Acidic and basic FGF mRNA expression in the middle ear mucosa during experimental acute and chronic otitis media

Koutnouyan, Hrair A.; Baird, Andrew; Ryan, Allen F.

doi:10.1288/00005537-199403000-00018

Cited by 18 publications

(13 citation statements)

References 24 publications

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“…It should be noted that increased levels of FGF1 and FGF2, as well as their receptors, have previously been demonstrated in experimental acute and chronic OM in the guinea pig [Koutnouyan et al, 1994;Palacios et al, 2002;Ryan and Baird, 1993]. The observation of increased FGF1 expression in these previous studies conflicts with our gene array data from the mouse, which may represent a species difference in the FGF family members that mediate responses in the ME during OM.…”

Section: Discussioncontrasting

confidence: 89%

“…The presence of both FGFs and VEGFs and their receptors during experimental OM has been well documented [Chae et al, 2003;Folkman and Klagsbrun, 1987;Jung et al, 1999;Koutnouyan et al, 1994;Mondain and Ryan, 1995;Ryan and Baird, 1991;Sporn and Roberts, 1991], suggesting that they may be involved in the regulation of angiogenesis. Recombinant VEGF has also been shown to contribute to the development of OM with effusion by increasing vascular permeability of the MEM [Kim et al, 2005].…”

Section: Introductionmentioning

confidence: 93%

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The Role of Vascular Endothelial Growth Factors and Fibroblast Growth Factors in Angiogenesis during Otitis Media

Husseman

Palacios²,

Rivkin³

et al. 2011

Audiol Neurotol

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The middle ear response to otitis media includes transformation and hyperplasia of the mucosal epithelium and subepithelial connective tissue. Significant neovascularization is also noted, which occurs both to support the hypertrophied mucosa and to mediate the increased trafficking of leukocytes. We investigated the role of two known potent angiogenic growth factor families, the fibroblast growth factors (FGFs) and vascular endothelial growth factors (VEGFs), in middle ear mucosal angiogenesis. DNA microarrays were used to evaluate the expression of FGFs and VEGFs, as well as their receptors and unique signaling proteins, in the middle ears of mice undergoing a complete course of acute bacterial otitis media. In addition, a member of each family was introduced to the middle ear submucosal compartment of the normal middle ears of guinea pigs, by a continuous-release osmotic minipump system over 1 week. During the course of bacterial otitis media, a significant regulation of a number of genes important for angiogenesis was identified. Histologic evaluation of middle ear mucosa following micropump infusion of both FGF1 and VEGF-A showed significant angiogenesis at the site of infusion in comparison to control saline infusion. These results support a role for FGFs and VEGFs in the neovascularization of the middle ear mucosa during otitis media, and offer a potential avenue for therapeutic intervention.

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Section: Discussioncontrasting

confidence: 89%

Section: Introductionmentioning

confidence: 93%

The Role of Vascular Endothelial Growth Factors and Fibroblast Growth Factors in Angiogenesis during Otitis Media

Husseman

Palacios²,

Rivkin³

et al. 2011

Audiol Neurotol

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“…This minimal mucosa ranges from 15 to 20 m thick. During otitis media the middle ear mucosa has the unique capacity to grow and proliferate to many times its original thickness, into a highly structured, pseudostratified, columnar epithelial complex (23,25,33,42). Hyperplasia of the mucosa is associated with many of the negative sequelae of middle ear infection.…”

mentioning

confidence: 99%

Role of p38 Mitogen-Activated Protein Kinase in Middle Ear Mucosa Hyperplasia during Bacterial Otitis Media

Palacios¹,

Pak

Rivkin³

et al. 2004

Infect Immun

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Hyperplasia of the middle ear mucosa contributes to the sequelae of acute otitis media. Understanding the signal transduction pathways that mediate hyperplasia could lead to the development of new therapeutic interventions for this disease and its sequelae. Endotoxin derived from bacteria involved in middle ear infection can contribute to the hyperplastic response. The p38 mitogen-activated protein kinase (MAPK) is known to be activated by endotoxin as well as cytokines and other inflammatory mediators that have been documented in otitis media. We assessed the activation of p38 in the middle ear mucosa of an in vivo rat bacterial otitis media model. Strong activity of p38 was observed 1 to 6 h after bacterial inoculation. Activity continued at a lower level for at least 7 days. The effects of p38 activation were assessed using an in vitro model of rat middle ear mucosal hyperplasia in which mucosal growth is stimulated by nontypeable Haemophilus influenzae during acute otitis media. Hyperplastic mucosal explants treated with the p38␣ and p38␤ inhibitor SB203580 demonstrated significant inhibition of otitis media-stimulated mucosal growth. The results of this study suggest that intracellular signaling via p38 MAPK influences the hyperplastic response of the middle ear mucosa during bacterial otitis media.Pathologic conditions related to otitis media include middle ear effusion, adhesive otitis, tympanic membrane perforation, tympanosclerosis, scarring of the middle ear mucosa, cholesteatoma, and atelectasis (4,24,37,38,43,46). These sequelae can lead to permanent damage of the middle ear cavity, resulting in hearing loss or impairment (1). A contributing factor to such morbidity during otitis media is the transformation of the inflamed middle ear mucosa. Normally, the middle ear mucosa consists of a simple squamous epithelium overlying a thin lamina propria that adheres to the underlying periosteum (21). This minimal mucosa ranges from 15 to 20 m thick. During otitis media the middle ear mucosa has the unique capacity to grow and proliferate to many times its original thickness, into a highly structured, pseudostratified, columnar epithelial complex (23,25,33,42). Hyperplasia of the mucosa is associated with many of the negative sequelae of middle ear infection. Production of mucus and other elements of middle ear effusions is closely linked to the production of additional mucosal cells and their transformation into a secretory phenotype (33,51

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“…For example, fibroblast growth factors 1 and 2 (FGF 1 and FGF 2) appear to play a role in the growth, hyperproliferation, and differentiation of the stromal compartment of the ME mucosa during OM, but not the mucosal epithelium [15], [16]. While some studies of epidermal growth factor (EGF), betacellulin, and keratinocyte growth factor (KGF) have implicated them in mucosal epithelial proliferation [17], [18], these represent only a fraction of the growth factors that can influence epithelial cells that might be expressed in the mucosa during OM.…”

Section: Introductionmentioning

confidence: 99%

A Mouse Model of Otitis Media Identifies HB-EGF as a Mediator of Inflammation-Induced Mucosal Proliferation

et al. 2014

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ObjectiveOtitis media is one of the most common pediatric infections. While it is usually treated without difficulty, up to 20% of children may progress to long-term complications that include hearing loss, impaired speech and language development, academic underachievement, and irreversible disease. Hyperplasia of middle ear mucosa contributes to the sequelae of acute otitis media and is of important clinical significance. Understanding the role of growth factors in the mediation of mucosal hyperplasia could lead to the development of new therapeutic interventions for this disease and its sequelae.MethodsFrom a whole genome gene array analysis of mRNA expression during acute otitis media, we identified growth factors with expression kinetics temporally related to hyperplasia. We then tested these factors for their ability to stimulate mucosal epithelial growth in vitro, and determined protein levels and histological distribution in vivo for active factors.ResultsFrom the gene array, we identified seven candidate growth factors with upregulation of mRNA expression kinetics related to mucosal hyperplasia. Of the seven, only HB-EGF (heparin-binding-epidermal growth factor) induced significant mucosal epithelial hyperplasia in vitro. Subsequent quantification of HB-EGF protein expression in vivo via Western blot analysis confirmed that the protein is highly expressed from 6 hours to 24 hours after bacterial inoculation, while immunohistochemistry revealed production by middle ear epithelial cells and infiltrating lymphocytes.ConclusionOur data suggest an active role for HB-EGF in the hyperplasia of the middle ear mucosal epithelium during otitis media. These results imply that therapies targeting HB-EGF could ameliorate mucosal growth during otitis media, and thereby reduce detrimental sequelae of this childhood disease.

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Acidic and basic FGF mRNA expression in the middle ear mucosa during experimental acute and chronic otitis media

Cited by 18 publications

References 24 publications

The Role of Vascular Endothelial Growth Factors and Fibroblast Growth Factors in Angiogenesis during Otitis Media

The Role of Vascular Endothelial Growth Factors and Fibroblast Growth Factors in Angiogenesis during Otitis Media

Role of p38 Mitogen-Activated Protein Kinase in Middle Ear Mucosa Hyperplasia during Bacterial Otitis Media

A Mouse Model of Otitis Media Identifies HB-EGF as a Mediator of Inflammation-Induced Mucosal Proliferation

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