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Zahid A, Wilson JC, Grice ID, Peak IR. Otitis media: recent advances in otitis media vaccine development and model systems. Front Microbiol 2024; 15:1345027. [PMID: 38328427 PMCID: PMC10847372 DOI: 10.3389/fmicb.2024.1345027] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2023] [Accepted: 01/08/2024] [Indexed: 02/09/2024] Open
Abstract
Otitis media is an inflammatory disorder of the middle ear caused by airways-associated bacterial or viral infections. It is one of the most common childhood infections as globally more than 80% of children are diagnosed with acute otitis media by 3 years of age and it is a common reason for doctor's visits, antibiotics prescriptions, and surgery among children. Otitis media is a multifactorial disease with various genetic, immunologic, infectious, and environmental factors predisposing children to develop ear infections. Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis are the most common culprits responsible for acute otitis media. Despite the massive global disease burden, the pathogenesis of otitis media is still unclear and requires extensive future research. Antibiotics are the preferred treatment to cure middle ear infections, however, the antimicrobial resistance rate of common middle ear pathogens has increased considerably over the years. At present, pneumococcal and influenza vaccines are administered as a preventive measure against otitis media, nevertheless, these vaccines are only beneficial in preventing carriage and/or disease caused by vaccine serotypes. Otitis media caused by non-vaccine serotype pneumococci, non-typeable H. influenza, and M. catarrhalis remain an important healthcare burden. The development of multi-species vaccines is an arduous process but is required to reduce the global burden of this disease. Many novel vaccines against S. pneumoniae, non-typeable H. influenza, and M. catarrhalis are in preclinical trials. It is anticipated that these vaccines will lower the disease burden and provide better protection against otitis media. To study disease pathology the rat, mouse, and chinchilla are commonly used to induce experimental acute otitis media to test new therapeutics, including antibiotics and vaccines. Each of these models has its advantages and disadvantages, yet there is still a need to develop an improved animal model providing a better correlated mechanistic understanding of human middle ear infections, thereby underpinning the development of more effective otitis media therapeutics. This review provides an updated summary of current vaccines against otitis media, various animal models of otitis media, their limitations, and some future insights in this field providing a springboard in the development of new animal models and novel vaccines for otitis media.
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Affiliation(s)
- Ayesha Zahid
- Institute for Glycomics, Griffith University, Gold Coast, QLD, Australia
| | - Jennifer C. Wilson
- School of Pharmacy and Medical Science, Griffith University, Gold Coast, QLD, Australia
| | - I. Darren Grice
- Institute for Glycomics, Griffith University, Gold Coast, QLD, Australia
- School of Pharmacy and Medical Science, Griffith University, Gold Coast, QLD, Australia
| | - Ian R. Peak
- Institute for Glycomics, Griffith University, Gold Coast, QLD, Australia
- School of Pharmacy and Medical Science, Griffith University, Gold Coast, QLD, Australia
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Yamamoto-Fukuda T, Pinto F, Pitt K, Senoo M. Inhibition of TGF-β signaling enables long-term proliferation of mouse primary epithelial stem/progenitor cells of the tympanic membrane and the middle ear mucosa. Sci Rep 2023; 13:4532. [PMID: 36941290 PMCID: PMC10027825 DOI: 10.1038/s41598-023-31246-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2022] [Accepted: 03/08/2023] [Indexed: 03/23/2023] Open
Abstract
The surface of the middle ear is composed of the tympanic membrane (TM) and the middle ear mucosa (MEM). A number of diseases and conditions such as otitis media, middle ear cholesteatoma, and perforation of the TM have been reported to cause dysfunction of the middle ear, ultimately leading to high-frequency hearing loss. Despite its importance in repairing the damaged tissues, the stem/progenitor cells of the TM and the MEM epithelia remains largely uncharacterized due, in part, to the lack of an optimal methodology to expand and maintain stem/progenitor cells long-term. Here, we show that suppression of TGF-β signaling in a low Ca2+ condition enables long-term proliferation of p63-positive epithelial stem/progenitor cells of the TM and the MEM while avoiding their malignant transformation. Indeed, our data show that the expanded TM and MEM stem/progenitor cells respond to Ca2+ stimulation and differentiate into the mature epithelial cell lineages marked by cytokeratin (CK) 1/8/18 or Bpifa1, respectively. These results will allow us to expand epithelial stem/progenitor cells of the TM and MEM in quantity for large-scale analyses and will enhance the use of mouse models in developing stem cell-mediated therapeutic strategies for the treatment of middle ear diseases and conditions.
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Affiliation(s)
- Tomomi Yamamoto-Fukuda
- Department of Molecular and Cell Biology, Boston University Henry M. Goldman School of Dental Medicine, 72 East Concord Street, Boston, MA, 02118, USA.
- Department of Otorhinolaryngology, Jikei University School of Medicine, 3-25-8 Nishishinbashi, Minato-Ku, Tokyo, 105-8461, Japan.
| | - Filipa Pinto
- Department of Molecular and Cell Biology, Boston University Henry M. Goldman School of Dental Medicine, 72 East Concord Street, Boston, MA, 02118, USA
| | - Keshia Pitt
- Department of Molecular and Cell Biology, Boston University Henry M. Goldman School of Dental Medicine, 72 East Concord Street, Boston, MA, 02118, USA
| | - Makoto Senoo
- Department of Molecular and Cell Biology, Boston University Henry M. Goldman School of Dental Medicine, 72 East Concord Street, Boston, MA, 02118, USA.
- Cell Exosome Therapeutics, Inc., 2-16-9 Higashi, Shibuya-Ku, Tokyo, 150-0011, Japan.
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Shigihara K, Yayoshi N, Sawada H, Momota Y, Hara Y. Surgical treatment of middle ear cholesteatoma using an oral approach in 2 dogs. THE CANADIAN VETERINARY JOURNAL = LA REVUE VETERINAIRE CANADIENNE 2022; 63:400-406. [PMID: 35368392 PMCID: PMC8922381] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Subscribe] [Scholar Register] [Indexed: 06/14/2023]
Abstract
Middle ear cholesteatoma is caused by the formation of epidermoid cysts that result in distention and enlargement of the tympanic bulla with subsequent destruction of surrounding tissues. We report treatment of middle ear cholesteatoma in 2 dogs, via an oral surgical approach. Abnormal tympanic bulla contents and the wall compressing the pharynx were successfully removed in both cases. Computed tomography imaging, surgical findings, and histopathology results were consistent with middle ear cholesteatoma in both cases. The outcomes in both cases suggest that an oral surgical approach may be an alternative treatment for middle ear cholesteatoma in dogs. Key clinical message: Despite the limited number of cases described herein, our report indicates that the direct oral approach for canine cholesteatoma may be and alternative approach.
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Affiliation(s)
- Kae Shigihara
- Nippon Veterinary and Life Science University, Tokyo, Japan (Shigihara, Yayoshi, Momota, Hara); Oregon State University, Corvallis, Oregon (Shigihara); Japan Small Animal Medical Center, Saitama, Japan (Sawada)
| | - Naoko Yayoshi
- Nippon Veterinary and Life Science University, Tokyo, Japan (Shigihara, Yayoshi, Momota, Hara); Oregon State University, Corvallis, Oregon (Shigihara); Japan Small Animal Medical Center, Saitama, Japan (Sawada)
| | - Harumi Sawada
- Nippon Veterinary and Life Science University, Tokyo, Japan (Shigihara, Yayoshi, Momota, Hara); Oregon State University, Corvallis, Oregon (Shigihara); Japan Small Animal Medical Center, Saitama, Japan (Sawada)
| | - Yutaka Momota
- Nippon Veterinary and Life Science University, Tokyo, Japan (Shigihara, Yayoshi, Momota, Hara); Oregon State University, Corvallis, Oregon (Shigihara); Japan Small Animal Medical Center, Saitama, Japan (Sawada)
| | - Yasushi Hara
- Nippon Veterinary and Life Science University, Tokyo, Japan (Shigihara, Yayoshi, Momota, Hara); Oregon State University, Corvallis, Oregon (Shigihara); Japan Small Animal Medical Center, Saitama, Japan (Sawada)
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Sex differences in the auditory functions of rodents. Hear Res 2021; 419:108271. [PMID: 34074560 DOI: 10.1016/j.heares.2021.108271] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/19/2020] [Revised: 04/07/2021] [Accepted: 04/28/2021] [Indexed: 12/30/2022]
Abstract
BACKGROUND In humans, it is well known that females have better hearing than males. The mechanism of this influence of sex on auditory function in humans is not well understood. Testing the hypothesis of underlying mechanisms often relies on preclinical research, a field in which sex bias still exists unconsciously. Rodents are popular research models in hearing, thus it is crucial to understand the sex differences in these rodent models when studying health and disease in humans. OBJECTIVES This review aims to summarize the existing sex differences in the auditory functions of rodent species including mouse, rat, Guinea pig, Mongolian gerbil, and chinchilla. In addition, a concise summary of the hearing characteristics and the advantages and the drawbacks of conducting auditory experiments in each rodent species is provided. DESIGNS Manuscripts were identified in PubMed and Ovid Medline for the queries "Rodent", "Sex Characteristics", and "Hearing or Auditory Function". Manuscripts were included if they were original research, written in English, and use rodents. The content of each manuscript was screened for the sex of the rodents and the discussion of sex-based results. CONCLUSIONS The sex differences in auditory function of rodents are prevalent and influenced by multiple factors including physiological mechanisms, sex-based anatomical variations, and stimuli from the external environment. Such differences may play a role in understanding and explaining sex differences in hearing of humans and need to be taken into consideration for developing clinical therapies aim to improve auditory performances.
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Global changes in epigenomes during mouse spermatogenesis: possible relation to germ cell apoptosis. Histochem Cell Biol 2020; 154:123-134. [PMID: 32653936 DOI: 10.1007/s00418-020-01900-x] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/02/2020] [Indexed: 12/11/2022]
Abstract
Mammalian spermatogenesis is characterized by disproportionate germ cell apoptosis. The high frequency of apoptosis is considered a safety mechanism that serves to avoid unfavorable transmission of paternal aberrant genetic information to the offspring as well as elimination mechanism for removal of overproduced immature or damaged spermatogenic cells. The molecular mechanisms involved in the induction of germ cell apoptosis include both intrinsic mitochondrial Bcl-2/Bax and extrinsic Fas/FasL pathways. However, little is known about the nuclear trigger of those systems. Recent studies indicate that epigenomes are essential in the regulation of gene expression through remodeling of the chromatin structure, and are genome-like transmission materials that reflect the effects of various environmental factors. In spermatogenesis, epigenetic errors can act as the trigger for elimination of germ cells with abnormal chromatin structure, abnormal gene expression and/or morphological defects (disordered differentiation). In this review, we focus on the relationship between global changes in epigenetic parameters and germ cell apoptosis in mice and other mammals.
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Samy RN, Earl BR, Lipschitz N, Schweinzger I, Currier M, Cripe T. Engineered oncolytic virus for the treatment of cholesteatoma: A pilot in vivo study. Laryngoscope Investig Otolaryngol 2019; 4:532-542. [PMID: 31637298 PMCID: PMC6793611 DOI: 10.1002/lio2.307] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2019] [Revised: 07/21/2019] [Accepted: 08/20/2019] [Indexed: 01/04/2023] Open
Abstract
Objective Determine if oncolytic herpes simplex virus (oHSV) can eradicate cholesteatoma (CHST) in a gerbil model. Methods An in vivo model of CHST was developed in Mongolian gerbils by combining Pseudomonas aeruginosa inoculation with double ligation of the external auditory canal (EAC). CHST size and bone thickness were measured using morphometric and volumetric quantification techniques via micro‐computed tomography (micro‐CT). The CHST induction and quantification techniques were then used in an additional group of 10 gerbils (n = 20 ears) to determine the within‐group treatment efficacy of oHSV against CHST in vivo. Treated animals received either one, two, or three intrabullar injections of oHSV between 2 and 6 weeks postinduction of CHST. Results The P. aeruginosa inoculation plus double EAC ligation technique successfully induced a range of CHST growth in 100% of the ears in the model‐development group. Osteolytic effects of CHST were observed in 6% of ears whereas osteoblastic effects were observed in 31% of ears. CHST volume decreased by 50% or more in 12 of the 20 ears in the oHSV‐treatment groups. An apparent reversal of osteoblastic effects was also observed in three out of four ears 6 weeks following the third oHSV injection. Conclusions P. aeruginosa inoculation plus double EAC ligation reliably induces CHST formation in gerbil. CT‐based volumetric measures are significantly more accurate than single‐slice morphometric area measures for quantification of CHST size. Treatment with oHSV appears to be efficacious for reducing CHST volume by as much as 77% with as few as one treatment. Level of Evidence NA
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Affiliation(s)
- Ravi N Samy
- Department of Otolaryngology-Head and Neck Surgery University of Cincinnati College of Medicine Cincinnati Ohio U.S.A.,Neurosensory Disorders Center at University of Cincinnati Gardner Neuroscience Institute Cincinnati Ohio U.S.A.,Cincinnati Children's Hospital Medical Center Cincinnati Ohio U.S.A
| | - Brian R Earl
- Department of Otolaryngology-Head and Neck Surgery University of Cincinnati College of Medicine Cincinnati Ohio U.S.A.,Department of Communication Sciences and Disorders University of Cincinnati College of Allied Health Sciences Cincinnati Ohio U.S.A
| | - Noga Lipschitz
- Department of Otolaryngology-Head and Neck Surgery University of Cincinnati College of Medicine Cincinnati Ohio U.S.A
| | - Ivy Schweinzger
- Department of Communication Sciences and Disorders University of Cincinnati College of Allied Health Sciences Cincinnati Ohio U.S.A
| | - Mark Currier
- Center for Childhood Cancer and Blood Diseases The Research Institute at Nationwide Children's Hospital Columbus Ohio U.S.A
| | - Timothy Cripe
- Center for Childhood Cancer and Blood Diseases The Research Institute at Nationwide Children's Hospital Columbus Ohio U.S.A.,Division of Hematology, Oncology, Blood and Marrow Transplant, Department of Pediatrics Nationwide Children's Hospital Columbus Ohio U.S.A
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Akiyama N, Yamamoto-Fukuda T, Yoshikawa M, Kojima H. Regulation of DNA methylation levels in the process of oral mucosal regeneration in a rat oral ulcer model. Histol Histopathol 2019; 35:247-256. [PMID: 31286466 DOI: 10.14670/hh-18-147] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
DNA methylation is an important epigenetic mechanism for cellular maintenance. However, the methylation pattern and the key molecule regulated epigenetically in oral mucosal regeneration is unclear. In this study, we generated a rat oral ulcer model and investigated the cell proliferative activities and DNA methylation patterns immunohistochemically. We also performed immunohistochemical analysis of a regulator of epithelial stem/progenitor cell differentiation in the rat model. We demonstrated immunohistochemistry using antibodies for the molecules as follows: Ki-67, a marker of cellular proliferation; 5-methylcytosine (5-mC), a marker of DNA methylation; 5-hydroxymethylcytosine (5-hmC), a marker of DNA demethylation; Dnmt1, a maintenance DNA methyltransferase; Dnmt3a and Dnmt3b, de novo DNA methyltransferases; and Wnt5a, a regulator of stem/progenitor cell differentiation. In this model, re-epithelialization was completed at Day 4 after ulceration. Regenerating mucosal hypertrophy reached a peak at Day 5 and appeared normal at Day 14. Ki-67-positive cells increased at Day 2 and returned to normal at Day 6 after ulceration. The ratio of the expression level of 5-mC to 5-hmC declined at Day 5 and returned to normal at Day 6. The expression level of Dnmt1 had not changed compared to the normal control at every time point. On the other hand, the expression levels of Dnmt3a and Dnmt3b had decreased significantly at Day 5 and returned to normal at Day 6. Moreover, Wnt5a-positive cells increased at Day 5. In conclusion, oral mucosal regeneration was strictly regulated by DNA methylation. Moreover, Wnt5a might play a critical role in oral mucosal regeneration.
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Affiliation(s)
- Naotaro Akiyama
- Department of Otorhinolaryngology, Toho University School of Medicine, Tokyo, Japan. .,Department of Histology and Cell Biology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Tomomi Yamamoto-Fukuda
- Department of Histology and Cell Biology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.,Department of Otorhinolaryngology, Jikei University School of Medicine, Tokyo, Japan
| | - Mamoru Yoshikawa
- Department of Otorhinolaryngology, Toho University School of Medicine, Tokyo, Japan
| | - Hiromi Kojima
- Department of Otorhinolaryngology, Jikei University School of Medicine, Tokyo, Japan
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Abstract
Case summary A 14-year-old neutered female Burmese cat was referred for investigation of a caudal oropharyngeal mass. CT showed a thin walled cyst-like structure filling and expanding from the right tympanic bulla. Histopathology showed fragments of mildly dysplastic squamous epithelium and aggregates of keratin. These findings were considered consistent with a diagnosis of cholesteatoma. Relevance and novel information To the best of our knowledge, this is the first reported case of a cholesteatoma in a cat. Cholesteatoma should be considered a differential diagnosis for cats presenting with a caudal oropharyngeal mass, a history of chronic ear disease or a history of previous, surgically managed middle ear disease. Advanced imaging and biopsies should be considered important in the diagnosis of these lesions.
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Østevik L, Rudlang K, Holt Jahr T, Valheim M, Njaa BL. Bilateral tympanokeratomas (cholesteatomas) with bilateral otitis media, unilateral otitis interna and acoustic neuritis in a dog. Acta Vet Scand 2018; 60:31. [PMID: 29788991 PMCID: PMC5964671 DOI: 10.1186/s13028-018-0386-4] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2018] [Accepted: 05/16/2018] [Indexed: 11/15/2022] Open
Abstract
Background An aural cholesteatoma, more appropriately named tympanokeratoma, is an epidermoid cyst of the middle ear described in several species, including dogs, humans and Mongolian gerbils. The cyst lining consists of stratified, keratinizing squamous epithelium with central accumulation of a keratin debris. This case report describes vestibular ganglioneuritis and perineuritis in a dog with chronic otitis, bilateral tympanokeratomas and presumed extension of otic infection to the central nervous system. Case presentation An 11-year-old intact male Dalmatian dog with chronic bilateral otitis externa and sudden development of symptoms of vestibular disease was examined. Due to the dog’s old age the owner opted for euthanasia without any further examination or treatment and the dog was submitted for necropsy. Transection of the ears revealed grey soft material in the external ear canals and pearly white, dry material consistent with keratin in the tympanic bullae bilaterally. The brain and meninges were grossly unremarkable. Microscopical findings included bilateral otitis externa and media, unilateral otitis interna, ganglioneuritis and perineuritis of the spiral ganglion of the vestibulocochlear nerve and multifocal to coalescing, purulent meningitis. A keratinizing squamous epithelial layer continuous with the external acoustic meatus lined the middle ear compartments, consistent with bilateral tympanokeratomas. Focal bony erosion of the petrous portion of the temporal bone and squamous epithelium and Gram-positive bacterial cocci were evident in the left cochlea. The findings suggest that meningitis developed secondary to erosion of the temporal bone and ganglioneuritis and/or perineuritis of the vestibulocochlear nerve. Conclusions Middle ear tympanokeratoma is an important and potentially life-threatening otic condition in the dog. Once a tympanokeratoma has developed expansion of the cyst can lead to erosion of bone and extension of otic infection to the inner ear, vestibulocochlear ganglion and nerve potentially leading to bacterial infection of the central nervous system. Electronic supplementary material The online version of this article (10.1186/s13028-018-0386-4) contains supplementary material, which is available to authorized users.
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Akiyama N, Yamamoto-Fukuda T, Yoshikawa M, Kojima H. Evaluation of YAP signaling in a rat tympanic membrane under a continuous negative pressure load and in human middle ear cholesteatoma. Acta Otolaryngol 2017; 137:1158-1165. [PMID: 28708445 DOI: 10.1080/00016489.2017.1351040] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
OBJECTIVES Mechanotransduction plays an important role in cell-proliferative activities. Negative pressure in the middle ear is thought to be an important factor related to the etiology of acquired middle ear cholesteatoma. However, the correlation between negative pressure in the middle ear and the mechanism of middle ear cholesteatoma formation remains unclear. In this study, we investigated the expression of key molecules for mechanotransduction immunohistochemically. METHODS An immunohistochemical analysis was performed using anti-Wnt5a (a marker of alternative Wnt signaling), -Yes-associated protein (YAP) (a marker of mechanosensing) and -pYAP (phosphorylated YAP at Ser 127: inactivated YAP) antibody in the tympanic membrane (TM) under a negative pressure load and in human middle ear cholesteatoma tissues. RESULTS The number of Wnt5a-positive cells had increased and YAP nuclear translocation was observed in epithelial and mesenchymal cells in the pars flaccida (PF) of the TM under a negative-pressure load and in human middle ear cholesteatoma tissues. CONCLUSIONS We demonstrated that negative pressure in the middle ear might possibly induce cell proliferation PF of TM in response to mechanical force (mechanotransduction) through YAP nuclear translocation mediated by alternative Wnt signaling, thus affecting human middle ear cholesteatoma formation.
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Affiliation(s)
- Naotaro Akiyama
- Department of Otorhinolaryngology, Toho University School of Medicine, Tokyo, Japan
| | | | - Mamoru Yoshikawa
- Department of Otorhinolaryngology, Toho University School of Medicine, Tokyo, Japan
| | - Hiromi Kojima
- Department of Otorhinolaryngology, Jikei University School of Medicine, Tokyo, Japan
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Ismi O, Unal M. Experimental models of cholesteatoma: A review. World J Otorhinolaryngol 2014; 4:23-27. [DOI: 10.5319/wjo.v4.i4.23] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/17/2014] [Revised: 08/19/2014] [Accepted: 09/17/2014] [Indexed: 02/07/2023] Open
Abstract
Cholesteatoma describes the keratinized, stratified squamous epithelium in the middle ear and mastoid, which has osteoclastic activity and is capable of bone resorption. Its origin is unknown and remains a topic of current investigation. In addition, ongoing studies are investigating new molecules for treatment. This review summarizes the various experimental models of cholesteatoma.
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Kuo CL. Etiopathogenesis of acquired cholesteatoma: prominent theories and recent advances in biomolecular research. Laryngoscope 2014; 125:234-40. [PMID: 25123251 DOI: 10.1002/lary.24890] [Citation(s) in RCA: 102] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Revised: 06/24/2014] [Accepted: 07/24/2014] [Indexed: 01/22/2023]
Abstract
OBJECTIVE To review recent biomolecular advances in etiopathogenesis of acquired cholesteatoma. DATA SOURCES MEDLINE via OVID (to March 2014) and PubMed (to March 2014). REVIEW METHODS All articles referring to etiopathogenesis of acquired cholesteatoma were identified in the above databases, from which 89 articles were included in this review. RESULTS The mechanisms underlying the etiopathogenesis of acquired cholesteatoma remain a subject of competing hypotheses. Four theories dominate the debate, including theories of invagination, immigration, squamous metaplasia, and basal cell hyperplasia. However, no single theory has been able to explain the clinical characteristics of all cholesteatoma types: uncoordinated hyperproliferation, invasion, migration, altered differentiation, aggressiveness, and recidivism. Modern technologies have prompted a number of researchers to seek explanations at the molecular level. First, cholesteatomas could be considered an example of uncontrolled cell growth, capable of altering the balance toward cellular hyperproliferation and enhancing the capacity for invasion and osteolysis. Second, the dysregulation of cell growth control involves internal genomic or epigenetic alterations and external stimuli, which induce excessive host immune response to inflammatory and infectious processes. This comprises several complex and dynamic pathophysiologic changes that involve extracellular and intracellular signal transduction cascades. CONCLUSIONS This article summarizes the existing theories and provides conceptual insights into the etiopathogenesis of acquired cholesteatoma, with the aim of stimulating continued efforts to develop a nonsurgical means of treating the disorder.
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Affiliation(s)
- Chin-Lung Kuo
- Department of Otolaryngology-Head and Neck Surgery, Taipei Veterans General Hospital; Department of Otolaryngology, National Yang-Ming University School of Medicine; Institute of Brain Science, National Yang-Ming University; Department of Otolaryngology, National Defense Medical Center, Taipei, Taiwan, R.O.C.; Department of Otolaryngology, Taoyuan Armed Forces General Hospital, Taoyuan, Taiwan, R.O.C
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Akiyama N, Yamamoto-Fukuda T, Takahashi H. Influence of continuous negative pressure in the rat middle ear. Laryngoscope 2014; 124:2404-10. [PMID: 24916143 DOI: 10.1002/lary.24767] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2014] [Revised: 04/14/2014] [Accepted: 05/12/2014] [Indexed: 11/10/2022]
Abstract
OBJECTIVES/HYPOTHESIS High negative pressure in the middle ear was thought to be closely related to the etiology of retraction-type cholesteatoma. Recently, it has been detected that mechanical forces are important factors in epithelial turnover and affect cytoskeletal remodeling. Continuous negative pressure in the middle ear may possibly accelerate the proliferation and differentiation of epithelial cells of the tympanic membrane. STUDY DESIGN Animal experimental study. METHODS Eleven adult male Sprague-Dawley rats were used, and continuous negative pressure was loaded by connecting a catheter from the rat's middle ear to the supply route of an implantable microinfusion pump, iPRECIO. At 7 days after implantation of the device, an otoendoscopic examination and micro-computed tomography (CT) analysis of the temporal bone were performed; the temporal bones were then collected for histological and immunohistochemical analysis. The degree of proliferation and differentiation of epithelial cells of the tympanic membrane was investigated immunohistochemically using the anti-cytokeratin-5 and anti-cytokeratin-10 antibodies. RESULTS Otoendoscopic examination revealed retraction of the pars flaccida in all of the ears under negative pressure. In the micro-CT analysis, soft tissue density area in the hypotympanum was observed in all ears under negative pressure. Histological analysis revealed thickened epithelium of the pars flaccida. In this region, the thickness of layers with cytokeratin-5-positive cells and cytokeratin-10-positive cells were increased. CONCLUSIONS Continuous negative pressure in the middle ear can lead to thickening of the epithelium of the pars flaccida, and may accelerate the proliferation and differentiation of epithelial cells.
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Affiliation(s)
- Naotaro Akiyama
- Department of Otolaryngology-Head and Neck Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
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Si Y, Chen YB, Chen QX, Liu Y, Jiang HL, Zhang ZG, Huang X. Autologous meatal skin graft implantation and intratympanic injection of Pseudomonas aeruginosa: a new experimental mouse model of acquired middle ear cholesteatoma. ORL J Otorhinolaryngol Relat Spec 2013; 75:274-81. [PMID: 24030443 DOI: 10.1159/000354348] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2013] [Accepted: 07/08/2013] [Indexed: 11/19/2022]
Abstract
AIM To create an experimental model for the biomedical research of middle ear cholesteatoma. METHODS Cholesteatoma was induced in the right ears of mice. An autologous meatal skin graft was implanted into the middle ear via the tympanic membrane followed by an intratympanic injection of Pseudomonas aeruginosa. Six weeks after surgery, the formation of acquired cholesteatoma was evaluated by macroscopic examination, CT scan, and histological analysis. The expressions of TNF-α, IL-1β, and IL-6 were measured with real-time PCR. Auditory-evoked brain stem response was used for assessing the changes in hearing levels. RESULTS None of the mice died during the modeling time. By the sixth postoperative week, cholesteatoma had successfully formed in 23 out of 25 mice, which equals a success rate of 92%. A CT scan revealed that the cholesteatoma was eroding the cochlea. Furthermore, histological analysis demonstrated a cystic structure covered by stratified squamous epithelium and keratin desquamation in the lamellae inside the cystic cavity in the bullae. All mice with experimentally induced cholesteatoma showed hearing impairment and an upregulated expression of TNF-α, IL-1β, and IL-6. CONCLUSION The present study successfully developed a mouse model of acquired middle ear cholesteatoma, which provides an extremely valuable tool for auditory and biomedical research. The modeling approach is technically easy and has a high success rate.
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Affiliation(s)
- Yu Si
- Department of Otolaryngology, Head and Neck Surgery, Sun Yat-Sen Memorial Hospital, Guangzhou, China
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Akiyama N, Yamamoto-Fukuda T, Takahashi H, Koji T. In situ tissue engineering with synthetic self-assembling peptide nanofiber scaffolds, PuraMatrix, for mucosal regeneration in the rat middle-ear. Int J Nanomedicine 2013; 8:2629-40. [PMID: 23926427 PMCID: PMC3728305 DOI: 10.2147/ijn.s47279] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
Middle-ear mucosa maintains middle-ear pressure. However, the majority of surgical cases exhibit inadequate middle-ear mucosal regeneration, and mucosal transplantation is necessary in such cases. The aim of the present study was to assess the feasibility of transplantation of isolated mucosal cells encapsulated within synthetic self-assembling peptide nanofiber scaffolds using PuraMatrix, which has been successfully used as scaffolding in tissue engineering, for the repair of damaged middle-ear. Middle-ear bullae with mucosa were removed from Sprague Dawley (SD) transgenic rats, transfected with enhanced green fluorescent protein (EGFP) transgene and excised into small pieces, then cultured up to the third passage. After surgical elimination of middle-ear mucosa in SD recipient rats, donor cells were encapsulated within PuraMatrix and transplanted into these immunosuppressed rats. Primary cultured cells were positive for pancytokeratin but not for vimentin, and retained the character of middle-ear epithelial cells. A high proportion of EGFP-expressing cells were found in the recipient middle-ear after transplantation with PuraMatrix, but not without PuraMatrix. These cells retained normal morphology and function, as confirmed by histological examination, immunohistochemistry, and electron microscopy, and multiplied to form new epithelial and subepithelial layers together with basement membrane. The present study demonstrated the feasibility of transplantation of cultured middle-ear mucosal epithelial cells encapsulated within PuraMatrix for regeneration of surgically eliminated mucosa of the middle-ear in SD rats.
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Affiliation(s)
- Naotaro Akiyama
- Department of Otolaryngology-Head and Neck Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
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Park MK, Lee BD. Development of animal models of otitis media. KOREAN JOURNAL OF AUDIOLOGY 2013. [PMID: 24653896 DOI: 10.787/kja.2013.17.1.9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
Otitis media is defined as inflammation of the middle ear, including the auditory ossicles and the Eustachian tube. Otitis media is a major health problem in many societies. The causes of otitis media includes infection and anatomic/physiologic, host, and environmental factors. In general, otitis media is a childhood disease, and anatomic and physiologic changes have great effects on its development. Thus, in vitro or human experimental studies of otitis media are difficult. Several experimental animal models have been introduced to investigate the pathogenesis and treatment of otitis media. However, none are ideal. The aim of this review is to provide a brief overview of the current status of animal models of otitis media with effusion, acute otitis media, and cholesteatoma. This review will assist determination of the most appropriate animal models of otitis media.
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Affiliation(s)
- Moo Kyun Park
- Department of Otolaryngology-Head and Neck Surgery, Soonchunhyang University College of Medicine, Seoul, Korea
| | - Byung Don Lee
- Department of Otolaryngology-Head and Neck Surgery, Soonchunhyang University College of Medicine, Seoul, Korea
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Park MK, Lee BD. Development of animal models of otitis media. KOREAN JOURNAL OF AUDIOLOGY 2013; 17:9-12. [PMID: 24653896 PMCID: PMC3936519 DOI: 10.7874/kja.2013.17.1.9] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/20/2013] [Revised: 02/28/2013] [Accepted: 03/10/2013] [Indexed: 12/18/2022]
Abstract
Otitis media is defined as inflammation of the middle ear, including the auditory ossicles and the Eustachian tube. Otitis media is a major health problem in many societies. The causes of otitis media includes infection and anatomic/physiologic, host, and environmental factors. In general, otitis media is a childhood disease, and anatomic and physiologic changes have great effects on its development. Thus, in vitro or human experimental studies of otitis media are difficult. Several experimental animal models have been introduced to investigate the pathogenesis and treatment of otitis media. However, none are ideal. The aim of this review is to provide a brief overview of the current status of animal models of otitis media with effusion, acute otitis media, and cholesteatoma. This review will assist determination of the most appropriate animal models of otitis media.
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Affiliation(s)
- Moo Kyun Park
- Department of Otolaryngology-Head and Neck Surgery, Soonchunhyang University College of Medicine, Seoul, Korea
| | - Byung Don Lee
- Department of Otolaryngology-Head and Neck Surgery, Soonchunhyang University College of Medicine, Seoul, Korea
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Animal models of middle ear cholesteatoma. J Biomed Biotechnol 2011; 2011:394241. [PMID: 21541229 PMCID: PMC3085392 DOI: 10.1155/2011/394241] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2010] [Revised: 12/15/2010] [Accepted: 02/10/2011] [Indexed: 12/21/2022] Open
Abstract
Middle ear acquired cholesteatoma is a pathological condition associated with otitis media, which may be associated with temporal bone resorption, otorrhea and hearing loss, and occasionally various other complications. Cholesteatoma is characterized by the enhanced proliferation of epithelial cells with aberrant morphologic characteristics. Unfortunately, our understanding of the mechanism underlying its pathogenesis is limited. To investigate its pathogenesis, different animal models have been used. This paper provides a brief overview of the current status of research in the field of pathogenesis of middle ear acquired cholesteatoma, four types of animal models previously reported on, up-to-date cholesteatoma research using these animal models, our current studies of the local hybrid ear model, and the future prospect of new animal models of middle ear cholesteatoma.
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