and cilia and weakly in the nuclei of columnar cells at all time points. These data indicate that development of the BMZ is a postnatal event in the rhesus monkey that involves FGF-2.

Inhibition of fibroblast growth factor receptor 3 induces differentiation and apoptosis in t(4;14) myeloma

Blood ◽  
2004 ◽  
Vol 103 (9) ◽  
pp. 3521-3528 ◽  
Author(s):  
Suzanne Trudel ◽  
Scott Ely ◽  
Yildiz Farooqi ◽  
Maurizio Affer ◽  
Davide F. Robbiani ◽  
...  
Keyword(s):  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Fibroblast Growth Factor Receptor ◽  
Growth Factor Receptor ◽  
Myeloma Cell ◽  
Fibroblast Growth ◽  
Genetic Changes ◽  
Functional Changes ◽  
Activating Mutations ◽  
Molecule Inhibitor

Abstract We have previously shown that dysregulation of fibroblast growth factor receptor 3 (FGFR3) by the t(4;14) translocation is a primary event in multiple myeloma (MM) and that activating mutations of FGFR3 are acquired in some cases. We describe here inhibition of wild-type (WT) and constitutively activated mutant FGFR3 autophosphorylation by the small molecule inhibitor, PD173074. Inhibition of FGFR3 in human myeloma cell lines was associated with decreased viability and tumor cell growth arrest. Further, morphologic, phenotypic, and functional changes typical of plasma cell (PC) differentiation, including increase in light-chain secretion and expression of CD31, were observed and this was followed by apoptosis. Finally, using a mouse model of FGFR3 myeloma, we demonstrate a delay in tumor progression and prolonged survival of mice treated with PD173074. These results indicate that inhibition of FGFR3, even in advanced disease associated with multiple genetic changes, may allow the cell to complete its developmental program and render it sensitive to apoptotic signals. In addition, this represents the validation of a therapeutic target in MM that may benefit patients who have a very poor prognosis with currently available treatments. (Blood. 2004;103:3521-3528)

scholarly journals De novo adipogenesis in mice at the site of injection of basement membrane and basic fibroblast growth factor

1998 ◽  
Vol 95 (3) ◽  
pp. 1062-1066 ◽  
Author(s):  
N. Kawaguchi ◽  
K. Toriyama ◽  
E. Nicodemou-Lena ◽  
K. Inou ◽  
S. Torii ◽  
...  
Keyword(s):  
Growth Factor ◽  
Basement Membrane ◽  
Fibroblast Growth Factor ◽  
Basic Fibroblast Growth Factor ◽  
De Novo ◽  
Fibroblast Growth

Heparin affects signaling pathways stimulated by fibroblast growth factor-1 and -2 in type II cells

2004 ◽  
Vol 287 (1) ◽  
pp. L191-L200 ◽  
Author(s):  
Donna R. Newman ◽  
Cheng-Ming Li ◽  
Rebecca Simmons ◽  
Jody Khosla ◽  
Philip L. Sannes
Keyword(s):  
Growth Factor ◽  
Protein Kinase ◽  
Basement Membrane ◽  
Dna Synthesis ◽  
Signaling Pathways ◽  
Fibroblast Growth Factor ◽  
Type Ii ◽  
Fibroblast Growth ◽  
End Points ◽  
Mitogen Activated Protein

Undersulfation of the basement membrane matrix of alveolar type II (AT2) cells compared with that of neighboring type I cells is believed to account for some of the known morphological and functional differences between these pneumocytes. Heparin, a model for sulfated components of basement membrane matrices, is known to inhibit fibroblast growth factor (FGF)-2-stimulated DNA synthesis as well as gene expression of FGF-2 and its receptor in AT2 cells. To determine whether these end points result from specific effects of heparin on FGF-related signaling pathways, isolated rat AT2 cells were treated with 100 ng/ml FGF-1 or FGF-2 in the presence of up to 500 μg/ml heparin. In addition, experiments were done on cells grown in the presence of 20 mM sodium chlorate (sulfation inhibitor). High-dose heparin reduced FGF-1- or FGF-2-stimulated phosphorylation of mitogen-activated protein kinase kinases (MEK1/2), p44/42 mitogen-activated protein kinases (MAPK/ERK1/2), stress-activated protein kinase/c-Jun NH2-terminal kinase, Akt/protein kinase B, and p90RSK. FGF-2-stimulated signaling was more sensitive to heparin's effects than was signaling stimulated by FGF-1. Heparin had an additive effect on the reduced [3H]thymidine incorporation in FGF-2-treated AT2 cells caused by inhibition of the MEK/ERK pathway by the MEK inhibitor PD-98059. The data suggest that heparin's known capacity to alter DNA synthesis and, possibly, other biological end points is realized via cross talk between multiple signaling pathways.

scholarly journals Fibroblast Growth Factor Signaling and Basement Membrane Assembly Are Connected during Epithelial Morphogenesis of the Embryoid Body

2001 ◽  
Vol 153 (4) ◽  
pp. 811-822 ◽  
Author(s):  
Xiaofeng Li ◽  
Yali Chen ◽  
Susanne Schéele ◽  
Esther Arman ◽  
Rebecca Haffner-Krausz ◽  
...  
Keyword(s):  
Growth Factor ◽  
Membrane Proteins ◽  
Basement Membrane ◽  
Fibroblast Growth Factor ◽  
Embryoid Body ◽  
Embryoid Bodies ◽  
Epithelial Morphogenesis ◽  
Growth Factor Signaling ◽  
Fibroblast Growth ◽  
Fibroblast Growth Factor Signaling

Fibroblast growth factors and receptors are intimately connected to the extracellular matrix by their affinity to heparan sulfate proteoglycans. They mediate multiple processes during embryonic development and adult life. In this study, embryonic stem cell–derived embryoid bodies were used to model fibroblast growth factor signaling during early epithelial morphogenesis. To avoid redundancy caused by multiple receptors, we employed a dominant negative mutation of Fgfr2. Mutant-derived embryoid bodies failed to form endoderm, ectoderm, and basement membrane and did not cavitate. However, in mixed cultures they displayed complete differentiation induced by extracellular products of the normal cell. Evidence will be presented here that at least one of these products is the basement membrane or factors connected to it. It will be shown that in the mutant, collagen IV and laminin-1 synthesis is coordinately suppressed. We will demonstrate that the basement membrane is required for embryoid body differentiation by rescuing columnar ectoderm differentiation and cavitation in the mutant by externally added basement membrane proteins. This treatment induced transcription of Eomesodermin, an early developmental gene, suggesting that purified basement membrane proteins can activate inherent developmental programs. Our results provide a new paradigm for the role of fibroblast growth factor signaling in basement membrane formation and epithelial differentiation.

Fibroblast Growth Factor-2 Up-regulates TGF-beta 1&2 In Airway Basal Cells In Situ

2010 ◽  
Author(s):  
Michael Evans ◽  
Lisa A. Miller ◽  
Michelle V. Fanucchi ◽  
Melinda Carlson ◽  
Susan Nishio ◽  
...  
Keyword(s):  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Fibroblast Growth Factor 2 ◽  
Fibroblast Growth ◽  
Basal Cells ◽  
Tgf Beta
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