H+/K+ATPase Expression in the Larynx of Laryngopharyngeal Reflux and Laryngeal Cancer Patients

Abstract

Objectives The gastric H+/K+ ATPase proton pump has previously been shown to be expressed in the human larynx, however its contribution to laryngopharyngeal reflux (LPR) signs, symptoms and associated diseases such as laryngeal cancer is unknown. Proton pump expression in the larynx of patients with LPR and laryngeal cancer was investigated herein. A human hypopharyngeal cell line expressing the proton pump was generated to investigate its effects. Study Design In‐vitro translational. Methods Laryngeal biopsies were obtained from three LPR and eight LSCC patients. ATP4A, ATP4B and HRPT1 were assayed via qPCR. Human hypopharyngeal FaDu cell lines stably expressing proton pump were created using lentiviral transduction and examined via transmission electron microscopy and qPCR for genes associated with inflammation or laryngeal cancer. Results Expression of ATP4A and ATP4B was detected in 3/3 LPR, 4/8 LSCC‐tumor and 3/8 LSCC‐adjacent specimens. Expression of ATP4A and ATP4B in FaDu elicited mitochondrial damage and expression of IL1B, PTGS2, and TNFA (P < .0001); expression of ATP4B alone did not. Conclusions Gastric proton pump subunits are expressed in the larynx of LPR and LSCC patients. Mitochondrial damage and changes in gene expression observed in cells expressing the full proton pump, absent in those expressing a single subunit, suggest that acid secretion by functional proton pumps expressed in upper airway mucosa may elicit local cell and molecular changes associated with inflammation and cancer. Level of Evidence NA Laryngoscope, 131:130–135, 2021

<p>Pump Proton and Laryngeal H⁺/K⁺ ATPases</p>

“…Zhang et al of the H + /K + ATPase α-and β-subunits in the stomach among different human tissues evaluated, including the larynx. 48 The above-cited studies provide convincing evidence of a laryngeal H + /K + ATPase [42][43][44][45][46][47] in normal laryngeal tissues but also suggest the potential role of the proton pump in the abnormal mucus secretion frequently seen in patients with chronic laryngitis. The discovery of a laryngeal proton pump may explain the pathologically acidic environment of the oropharynx in patients without gastroesophageal reflux, with profound implications for PPI therapy, as the larynx is one of the extragastric targets of these drugs.…”

“…Although its small sample size and absence of a reflux and laryngeal cancer-free control cohort, they suggested that acid secretion by functional H + /K + ATPase proton pumps expressed in laryngeal mucosa may elicit laryngeal mucosa cells and molecular changes associated with inflammation and cancerogenesis. 47…”

Relationship Between Pepsin Expression and Dysplasia Grade in Patients With Vocal Cord Leukoplakia

“…1 Laryngopharyngeal reflux (LPR) has recently received attention in the context of laryngeal lesions, including vocal cord leukoplakia. 4-10…”

Laringopharingeal Reflux Impacts Immune Microenvironment of Laryngeal Carcinoma

“…Виявлені в роботі морфологічні зміни при ЛФР є досить закономірними з огляду на рівень рН та дію ферментів. Раніше було показа но, що за умов рефлюксу в слизовій обо лон ці гортані зростає експресія та ензиматична активність матриксної металопротеїнази-7 [20] при порушенні експресії Е-кадгерину, H + ,K + -ATФази та карбоангідрази ІІІ [21]. Це обмежує бар'єрні властивості покривного епітелію та сприяє розвитку ушкодження та хронічного запалення.…”