Mechanisms of Bicarbonate Secretion: Lessons from the Airways

The recognition that HCO3− secretion is impaired in CF patients dates back to the studies of Hadorn and coworkers in the 1960s (Hadorn et al. 1968). These investigators showed that pancreatic HCO3− and fluid secretion were diminished in CF patients. Moreover, CF patients were refractory to secretin, a cAMP-mediated secretory agonist in the pancreas. These studies were confirmed by Gaskin et al. (1982) and Kopelman et al. (1985, 1988). Extensive transport studies of the exocrine pancreas have shown that HCO3− is the primary anion secreted by the ductal cells, the predominate site of CFTR expression (Marino et al. 1991). The human pancreas can secrete a fluid of 130 mm HCO3− (Schultz 1987). Secreted HCO3− electrically draws Na+ into the lumen and H2O follows osmotically. The secreted fluid and electrolytes serve to flush the digestive enzymes from the acini and ducts of the pancreas. Thus, impaired HCO3− secretion results in poor clearance of the digestive enzymes, and their premature activation eventuates in the destruction of the pancreas in CF. We surmise that a similar sequela follows from impaired HCO3− secretion in the submucosal glands and airways of CF patients. Indeed, several recent studies from Wine and coworkers have shown cAMP-stimulated fluid secretion is impaired from CFTR-deficient submucosal glands (Joo et al. 2006). Verkman and coworkers have also shown impaired fluid secretion from the submucosal glands of CF patients and shown that the secreted fluid is hyperviscous and acidic compared with glands from non-CF patients (Salinas et al. 2005; Song et al. 2006). Analogous to the pancreas, the submucosal glands secrete mucins, protease inhibitors, antibiotic peptides, and enzymes that must be flushed from the glands onto the airway surface epithelium (Basbaum et al. 1990). Moreover, the physical properties of mucus are intrinsically dependent on the composition of the fluid. Most notably, alterations in ionic strength, divalent cation concentration, and pH have profound effects on the viscoelastic properties of mucins (Forstner et al. 1976; List et al. 1978; Tam et al. 1981; Lin et al. 1993). In the pancreas, the pH of the ductal fluid plays a critical role in regulating the activity of the exocytosed digestive enzymes. In contrast, very little is known regarding the electrolyte composition and pH of the submucosal gland fluid and the role it might play in the 1000-fold expansion that a mucin granule undergoes upon release and degranulation (Yeates et al. 1997; Verdugo and Hauser 2012). In addition, the surface epithelium must maintain a periciliary fluid of appropriate volume and composition to ensure proper mucociliary clearance (Randell and Boucher 2006; Boucher 2007). Adversely affected mucus leads to impaired mucociliary clearance from the submucosal glands and airway surface. The uncleared mucus then becomes a sink for bacterial binding, infection, and inflammation, thereby perpetuating a vicious cycle leading to further mucus secretion (Quinton 1999). This sequence of events is not restricted to the 40,000 individuals suffering from CF, but also occurs in more than 10 million patients suffering from COPD (chronic obstructive pulmonary disease) (Celli et al. 1995; O'Byrine et al. 1999). Thus, impaired fluid secretion by the submucosal glands or surface epithelium hinders clearance from the glands and airway surface. Until recently, Cl− was considered to be the secreted anion responsible for fluid secretion in the airways. However, recent studies suggest that HCO3− secretion importantly contributes to the airway surface and submucosal gland microenvironments.