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- Furukawa, Masayuki, et al.
(author)
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Jun N-terminal protein kinase enhances middle ear mucosal proliferation during bacterial otitis media
- 2007
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In: Infection and Immunity. - 1098-5522 .- 0019-9567. ; 75:5, s. 2562-2571
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Journal article (peer-reviewed)abstract
- Mucosal hyperplasia is a characteristic component of otitis media. The present study investigated the participation of signaling via the Jun N-terminal protein kinase (JNK) mitogen-activated protein kinase in middle ear mucosal hyperplasia in animal models of bacterial otitis media. Otitis media was induced by the inoculation of nontypeable Haemophilus influenzae into the middle ear cavity. Western blotting revealed that phosphorylation of JNK isoforms in the middle ear mucosa preceded but paralleled mucosal hyperplasia in this in vivo rat model. Nuclear JNK phosphorylation was observed in many cells of both the mucosal epithelium and stroma by immunohistochemistry. In an in vitro model of primary rat middle ear mucosal explants, bacterially induced mucosal growth was blocked by the Rac/Cdc42 inhibitor Clostridium difficile toxin B, the mixed-lineage kinase inhibitor CEP11004, and the JNK inhibitor SP600125. Finally, the JNK inhibitor SP600125 significantly inhibited mucosal hyperplasia during in vivo bacterial otitis media in guinea pigs. Inhibition of JNK in vivo resulted in a diminished proliferative response, as shown by a local decrease in proliferating cell nuclear antigen protein expression by immunohistochemistry. We conclude that activation of JNK is a critical pathway for bacterially induced mucosal hyperplasia during otitis media, influencing tissue proliferation.
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- Palacios, Sean D., et al.
(author)
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Participation of Ras and extracellular regulated kinase in the hyperplastic response of middle-ear mucosa during bacterial otitis media
- 2002
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In: Journal of Infectious Diseases. - : Oxford University Press (OUP). - 0022-1899 .- 1537-6613. ; 186:12, s. 1761-9
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Journal article (peer-reviewed)abstract
- Hyperplasia of middle-ear mucosa (MEM) during otitis media (OM) is thought to be partially mediated by the actions of growth factors and their receptors. The intracellular pathway leading from the small G-protein Ras to the extracellular regulated kinases (Erks) often links growth factor stimulation to cellular proliferation. This study assessed whether this pathway is involved in MEM hyperplasia during bacterial OM via the activation of Erk1/Erk2 in MEM of an in vivo rat bacterial OM model. Activation was maximal at 1 and 6 h and at 1 week after introduction of bacteria into the middle ear. Additionally, an in vitro model of rat MEM in bacterial OM was treated with farnesyl transferase inhibitor 277 or the Mek inhibitor U0126. MEM explants treated with either inhibitor demonstrated significant suppression of bacterially induced growth. These data support a role for Ras and Erk signaling in MEM hyperplasia during bacterial OM.
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- Palacios, Sean D., et al.
(author)
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Role of p38 mitogen-activated protein kinase in middle ear mucosa hyperplasia during bacterial otitis media
- 2004
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In: Infection and Immunity. - 0019-9567 .- 1098-5522. ; 72:8, s. 4662-7
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Journal article (peer-reviewed)abstract
- 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 alpha and p38 beta 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.
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- Ryan, Allen F., et al.
(author)
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Mouse models of induced otitis media
- 2006
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In: Brain Research. - : Elsevier BV. - 0006-8993 .- 1872-6240. ; 1091:1, s. 3-8
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Journal article (peer-reviewed)abstract
- The mouse has seen limited use as a model for experimental otitis media, due primarily to the small size of its middle ear. However, the genetic resources of this species offer substantial potential benefits. These include detailed genomic information, a wealth of genetic models, and gene arrays that represent virtually all mouse genes. This has led to the development of methods for inducing otitis in mice. These include surgical approaches to the middle ear, documentation of the murine middle ear response to various pathogens and inflammatory factors, as well as characterization of induced otitis media in several mouse strains. The results indicate that induced otitis media in the normal mouse is in most respects comparable to that observed in other animal models and in humans. They further suggest that the considerable genetic resources of this species can be harnessed to increase our understanding of this disease.
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