Objectives-Middle ear mucins are associated with otitis media (OM), contribute to hearing loss and are regulated by cytokines. This work investigates the regulation of mucin secretion from human middle ear epithelial cells (HMEEC) by inflammatory cytokines interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α) and cytokine inhibitors interleukin-1 receptor antagonist (IL-1ra) and antitumor necrosis factor-α antibody (TNFab).Methods-HMEEC were exposed to IL-1β and TNF-α in a dose-and time-dependent manner. Cytokine stimulated HMEEC were also exposed to IL-1ra and TNFab in a dose-dependent manner. Mucin secretion was characterized by exclusion chromatography and liquid scintillation.Results-HMEEC exposed to IL-1β and TNF-α demonstrated significant upregulation of mucin secretion in a dose-dependent fashion. Cultures exposed to IL-1β at 100ng/ml and TNF-α at 200ng/ ml showed increased mucin secretion in time-dependent experiments at 16 hours (P=0.00008) for TNF-α and 8 (P=0.028) and 16 hours (P=0.00001) for IL-1 β. IL-1ra and TNFab inhibited the effects of increased mucin secretion by IL-1β and TNF-α. Conclusions-IL-1βand TNF-α upregulate mucin secretion from HMEEC in a dose-and timedependant manner and these effects can be inhibited by cytokine blockade. Improved understanding of these mechanisms has the potential to alter the approach and management of OM and lead to novel therapeutic interventions.Keywords otitis media; mucin; interleukin-1 β; tumor necrosis factor -α IntroductionOtitis media (OM) is the most common diagnosis in children who visit physicians for illness in the United States [1]. Along with this disease prevalence is an economic burden of treatment in the billions of dollars per year in the US [2]. A more thorough understanding of the pathophysiology and the inflammatory events that occur during this disease process is needed to provide novel solutions in the treatment of OM. In particular, although antibiotic treatment has been the mainstay of otitis media treatment, the increasing prevalence of microbial resistance will make the singular use of antibiotics challenging. Additionally, evidence has Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access Author ManuscriptCytokine. Author manuscript; available in PMC 2009 January 1. Published in final edited form as:Cytokine. 2008 January ; 41(1): 38-43. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript been generated suggesting that chronic inflammatory responses to middle ear pathogens may be important in the development of otitis media with effusion (OME) and rais...

Cough induces a rise in UES pressure, and this response is preserved in elderly people. A cough-induced rise in UES pressure is significantly higher than that in the esophagus and stomach,thereby providing a barrier against retrograde entry of gastric contents into the pharynx.

Background The insula plays a significant role in the interoceptive processing of visceral stimuli. We have previously shown that GERD patients have increased insular cortex activity during esophageal stimulation, suggesting a sensitized esophago-cortical neuraxis. However, information regarding the functional connectivity (FC) of the insula during visceral stimulation is lacking. The primary aim of this study was to investigate the FC of insular subregions during esophageal acid stimulation. Methods Functional imaging data was obtained from 12 GERD patients and 14 healthy subjects during four steady state conditions: (1) presence of transnasal esophageal catheter (pre-infusion); (2) neutral solution; (3) acid infusion; (4) presence of transnasal esophageal catheter following infusions (post-infusion). The insula was parcellated into 6 regions of interest (ROI). FC maps between each insular ROI and interoceptive regions were created. Differences in FC between GERD patients and healthy subjects were determined across the 4 study conditions. Key Results All GERD patients experienced heartburn during and after esophageal acidification. Significant differences between GERD patients and healthy subjects were seen in: (1) insula-thalamic FC (neutral solution infusion, acid infusion, post-infusion); (2) insula-amygdala FC (acid infusion, post-infusion); (3) insula-hippocampus and insula-cingulate FC (post-infusion). Conclusions & Inferences Esophageal stimulation in GERD patients revealed significant insular cortex FC differences with regions involved in viscerosensation and interoception. The results of our study provide further evidence that the insula, located at the transition of afferent physiologic information to human feelings, is essential for both visceral homeostasis and the experience of heartburn in GERD patients.

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