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

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␣ 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

Jun N-Terminal Protein Kinase Enhances Middle Ear Mucosal Proliferation during Bacterial Otitis Media

“…However, in our earlier studies, ERK activation was not well correlated temporally with ME mucosal hyperplasia in an animal model of OM since it occurred very early and very late in OM (24). p38 activation also occurred primarily very early in OM, with peak activation 1 to 6 h after bacterial inoculation (25). Moreover, even at saturating levels of the MAPK kinase (MKK)/ERK inhibitor U0126 or the p38 inhibitor SB203580, mucosal growth was still observed in vitro (24,25).…”

“…We have previously shown that ME mucosal explants from the MEs of rats infected 48 h before dissection with NTHI display permanently enhanced tissue proliferation (see Fig. 1 in reference 24), which can be used as a model for bacterial enhancement of ME mucosal growth (24,25). All explants maintained a healthy appearance and remained firmly attached to the plate surface throughout the duration of the study.…”

“…To evaluate ME mucosal signal transduction in vitro, we used our established model of bacterially induced mucosal proliferation (24,25). In brief, the bullae of male Sprague-Dawley rats weighing 250 to 300 g were injected with NTHI in the manner described above.…”

“…Recent studies in our laboratory investigated the roles of ERK and p38 in OM. It was found that both ERK and p38 can be activated in OM and that inhibition of either the ERK or the p38 pathway can reduce ME mucosal hyperplasia in vitro (24,25). Others have found that p38 inhibition reduces bacterially induced mucin gene expression in human ME epithelial cell lines (14).…”

“…p38 activation also occurred primarily very early in OM, with peak activation 1 to 6 h after bacterial inoculation (25). Moreover, even at saturating levels of the MAPK kinase (MKK)/ERK inhibitor U0126 or the p38 inhibitor SB203580, mucosal growth was still observed in vitro (24,25). This suggests that other pathways are involved in regulating hyperplasia.…”