The microenvironment of the cochlea is maintained by the barrier between the systemic circulation and the fluids inside the stria vascularis. However, the mechanisms that control the permeability of the intrastrial fluid-blood barrier remain largely unknown. The barrier comprises endothelial cells connected to each other by tight junctions and an underlying basement membrane. In a recent study, we found that the intrastrial fluid-blood barrier also includes a large number of perivascular cells with both macrophage and melanocyte characteristics. The perivascular-resident macrophage-like melanocytes (PVM/Ms) are in close contact with vessels through cytoplasmic processes. Here we demonstrate that PVM/Ms have an important role in maintaining the integrity of the intrastrial fluid-blood barrier and hearing function. Using a cell culture-based in vitro model and a genetically induced PVM/M-depleted animal model, we show that absence of PVM/Ms increases the permeability of the intrastrial fluid-blood barrier to both lowand high-molecular-weight tracers. The increased permeability is caused by decreased expression of pigment epithelial-derived factor, which regulates expression of several tight junction-associated proteins instrumental to barrier integrity. When tested for endocochlear potential and auditory brainstem response, PVM/ M-depleted animals show substantial drop in endocochlear potential with accompanying hearing loss. Our results demonstrate a critical role for PVM/Ms in regulating the permeability of the intrastrial fluid-blood barrier for establishing a normal endocochlear potential hearing threshold. mouse cochlea | paracellular permeability | tight junction | capillary T he intrastrial fluid-blood barrier separates the stria vascularis (SV) from peripheral circulation. The integrity of the barrier is critical for maintaining inner ear homeostasis, especially for sustaining the endocochlear potential (EP), an essential driving force for hearing function (1-4). Disruption of the barrier is closely associated with a number of hearing disorders, including autoimmune inner ear disease, noise-induced hearing loss, agerelated hearing loss, and several genetically linked diseases (5-10). Despite the importance of the intrastrial fluid-blood barrier, little is understood about regulation of the barrier and the mechanisms that control its permeability.In the classic view, the intrastrial fluid-blood barrier comprises basement membrane and endothelial cells (ECs) that connect to each other with tight junctions (11) to form a diffusion barrier that prevents most blood-borne substances from entering the ear (2). In a recent study, we found that the intrastrial fluid-blood barrier also includes a large number of pericytes and perivascular-resident macrophage-like melanocytes (PVM/Ms) (12, 13). The PVM/Ms are not observed in other capillary regions such as in capillary beds of the spiral ligament. The PVM/Ms are in close contact with vessels through cytoplasmic processes. The structural complexity of PVM/Ms' capillar...
All tympanocentesis and blood specimens grew gram-negative Klebsiella oxytoca, which was confirmed by PCR. Histopathology confirmed an intense inflammatory reaction and gram-negative bacteria in the middle and inner ears. Electron microscopy of the middle ears revealed abundant rod-shaped Klebsiella bacteria, both free and being engulfed by neutrophils.
HypothesisThe middle ear contains homeostatic mechanisms that control the movement of ions and fluids similar to those present in the inner ear, and are altered during inflammation.BackgroundThe normal middle ear cavity is fluid-free and air-filled to allow for effective sound transmission. Within the inner ear, the regulation of fluid and ion movement is essential for normal auditory and vestibular function. The same ion and fluid channels active in the inner ear may have similar roles with fluid regulation in the middle ear.MethodsMiddle and inner ears from BALB/c mice were processed for immunohistochemistry of 10 specific ion homeostasis factors to determine if similar transport and barrier mechanisms are present in the tympanic cavity. Examination also was made of BALB/c mice middle ears after transtympanic injection with heat-killed Haemophilus influenza to determine if these channels are impacted by inflammation.ResultsThe most prominent ion channels in the middle ear included aquaporins 1, 4 and 5, claudin 3, ENaC and Na+,K+-ATPase. Moderate staining was found for GJB2, KCNJ10 and KCNQ1. The inflamed middle ear epithelium showed increased staining due to expected cellular hypertrophy. Localization of ion channels was preserved within the inflamed middle ear epithelium.ConclusionsThe middle ear epithelium is a dynamic environment with intrinsic mechanisms for the control of ion and water transport to keep the middle ear clear of fluids. Compromise of these processes during middle ear disease may underlie the accumulation of effusions and suggests they may be a therapeutic target for effusion control.
Objective The middle ear innate immune response to bacteria leads to acute inflammation consisting of fluid accumulation, infiltration of inflammatory cells, and mucosal thickening. Although inflammation from otitis media generally subsides after 5–7 days, suppression of this response would help alleviate suffering and minimize risk to the inner ear. Glucocorticoids and mineralocorticoids have differential effects on inflammation and fluid absorption, but little is known of their control of middle and inner ear manifestations of acute otitis media. Therefore, steroids were investigated for their potential for therapeutic approaches to control of otitis media. Design Both glucocorticoid (prednisolone, dexamethasone) and mineralocorticoid (aldosterone, fludrocortisone) steroids were investigated for their ability to reduce inflammatory symptoms in a mouse otitis media model. Subjects Acute inflammation was induced by transtympanic injection of heat killed Streptococcus pneumoniae to 100 Balb/c mice. Interventions Twenty mice in each experimental group (prednisolone, dexamethasone, aldosterone, fludrocortisone) were given a steroid in their drinking water the day before inoculation and continued on these treatments until histologic observance. Twenty control mice were treated with water only. Results Histologic middle ear morphometrics showed significant steroid effects at both 3 and 5 days in reduction of fluid area, cell number and tympanic membrane thickness. Conclusions Glucocorticoids were most effective in controlling inflammation. Interestingly, the mineralocorticoids were also effective in reducing the inflammatory response at 5 days, suggesting their fluid transport function helped clear disease. Thus, steroid control of middle ear disease may be useful in alleviating symptoms faster and reducing risk to the inner ear.
Objective-The impact of glucocorticoids and mineralocorticoids on chronic otitis media (COM) in toll-like receptor 4-deficient C3H/HeJ mice was investigated.Study Design-To evaluate control of COM by steroids with differences in their antiinflammatory (prednisolone, dexamethasone), and fluid absorption functions (fludrocortisone, aldosterone). A minimum sample size of 5 animals for each group was required based on power analysis calculations. Sample sizes ranged from 7-17 mice per treatment group.Subjects and Methods-ABR thresholds were performed at baseline, 2 weeks and 4 weeks. Histopathology was evaluated on all mice ears at the end of the study.Results-ANOVA of ABR threshold change showed significant treatment effects (p <0.05) by both steroid types at all time intervals and ABR frequencies except 4 weeks/8 kHz. Histologic assessment showed prednisolone-treated mice had a higher rate of clearance of middle and inner ear inflammation (62%) than control mice (4%).Conclusion-It was concluded that steroid treatments can improve the physiology of chronic middle and inner ear disease seen with COM.
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