Over the past 6 years, we have established a unique, NIH funded, Clinical Research Center focused on the physiology of middle ear (ME) pressure (MEP) regulation. The integrating theme is the role played by MEP disregulation (MEPD) in the pathogenesis of otitis media (OM) with effusion (OME). We are requesting 5 years of NIH support to further develop this research theme. We include three Projects supported by two Cores. Project 1 evaluates MEP-regulation during health and disease, defines the diagnostic utility of current and newly developed methods to assess MEP-regulation, explores those physiological mechanisms that potentially modulate MEP-regulation and initiates the transfer of these tests and results to the clinical environment. Project 2 is a continuation of an ongoing, 5-year follow-up of three groups of children who were entered at 3 years of age with a documented history of chronic OME, recurrent acute OM or no significant OM. For each group, we are following the children to 7-8 years of age with repeated evaluations of MEP-regulation using standardized test protocols and periodic measures of the anatomy of the Eustachian tube (ET)/ME system. These data will be used to define the differences in ET/ME anatomy and function between groups at each age, the changes in anatomy and function for each group with growth and development, and the effect of the anatomical substrate on function. The goals are to determine if any anatomic or functional measure predicts group assignment and if any of the measures predict the future course of disease in a given child. Project 5 continues our work on modeling MEP-regulation for normal and diseased MEs. These models are used to develop functional-anatomic relationships, to aid in the interpretation of data from the Projects and to define possible treatment options for OME. Core A administers the Center, guides its future direction and provides data entry and statistical services to all Projects. Core B develops new tests, protocols and instruments to assess MEP-regulation and provides all testing/imaging services required by the three Projects. This Clinical Research Center is unique in its focus on MEP-regulation and the role played by MEPD in OME pathogenesis.

Public Health Relevance

OME is a common disease that adversely affects the health and welfare of affected children, adolescents and adults. MEPD was demonstrated to initiate and sustain OME episodes. Determining those factors that cause MEPD holds promise to identify persons at risk for OME, to accurately predict future OME experience in affected individuals, and to develop new intervention strategies to prevent/resolve OME. Subproject 1 Gas Supply, Demand and Middle Ear Gas Balance Principle Investigator: William J. Doyle, Ph.D. Co-Investigators: Cuynet M. Alper, M.D. and Charles D. Bluestone, M.D. DESCRIPTION (provided by applicant): Otitis media with effusion (OME) is a common disease in the pediatric population that also occurs at lesser prevalences in older children, adolescents and adults. With the possible exceptions of a conductive hearing loss and balance disturbances, OME is usually asymptomatic and characterized by middle ear (ME) mucosal (MEM) inflammation and the development of ME effusion (MEE). OME is often caused and/or sustained by poor ME pressure (MEP)-regulation (i.e. MEP disregulation [MEPD]) which, if prolonged, can result in a chronic disease condition (cOME). One hypothesized mechanism for the development of OME during MEPD is hydrops ex vacuo wherein hydrostatic pressure differences between the MEM capillaries and ME airspace cause capillary disruption, MEM swelling and the transudation of fluids into the ME. Recent studies suggest that this presumably passive process is augmented by the active participation of MEM epithelial cells that produce/release inflammatory chemicals in response to established pressure gradients. Past studies show that these events are precipitated at a ME-ambient pressure difference of approximately -250 to -350 daPa. Because the ME is a relatively fixed-volume, temperature stable, gas pocket, its pressure is proportional to the contained gas moles and the addition or removal of ME gas changes MEP. Our past studies show that the major pathway for ME gas loss is by transMEM N2 transfer to local blood in response to the extant N2-pressure difference between those two compartments which approximates -600 daPa. However, under conditions of adequate MEP-regulation, that level of underpressure is not attained because mixed gas is re-supplied to the ME during transient Tensor Veli Palatini muscle (mTVP)-assisted opening of the Eustachian tube (ET) lumen. This allows for gas transfer between the nasopharynx (NP) and ME which re-establishes approximate equality between ME and ambient pressure and aborts the pathological consequences of significant ME-MEM pressure differences. We define this set of conditions as adequate MEP-regulation. In contrast, MEPD is defined as a greater ME gas loss due to transMEM N2 exchange than that supplied during ET openings (ET function [ETF]) for a time sufficient to develop the ME underpressure that precipitates pathology. With the exception of the insertion of ventilation tubes (VTs) which bypass the ET to achieve ambient-MEP equality, no interventions have been documented to improve MEP-regulation, though we examine some possibilities in this proposal. We hypothesize that both transMEM gas exchange and ETF have a relatively stable constitutive component dependent on the functional anatomy of the respective systems and a variable component that reflects extant conditions. Thus, marginal constitutive MEP-regulation can be downgraded to MEPD by nasal allergy in atopic individuals, viral upper respiratory tract infections (vURls), gastroesophageal reflux disease (GERD), MEM inflammation or rapid changes in ambient pressure. Other proposed factors that could affect MEP-regulation are an increase in transMEM gas exchange secondary to the extension of nasal inflammation to the ME and/or modulation of ETF by proposed feedback mechanisms. However neither of these latter effects has been fully demonstrated in either animals or humans. Moreover, in some individuals, the existence of marginal MEP-regulation is only revealed under conditions that stress MEP-regulation such as occur during underwater diving or airplane flights. Here, we propose to explore the fundamental physiological properties of MEP-regulation not evaluated previously in humans and to incorporate the results into mathematical models of MEP-regulation. We also plan to develop new and to validate existing tests for their capability of diagnosing MEPD, determining its cause and predicting disease course and surgical outcomes in children and adults. We place a special emphasis on tests that can be easily extended to clinical situations.

National Institute of Health (NIH)
National Institute on Deafness and Other Communication Disorders (NIDCD)
Specialized Center (P50)
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Special Emphasis Panel (ZDC1)
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Watson, Bracie
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University of Pittsburgh
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Cetin, Selma; Teixeira, Miriam S; Alper, Cuneyt M (2017) Quantitative representation of Eustachian tube component movements during swallowing. Auris Nasus Larynx :
Teixeira, Miriam S; Alper, Cuneyt M; Martin, Brian S et al. (2017) Histamine Applied Topically to the Nasal Mucosa Increases the Transmucosal Nitrous Oxide Exchange for the Middle Ear. Ann Otol Rhinol Laryngol 126:284-289
Higuita-Castro, N; Nelson, M T; Shukla, V et al. (2017) Using a Novel Microfabricated Model of the Alveolar-Capillary Barrier to Investigate the Effect of Matrix Structure on Atelectrauma. Sci Rep 7:11623
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Malik, J E; Swarts, J D; Ghadiali, S N (2016) Multi-scale finite element modeling of Eustachian tube function: influence of mucosal adhesion. Int J Numer Method Biomed Eng 32:
Higuita-Castro, N; Shukla, V C; Mihai, C et al. (2016) Simvastatin Treatment Modulates Mechanically-Induced Injury and Inflammation in Respiratory Epithelial Cells. Ann Biomed Eng 44:3632-3644
Mandel, Ellen M; Casselbrant, Margaretha L; Richert, Beverly C et al. (2016) Eustachian Tube Function in 6-Year-Old Children with and without a History of Middle Ear Disease. Otolaryngol Head Neck Surg 154:502-7
Teixeira, Miriam S; Alper, Cuneyt M; Martin, Brian S et al. (2016) Oxymetazoline Applied Topically to the Nasal Mucosa Decreases Trans-Mucosal Nitrous Oxide Exchange for the Middle Ear. Ann Otol Rhinol Laryngol 125:400-7
Alper, Cuneyt M; Teixeira, Miriam S; Swarts, J Douglas (2016) Correlations between videoendoscopy and sonotubometry of eustachian tube opening during a swallow. Laryngoscope 126:2778-2784
Alper, Cuneyt M; Losee, Joseph E; Seroky, James T et al. (2016) Resolution of Otitis Media With Effusion in Children With Cleft Palate Followed Through Five Years of Age. Cleft Palate Craniofac J 53:607-13

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