Role of epithelial HCO₃⁻ transport in mucin secretion: lessons from cystic fibrosis

Abstract

The invitation to present the 2010 Hans Ussing lecture for the Epithelial Transport Group of the American Physiological Society offered me a unique, special, and very surprising opportunity to join in saluting a man whom I met only once, but whose work was the basis, not only for my career, but also for finding the molecular defect in the inherited disease cystic fibrosis (CF). In this context, I will venture to make the tribute with a new explanation of why a mutation in a single gene that codes for an anion channel can cause devastation of multiple epithelial systems with pathogenic mucus. In so doing, I hope to raise awareness of a new role for that peculiar anion around which so much physiology revolves, HCO3−. I begin by introducing CF pathology as I question the name of the disease as well as the prevalent view of the basis of its pathology by considering: 1) mucus, 2) salt, and 3) HCO3−. I then present recent data showing that HCO3− is required for normal mucus discharge, and I will close with conjecture as to how HCO3− may support mucus discharge and why the failure to transport this electrolyte is pathogenic in CF.

Human cystic fibrosis airway epithelia have reduced Cl − conductance but not increased Na + conductance

“…(v) The paradoxical influence on electrophysiological properties of the absence of Cl − conductance is readily apparent in the sweat gland duct. In CF ducts, Na + absorption is decreased by ∼80%, but absolute Vt can be increased 10-fold (29). Decreased Cl − conductance, not increased Na + conductance, causes the increased Vt.…”

Cystic Fibrosis: Does CFTR Malfunction Alter pH Regulation?

“…Quinton's new hypothesis [55], that in a healthy person the extracellular bicarbonate functions to chelate calcium from the mucins at the moment of secretion to allow the mucins to fully expand but in CF the mucins don't fully expand and appear as "dehydrated." The possibility that mucus build up in cystic fibrosis patients may largely be caused by bicarbonate disruption, not by salt and fluid imbalance, is intriguing idea from a man who has been correct before.…”

“…In CF disease the mucins don't fully expand and appear as "dehydrated mucus." Lastly in a 2010 review, Quinton [55] put forward the possibility that mucus build up in cystic fibrosis patients may largely be caused by bicarbonate disruption, not by salt/fluid imbalance as traditionally explained. This now has supplemented an existing hypothesis of how lung disease develops, that is that the mucus from the submucosal glands is already defective as it emerges and adheres to the glands and airway surface providing an island for bacterial growth.…”

Impact of Mesenchymal Stem Cells on Lipopolysaccharide-Induced Apoptosis in Acute Lung Injury Rat Model

“…According to Quinton (2010), IL-1beta may be an important defense mechanism of the airway epithelium to enhance mucociliary clearance during airway inflammation. IL-1beta increased the secretion of MUC5AC, but not MUC5B.…”