Participation of Ras and Extracellular Regulated Kinase in the Hyperplastic Response of Middle‐Ear Mucosa during Bacterial Otitis Media

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.

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

“…Others have found that p38 inhibition reduces bacterially induced mucin gene expression in human ME epithelial cell lines (14). 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).…”

“…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.…”