The Role of Gastric Pepsin in the Inflammatory Cascade of Pediatric Otitis Media

O’Reilly, Robert; Soundar, Sam; Tonb, Dalal; Bolling, Laura; Yoo, Estelle; Nadal, T.; Grindle, Christopher R.; Field, Erin; He, Zhaoping

doi:10.1001/jamaoto.2014.3581

Cited by 40 publications

(57 citation statements)

References 47 publications

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“…However, during weak and nonacid reflux commonly experienced by patients taking PPIs, the enzymatic activity of pepsin is transiently inhibited, allowing interaction with an unidentified cell surface receptor, endocytosis, and retention in acidic intracellular vesicles where its enzymatic activity would be restored . Pepsin has been observed in a variety of airway and esophageal epithelial cells where it initiates a cascade of inflammation and cancer‐associated changes . We previously demonstrated that <24‐hour pepsin exposure induces a cancer‐promoting gene expression profile, anchorage‐independent growth, and cell migration in hypopharyngeal and laryngeal cells in vitro, and that pepsin promoted oral tumor growth in vivo .…”

Section: Discussionmentioning

confidence: 99%

“…The gastric enzyme pepsin has previously been shown to promote chronic inflammation and carcinogenesis in the upper airways during extraesophageal reflux, which is typically weak or nonacidic and similar to that of patients taking PPIs . Furthermore, parietal and chief cells observed in BE, in the background of EAC and in heterotopic gastric mucosa patches in the esophagus, represent a potential source of locally synthesized pepsin and acid that may contribute to disease progression .…”

Section: Introductionmentioning

confidence: 99%

“…The gastric enzyme pepsin has previously been shown to promote chronic inflammation and carcinogenesis in the upper airways during extraesophageal reflux, which is typically weak or nonacidic and similar to that of patients taking PPIs. [15][16][17][18][19][20][21][22][23][24][25][26][27][28][29] Furthermore, parietal and chief cells observed in BE, in the background of EAC and in heterotopic gastric mucosa patches in the esophagus, represent a potential source of locally synthesized pepsin and acid that may contribute to disease progression. [30][31][32][33] We recently reported pepsinogen synthesis in BE mucosa in a small cohort of BE patients, and demonstrated pepsin-induced inflammatory changes in esophageal cells in vitro.…”

Section: Introductionmentioning

confidence: 99%

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Esophageal pepsin and proton pump synthesis in barrett's esophagus and esophageal adenocarcinoma

et al. 2019

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Objectives/Hypothesis Gastroesophageal reflux disease and associated metaplasia of the esophagus (Barrett's esophagus [BE]) are primary risk factors for esophageal adenocarcinoma (EAC). Widespread use of acid suppression medications has failed to stem the rise of EAC, suggesting that nonacid reflux may underlie its pathophysiology. Pepsin is a tumor promoter in the larynx and has been implicated in esophageal carcinogenesis. Herein, specimens from the esophageal cancer spectrum were tested for pepsin presence. Pepsin‐induced carcinogenic changes were assayed in an esophageal cell culture model. Study Design Laboratory analysis. Methods Pepsin was assayed in reflux and cancer free esophagi, BE, EAC, and esophageal cancer lacking association with reflux (squamous cell carcinoma [SCC]). Refluxed or locally synthesized pepsin was assayed by Western blot. Local synthesis of pepsin and proton pumps was assayed via reverse transcription–polymerase chain reaction. The effect of pepsin on BE and EAC markers was investigated via enzyme‐linked immunosorbent assay and quantitative polymerase chain reaction in human esophageal epithelial cells treated with pepsin or control diluent. Results Pepsinogen and proton pump mRNA were observed in BE (3/5) and EAC (4/4) samples, but not in normal adjacent specimens, SCC (0/2), or reflux and cancer‐free esophagi. Chronic pepsin treatment (0.1–1 mg/mL, 4 weeks) of human esophageal cells in vitro induced BE and EAC markers interleukin 8 and KRT8 and depleted normal esophageal marker KRT10 (P < .05) expression. Conclusions Local synthesis of pepsin and proton pumps in BE and EAC is not uncommon. Absence of these molecules in normal (noncancer) esophagi, SCC, and in vitro data support a role for pepsin in reflux‐attributed carcinogenic changes in the esophagus. Level of Evidence NA Laryngoscope, 129:2687–2695, 2019

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Section: Discussionmentioning

confidence: 99%

“…The gastric enzyme pepsin has previously been shown to promote chronic inflammation and carcinogenesis in the upper airways during extraesophageal reflux, which is typically weak or nonacidic and similar to that of patients taking PPIs . Furthermore, parietal and chief cells observed in BE, in the background of EAC and in heterotopic gastric mucosa patches in the esophagus, represent a potential source of locally synthesized pepsin and acid that may contribute to disease progression .…”

Section: Introductionmentioning

confidence: 99%

“…The gastric enzyme pepsin has previously been shown to promote chronic inflammation and carcinogenesis in the upper airways during extraesophageal reflux, which is typically weak or nonacidic and similar to that of patients taking PPIs. [15][16][17][18][19][20][21][22][23][24][25][26][27][28][29] Furthermore, parietal and chief cells observed in BE, in the background of EAC and in heterotopic gastric mucosa patches in the esophagus, represent a potential source of locally synthesized pepsin and acid that may contribute to disease progression. [30][31][32][33] We recently reported pepsinogen synthesis in BE mucosa in a small cohort of BE patients, and demonstrated pepsin-induced inflammatory changes in esophageal cells in vitro.…”

Section: Introductionmentioning

confidence: 99%

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Esophageal pepsin and proton pump synthesis in barrett's esophagus and esophageal adenocarcinoma

et al. 2019

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“…3). Host factors that increase the risk of OM include: young age 32 , male sex 33 , race and ethnicity 33 , genetic factors and a family history of OM 34 , craniofacial anomaly such as cleft palate 35 , atopy 34 , immunodeficiency 36 , upper respiratory tract infections (URTIs) and adenoid hypertrophy 34,37 , and laryngopharyngeal reflux 38 . Environmental factors that increase the risk of OM include: low socioeconomic status, exposure to tobacco smoke 34 , having older siblings 39 , day-care attendance 32,39,40 and the use of a pacifier 41,42 .…”

Section: Social and Environmental Risk Factorsmentioning

confidence: 99%

Otitis media

Schilder

Chonmaitree

Cripps

et al. 2016

Nat Rev Dis Primers

391

361

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Otitis media (OM) or middle ear inflammation is a spectrum of diseases, including acute otitis media (AOM), otitis media with effusion (OME; 'glue ear') and chronic suppurative otitis media (CSOM). OM is among the most common diseases in young children worldwide. Although OM may resolve spontaneously without complications, it can be associated with hearing loss and life-long sequelae. In developing countries, CSOM is a leading cause of hearing loss. OM can be of bacterial or viral origin; during 'colds', viruses can ascend through the Eustachian tube to the middle ear and pave the way for bacterial otopathogens that reside in the nasopharynx. Diagnosis depends on typical signs and symptoms, such as acute ear pain and bulging of the tympanic membrane (eardrum) for AOM and hearing loss for OME; diagnostic modalities include (pneumatic) otoscopy, tympanometry and audiometry. Symptomatic management of ear pain and fever is the mainstay of AOM treatment, reserving antibiotics for children with severe, persistent or recurrent infections. Management of OME largely consists of watchful waiting, with ventilation (tympanostomy) tubes primarily for children with chronic effusions and hearing loss, developmental delays or learning difficulties. The role of hearing aids to alleviate symptoms of hearing loss in the management of OME needs further study. Insertion of ventilation tubes and adenoidectomy are common operations for recurrent AOM to prevent recurrences, but their effectiveness is still debated. Despite reports of a decline in the incidence of OM over the past decade, attributed to the implementation of clinical guidelines that promote accurate diagnosis and judicious use of antibiotics and to pneumococcal conjugate vaccination, OM continues to be a leading cause for medical consultation, antibiotic prescription and surgery in high-income countries.

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“…However, little is known about the esophageal reflux symptoms these children do or do not present, the results of reflux tests in those without pepsin in the middle air fluid, the long-term outcome and the impact of reflux therapy. A proof of cause and effect between extra-esophageal reflux and middle ear inflammation is still missing [59].…”

Section: Ger(d) and Other Manifestationsmentioning

confidence: 99%

An updated review on gastro-esophageal reflux in pediatrics

Vandenplas¹,

Hauser

2015

Expert Review of Gastroenterology & Hepatology

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Comprehensive guidelines for the diagnosis and management of gastro-esophageal reflux (GER) and GER disease (GERD) were developed by the European and North American Societies for Pediatric Gastroenterology, Hepatology and Nutrition. GERD is reflux associated with troublesome symptoms or complications. The recognition of GER and GERD is relevant to implement best management practices. A conservative management is indicated in infants with uncomplicated physiologic reflux. Children with GERD may benefit from further evaluation and treatment. Since the publications of the European and North American Societies for Pediatric Gastroenterology, Hepatology and Nutrition guidelines in 2009, no important novelties in drug treatment have been reported. Innovations are mainly restricted to the management of regurgitation in infants. During the last 5 years, pros and cons of multichannel intraluminal impedance have been highlighted. However, overall 'not much has changed' in the diagnosis and management of GER and GERD in infants and children.

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The Role of Gastric Pepsin in the Inflammatory Cascade of Pediatric Otitis Media

Cited by 40 publications

References 47 publications

Esophageal pepsin and proton pump synthesis in barrett's esophagus and esophageal adenocarcinoma

Esophageal pepsin and proton pump synthesis in barrett's esophagus and esophageal adenocarcinoma

Otitis media

An updated review on gastro-esophageal reflux in pediatrics

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