Duodenal Contents Reflux-Induced Laryngitis in Rats: Possible Mechanism of Enhancement of the Causative Factors in Laryngeal Carcinogenesis

Ling, Zhi‐Qiang; Mukaisho, Ken‐ichi; Hidaka, Miyoko; Chen, Kuan-Hao; Yamamoto, Go; Hattori, Takanori

doi:10.1177/000348940711600613

Cited by 10 publications

(11 citation statements)

References 45 publications

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“…A recent study suggested that swallowing abnormalities, probably via GERD comorbidity, were associated with frequent COPD exacerbations [37]. Our previous study using the same rat reflux model as the present study showed that the reflux of gastro-duodenal contents causes severe laryngitis [30]. Inflammation of the larynx must play a role in impairment of the swallowing reflex.…”

Section: Discussionsupporting

confidence: 53%

“…In order to establish experimental evidence for causal relationships between GER and respiratory disorders, we examined both lungs of the reflux model, which had previously been used to investigate the histogenesis of Barrett's esophagus and esophageal carcinoma [11,12] and was recently used to examine the mechanism of development of extraesophageal syndromes including laryngitis and dental erosion [26,30].…”

Section: Introductionmentioning

confidence: 99%

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Histological Examination of the Relationship between Respiratory Disorders and Repetitive Microaspiration Using a Rat Gastro-Duodenal Contents Reflux Model

et al. 2011

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Microaspiration due to gastroesophageal reflux (GER) has been suggested as a factor contributing to the development and exacerbation of several respiratory disorders. To explore the relationship between GER and respiratory disorders, we histologically examined the bilateral lungs of a rat gastroduodenal contents reflux model, which was previously used to investigate the histogenesis of Barrett's esophagus and esophageal carcinoma. GER was surgically induced in male Wistar rats. The bilateral lungs of the reflux rats were examined with hematoxylin and eosin (HE), PAS-Alcian blue, and Azan staining at 10 and 20 weeks after surgery. Immunohistochemical staining of CD68 and α-SMA was also performed. Aspiration pneumonia with severe peribronchiolar neutrophilic and lymphocytic infiltrates, goblet cell hyperplasia, prominence of blood vessels, and increased thickness of the smooth muscle layer were detected. Bronchiolitis obliterans (BO)-like lesions comprising granulation tissue with macrophages, spindle cells, and multinucleated giant cells in the lumen of respiratory bronchioles were observed in the bilateral lungs of the reflux animals. These findings suggest that the severe inflammation and the BO-like lesions may play a role in exacerbation of the forced expiratory volume in 1 second (FEV 1) in human cases. In conclusion, we speculate that repetitive microaspiration due to GER may contribute to the exacerbation of various respiratory diseases, particularly asthma and chronic obstructive pulmonary disease (COPD), and the development of BO syndrome following lung transplantation. The reflux model is a good tool for examining the causal relationships between GER and respiratory disorders.

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Section: Discussionsupporting

confidence: 53%

Section: Introductionmentioning

confidence: 99%

Histological Examination of the Relationship between Respiratory Disorders and Repetitive Microaspiration Using a Rat Gastro-Duodenal Contents Reflux Model

et al. 2011

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“…Many others have also suggested an association 7, 11–14. To further explore the association between LPR and laryngeal cancer, several investigators have examined the direct effect of the individual components of gastric refluxate—mainly acid, pepsin, and bile acids—on laryngeal cell biology 7, 15, 16. These studies demonstrated a significant role for pepsin and bile acids in carcinogenesis, in a dose‐dependent manner with greater toxicity at lower pH levels.…”

Section: Introductionmentioning

confidence: 99%

Pepsin promotes proliferation of laryngeal and pharyngeal epithelial cells

et al. 2012

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Objective/Hypothesis Laryngopharyngeal reflux (LPR) is thought to be a significant risk factor for laryngeal squamous cell carcinoma (SCC), but causality has never been proven. It is accepted that chronic reflux into the esophagus can induce metaplastic changes in esophageal mucosa with subsequent increased risk of esophageal adenocarcinoma, but no similar associations have been established for LPR and laryngopharyngeal SCC. The objective of this study was to test the hypothesis that reflux of pepsin into the laryngopharynx can promote carcinogenesis. Study Design Translational research study Methods Normal human laryngeal primary epithelial cell cultures and hypopharyngeal FaDu SCC cells were exposed to human pepsin and analyzed by Human Cancer PathwayFinder and miRNA Superarrays, flow cytometry and Western blot to determine the effect of pepsin on carcinogenesis. Laryngeal biopsy specimens, taken from cancer patients and normal control subjects, were analyzed for the presence of pepsin by Western blot. Results Microarray analysis demonstrated that pepsin significantly altered the expression of 27 genes implicated in carcinogenesis and also affected the expression of 22 microRNAs known to be altered in human head and neck cancers. Pepsin increased proliferation in both FaDu SCC cells and cultured normal laryngeal epithelial primary cells by increasing S phase distribution on flow cytometry analysis in a time and dose dependent manner. Furthermore, pepsin was detected in 60% (3/5) human laryngeal cancer biopsies, absent in all (0/5) normal control specimens. Conclusion These data support a role for refluxed pepsin in the promotion of epithelial proliferation and carcinogenesis of the larynx and pharynx.

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“…Additional studies examined the direct effect of various individual components of refluxate including acid, pepsin and bile salts on laryngeal cells. These demonstrated a significant role for pepsin and bile acids in carcinogenesis, in a dose-dependent manner with greater toxicity at a lower pH [53]. Using an in vivo hamster buccal pouch model of squamous cell carcinoma (SCC), our group found a significant increase in tumor volume in hamster cheek pouches exposed to pepsin (0.1 mg/ml; pH 2) plus a known carcinogen-7, 1 dimethylbenzanthracene (DMBA)-compared to exposure to DMBA alone, suggesting that pepsin in acid reflux does promote tumorigenesis [54].…”

Section: Pepsin: Mediator Of Cell Damagementioning

confidence: 97%

The Role of Pepsin in LPR: Will It Change Our Diagnostic and Therapeutic Approach to the Disease?

Luebke

Samuels

Johnston

2016

Curr Otorhinolaryngol Rep

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Laryngopharyngeal reflux (LPR) is the back flow of gastric contents into the laryngopharynx. It is estimated that this disease affects 20-40 % of the United States population and is commonly encountered by otolaryngologists. Patients with LPR present with symptoms due to chronic laryngeal irritation such as hoarseness and cough. Pepsin, a gastric enzyme, has been shown to be a specific and sensitive biomarker for LPR. Measurement of pepsin in patients with LPR symptoms holds promise as a reliable diagnostic test. Studies have shown that pepsin induces cell damage, inflammation, and neoplastic changes independently of gastric acid in an endocytosis-dependent manner. Thus, pepsin has been proposed as a novel therapeutic target, especially for patients experiencing refractory symptoms on currently available anti-reflux medications. Further research is needed to elucidate the exact role that pepsin plays in inflammatory and neoplastic diseases of the laryngopharynx and to develop pharmacologic agents targeting pepsin.

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Duodenal Contents Reflux-Induced Laryngitis in Rats: Possible Mechanism of Enhancement of the Causative Factors in Laryngeal Carcinogenesis

Cited by 10 publications

References 45 publications

Histological Examination of the Relationship between Respiratory Disorders and Repetitive Microaspiration Using a Rat Gastro-Duodenal Contents Reflux Model

Histological Examination of the Relationship between Respiratory Disorders and Repetitive Microaspiration Using a Rat Gastro-Duodenal Contents Reflux Model

Pepsin promotes proliferation of laryngeal and pharyngeal epithelial cells

The Role of Pepsin in LPR: Will It Change Our Diagnostic and Therapeutic Approach to the Disease?

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