Sandra Villanueva

Maintenance of potassium (K ⁺ ) homeostasis across cell membranes is essential for life. While systemic K ⁺ balance is primarily regulated by the kidneys and intestines, ion channels, pumps, and transporters govern K ⁺ movement across epithelial barriers at the cellular level. Despite the prevalence of diseases caused by disrupted K ⁺ homeostasis, the role of K ⁺ channels in the lungs has received comparatively little attention. The airway epithelium expresses a diverse array of K ⁺ channels that regulate key functions such as transepithelial ion transport, ciliary beating, and mucus secretion. These processes are fundamental components of mucociliary clearance (MCC), the primary innate defense mechanism of the lungs. Dysfunction of MCC is central to muco‐obstructive diseases, including cystic fibrosis (CF), chronic obstructive pulmonary disease (COPD), and asthma. While K ⁺ channels were once considered therapeutic targets for enhancing anion secretion in CF, initial interest waned. However, it has been reinvigorated by recent findings showing that drugs targeting CFTR can also modulate airway epithelial K ⁺ channels and facilitate MCC. In this review, we compile current evidence on targeting K ⁺ channels to treat muco‐obstructive diseases. We discuss therapeutic opportunities offered by K ⁺ channel modulators, highlight emerging functions of these channels in the airways, and outline priorities for future research.

This study provides the first spatiotemporal map of Foxi1 ⁺ pulmonary ionocytes in mouse airways. These rare cells, which express the majority of CFTR mRNA, emerge postnatally near developing submucosal glands and concentrate in the laryngeal subglottis during adulthood. Their distribution remains unaltered in Cftr ^{ΔF508/ΔF508} mice, suggesting CFTR dysfunction does not disrupt ionocyte patterning.

Bicarbonate secretion is a fundamental process involved in maintaining acid-base homeostasis. Disruption of bicarbonate entry into airway lumen, as has been observed in cystic fibrosis, produces several defects in lung function due to thick mucus accumulation. Bicarbonate is critical for correct mucin deployment and there is increasing interest in understanding its role in airway physiology, particularly in the initiation of lung disease in children affected by cystic fibrosis, in the absence of detectable bacterial infection. The current model of anion secretion in mammalian airways consists of CFTR and TMEM16A as apical anion exit channels, with limited capacity for bicarbonate transport compared to chloride. However, both channels can couple to SLC26A4 anion exchanger to maximise bicarbonate secretion. Nevertheless, current models lack any details about the identity of the basolateral protein(s) responsible for bicarbonate uptake into airway epithelial cells. We report herein that the electrogenic, sodium-dependent, bicarbonate cotransporter, SLC4A4, is expressed in the basolateral membrane of human and mouse airways, and that it’s pharmacological inhibition or genetic silencing reduces bicarbonate secretion. In fully differentiated primary human airway cells cultures, SLC4A4 inhibition induced an acidification of the airways surface liquid and markedly reduced the capacity of cells to recover from an acid load. Studies in the Slc4a4-null mice revealed a previously unreported lung phenotype, characterized by mucus accumulation and reduced mucociliary clearance. Collectively, our results demonstrate that the reduction of SLC4A4 function induced a CF-like phenotype, even when chloride secretion remained intact, highlighting the important role SLC4A4 plays in bicarbonate secretion and mammalian airway function.

Rett syndrome is best known due to its severe and devastating symptoms in the central nervous system. It is produced by mutations affecting the Mecp2 gene that codes for a transcription factor. Nevertheless, evidence for MECP2 activity has been reported for tissues other than those of the central nervous system. Patients affected by Rett presented with intestinal affections whose origin is still not known. We have observed that the Mecp2-null mice presented with episodes of diarrhea, and decided to study the intestinal phenotype in these mice. Mecp2-null mice or bearing the conditional intestinal deletion of MECP2 were used. Morphometirc and histologic analysis of intestine, and RT-PCR, western blot and immunodetection were perfomed on intestinal samples of the animals. Electrical parameters of the intestine were determined by Ussing chamber experiments in freshly isolated colon samples. First we determined that MECP2 protein is mainly expressed in cells of the lower part of the colonic crypts and not in the small intestine. The colon of the Mecp2-null mice was shorter than that of the wild-type. Histological analysis showed that epithelial cells of the surface have abnormal localization of key membrane proteins like ClC-2 and NHE-3 that participate in the electroneutral NaCl absorption; nevertheless, electrogenic secretion and absorption remain unaltered. We also detected an increase in a proliferation marker in the crypts of the colon samples of the Mecp2-null mice, but the specific silencing of Mecp2 from intestinal epithelium was not able to recapitulate the intestinal phenotype of the Mecp2-null mice. In summary, we showed that the colon is severely affected by Mecp2 silencing in mice. Changes in colon length and epithelial histology are similar to those observed in colitis. Changes in the localization of proteins that participate in fluid absorption can explain watery stools, but the exclusive deletion of Mecp2 from the intestine did not reproduce colon changes observed in the Mecp2-null mice, indicating the participation of other cells in this phenotype and the complex interaction between different cell types in this disease.