Pump Proton and Laryngeal H+/K+ ATPases

Abstract

Purpose: The presence of extra-gastric H⁺/K⁺ ATPases may explain the clinically significant effect of proton pump inhibitor (PPI) pharmacotherapy in patients with chronic laryngitis related to laryngopharyngeal reflux disease (LPRD) but without gastroesophageal reflux disease (GERD) symptoms. Given the need for a better understanding of GERD and LPRD, we review the various proton pumps with respect to their classification, function, and distribution. We then consider the potential role of the laryngeal H⁺/K⁺ ATPase pump in LPRD.

Methods: We searched databases of PubMed, EMBASE, and Web of Science to achieve related published before September 15, 2020.

Results: There were only seven English-literatures meeting inclusive criteria about laryngeal H⁺/K⁺ ATPases. Some studies provide convincing evidence of a laryngeal H⁺/K⁺ ATPase 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.

Conclusion: A laryngeal H⁺/K⁺ ATPase expresses in normal laryngeal tissues. These findings question the current understanding of GERD and LPRD.

Keywords: H+/K+ ATPases; chronic laryngitis; gastroesophageal reflux disease; laryngopharyngeal reflux disease; larynx; proton pump.

Figure 1

Gastric proton pump H⁺/K⁺ ATPase and its functions. The gastric H⁺/K⁺ ATPase mediates the transport of K⁺ ions in the extracellular fluid into the cell, while intracellular H⁺ ions are simultaneously pumped out of the cell against a high concentration gradient to complete ion transport and gastric acid secretion. H⁺/K⁺ ATPase activity is stimulated by inflammatory and other factors by the bacterium Helicobacter pylori, leading to excessive gastric acid secretion and GERD. This is the mechanism targeted by PPI therapy. H⁺/K⁺ ATPases contain the α-subunit and β-subunit. The α-subunit is made up of 1035 amino acids. ATP-binding, acyl-phosphorylation, inhibitor-binding, and ion-recognition sites are included in the α-subunit. The 290-amino-acid β-subunit is responsible for enzyme assembly and plays a role in enzyme activity.

Figure 2

Laryngeal H⁺/K⁺ ATPases. The H⁺/K⁺ ATPase proton pump is located mainly in the laryngeal seromucinous glands and ducts rather than in the squamous epithelium, which may be responsible for regulating seromucinous secretion in two conditions: (1) direct acid reflux in LPRD, (2) first-stage reflux, when reactivation during subsequent acid exposure leads to pepsin binding and thus to tissue autodigestion, which together with cellular necrosis regulates the pH of the interstitium and may lead to laryngopharyngeal reflux-induced acid exposure. The laryngeal H⁺/K⁺ ATPase is activated by laryngopharyngeal reflux and other infectious or inflammatory stimuli. The laryngeal H⁺/K⁺ ATPase secretes low levels of acid, which may induce laryngeal damage and, subsequently, chronic laryngitis or other laryngeal diseases. The pathologically acidic environment of the oropharynx in patients without gastroesophageal reflux is effective for PPI therapy, as the larynx is one of the extragastric targets of these drugs.