Lipopolysaccharide-Induced Middle Ear Inflammation Disrupts the cochlear Intra-Strial Fluid–Blood Barrier through Down-Regulation of Tight Junction Proteins

Abstract

Middle ear infection (or inflammation) is the most common pathological condition that causes fluid to accumulate in the middle ear, disrupting cochlear homeostasis. Lipopolysaccharide, a product of bacteriolysis, activates macrophages and causes release of inflammatory cytokines. Many studies have shown that lipopolysaccharides cause functional and structural changes in the inner ear similar to that of inflammation. However, it is specifically not known how lipopolysaccharides affect the blood-labyrinth barrier in the stria vascularis (intra-strial fluid–blood barrier), nor what the underlying mechanisms are. In this study, we used a cell culture-based in vitro model and animal-based in vivo model, combined with immunohistochemistry and a vascular leakage assay, to investigate lipopolysaccharide effects on the integrity of the mouse intra-strial fluid–blood barrier. Our results show lipopolysaccharide-induced local infection significantly affects intra-strial fluid–blood barrier component cells. Pericytes and perivascular-resident macrophage-like melanocytes are particularly affected, and the morphological and functional changes in these cells are accompanied by substantial changes in barrier integrity. Significant vascular leakage is found in the lipopolysaccharide treated-animals. Consistent with the findings from the in vivo animal model, the permeability of the endothelial cell monolayer to FITC-albumin was significantly higher in the lipopolysaccharide-treated monolayer than in an untreated endothelial cell monolayer. Further study has shown the lipopolysaccharide-induced inflammation to have a major effect on the expression of tight junctions in the blood barrier. Lipopolysaccharide was also shown to cause high frequency hearing loss, corroborated by previous reports from other laboratories. Our findings show lipopolysaccharide-evoked middle ear infection disrupts inner ear fluid balance, and its particular effects on the intra-strial fluid–blood barrier, essential for cochlear homeostasis. The barrier is degraded as the expression of tight junction-associated proteins such as zona occludens 1, occludin, and vascular endothelial cadherin are down-regulated.

Pathophysiology of the cochlear intrastrial fluid-blood barrier (review)

“…In support of the hypothesis, Zhang et al, (2015) recently showed lipopolysaccharide-induced middle ear inflammation to disrupt the cochlear intrastrial fluid-blood barrier by down-regulating tight junction protein expression. Correspondingly, Hirose et al, (2014) demonstrated that lipopolysaccharide increases entry of serum fluorescein into the perilymph via the blood barrier (Hirose et al, 2014) .…”

“…Recent experimental results from different laboratories demonstrate the potential link of dysfunction of the intrastrial fluid-blood barrier in different hearing disorders, including noise-induced hearing loss (Shi, 2009; Shi et al, 2003; Zhang et al, 2012), age-related hearing loss (Gratton et al, 1996; Gratton et al, 1997; Neng et al, 2015; Ohlemiller et al, 2009), autoimmune disease (Lin et al, 1997; Ruckenstein et al, 1999), genetic hearing disorders (Cohen-Salmon et al, 2007; Fujimura et al, 2005; Jabba et al, 2006; Kitamura et al, 1994), and inflammatory edema and hydrops (Hirose et al, 2014; Zhang et al, 2015). In addition, the barrier is also the point of entry for certain ototoxic drugs, such as cisplatin and gentamicin, which permeate the cochlea through the blood barrier and damage hearing function (Dai et al, 2008; Laurell et al, 2000; Wang et al, 2009).…”

“…Normal function of the stria vascularis (referred to as the “intrastrial fluid-blood barrier”) is critical for maintaining the ionic gradients and endocochlear potential (EP) required for sensory hair cell transduction (Hibino et al, 2010; Marcus et al, 1983; Quraishi et al, 2008; Salt et al, 1987; Spicer et al, 1996; Wangemann, 2002; Zhang et al, 2012). Dysfunction of the stria, including the intrastrial fluid-blood barrier, is considered to be one of the etiologies in a number of hearing disorders, including autoimmune inner ear disease, noise-induced hearing loss, age-related hearing loss , and genetically linked hearing diseases (Lin et al, 1997; Neng et al, 2015; Shi, 2009; Yang et al, 2011; Zhang et al, 2015). Despite the importance of the intrastrial fluid-blood barrier, the physiology of the barrier is largely unknown.…”

Impact of Sensory Impairments on Functional Disability in Adults With Arthritis

“…The reasons for the effects of arthritis with visual symptoms are also unknown but may be, at least in part, associated with inflammation, which is commonly seen in arthritis and increasingly recognized in other conditions. 33-35 Another possibility is that arthritis with concomitant visual impairment reflects frailty, 36 which itself is associated with reduced physical activity and greater disability across multiple health domains, particularly cardiovascular disease. 37-39 Although concomitant ocular disease is not noted to occur commonly in people with arthritis, those with inflammatory ocular diseases such as keratoconjunctivitis sicca (dry eye syndrome), scleritis, uveitis, and retinal vasculitis are frequently noted to have arthritis.…”

Effect of sepsis and systemic inflammatory response syndrome on neonatal hearing screening outcomes following gentamicin exposure

“…Prior studies have shown that LPS potentiates the ototoxicity of aminoglycosides and loop diuretics, leading to extensive high frequency hearing loss [7, 22]. Markers of inflammation and LPS increase cochlear uptake of aminoglycosides, particularly into the highly-vascularized stria vascularis, potentially due to dysregulation of the integrity of the blood-labyrinth barrier [7, 24, 25]. Increased aminoglycoside trafficking across the stria vascularis will lead to greater clearance into endolymph and uptake by cochlear hair cells across their apical membrane and greater ototoxicity and sensory hair cell loss [7, 26–28].…”