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Rehman, T.; Welsh, M.J. Regulating Airway Surface Liquid pH through Inflammation. Encyclopedia. Available online: (accessed on 23 June 2024).
Rehman T, Welsh MJ. Regulating Airway Surface Liquid pH through Inflammation. Encyclopedia. Available at: Accessed June 23, 2024.
Rehman, Tayyab, Michael J. Welsh. "Regulating Airway Surface Liquid pH through Inflammation" Encyclopedia, (accessed June 23, 2024).
Rehman, T., & Welsh, M.J. (2023, May 05). Regulating Airway Surface Liquid pH through Inflammation. In Encyclopedia.
Rehman, Tayyab and Michael J. Welsh. "Regulating Airway Surface Liquid pH through Inflammation." Encyclopedia. Web. 05 May, 2023.
Regulating Airway Surface Liquid pH through Inflammation

The airway surface liquid (ASL) is a thin sheet of fluid that covers the luminal aspect of the airway epithelium. The ASL is a site of several first-line host defenses, and its composition is a key factor that determines respiratory fitness. Specifically, the acid–base balance of ASL has a major influence on the vital respiratory defense processes of mucociliary clearance and antimicrobial peptide activity against inhaled pathogens. In the inherited disorder cystic fibrosis (CF), loss of cystic fibrosis transmembrane conductance regulator (CFTR) anion channel function reduces HCO3 secretion, lowers the pH of ASL (pHASL), and impairs host defenses. These abnormalities initiate a pathologic process whose hallmarks are chronic infection, inflammation, mucus obstruction, and bronchiectasis. Inflammation is particularly relevant as it develops early in CF and persists despite highly effective CFTR modulator therapy. Inflammation may alter HCO3 and H+ secretion across the airway epithelia and thus regulate pHASL. Moreover, inflammation may enhance the restoration of CFTR channel function in CF epithelia exposed to clinically approved modulators. 

airway surface liquid cystic fibrosis inflammation host defense pH

1. Introduction

The airway surface liquid (ASL) is a thin layer of fluid that covers the luminal aspect of the airway epithelium [1][2][3]. The ASL thus forms a point of contact with the environment and is a site of several first-line host defenses. Antimicrobial peptides within ASL disrupt microbial cell membrane integrity, and thereby kill inhaled pathogens [4]. Gel-forming mucins, secreted into ASL, engage inhaled particles and pathogens, and the coordinated beating of cilia removes them from the lungs (mucociliary clearance) [5]. Neutrophils and macrophages phagocytose microbes that settle within ASL or kill them by extruding a meshwork of chromatin fibers [6][7]. Reactive oxygen species, released into ASL, suppress bacterial growth [8][9], and secreted purinergic nucleotides regulate ASL volume [10][11].
The abnormal acidification of ASL initiates a pathologic process in the airways, and for some lung disorders may provide a therapeutic target [12]. A preeminent example is cystic fibrosis (CF), an inherited disorder caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene [13][14]. The protein encoded by this gene forms an anion channel that conducts Cl and HCO3 across the apical membrane of several epithelia, including airway epithelia [15][16]. CFTR mutations eliminate or markedly reduce anion flow, thereby decreasing HCO3 secretion and lowering the pH of ASL (pHASL). The abnormally acidic ASL impairs, at least in part, an array of first-line host defenses (Figure 1) [17][18][19][20][21][22][23].
Figure 1. pHASL influences respiratory host defenses. The acid–base balance of ASL controls key first-line airway host defenses including secreted antimicrobial peptide activity and synergism against inhaled bacteria; mucus viscosity and elasticity; ciliary beat frequency (CBF)#; innate immune cell activities such as phagocytosis and extracellular killing of microbes through release of chromatin; activities of apical channels (e.g., acidic pHASL inhibits short palate lung and nasal epithelial clone 1-mediated inhibition of ENaC, promoting increased Na+ absorption [22]; extracellular HCO3 concentration, sensed by soluble adenylyl cyclase, regulates CFTR expression [24][25]); and entry of respiratory viruses into airway epithelial cells (e.g., pH-dependent entry of SARS-CoV-2 in TMPRSS2-expressing cells [26])##. ASL = airway surface liquid, ENaC = epithelial Na+ channel, CFTR = cystic fibrosis transmembrane conductance regulator, TMPRSS2 = transmembrane serine protease 2. #The mechanism by which pHASL alters CBF is not clear. In one study, CBF in bronchial cells increased as extracellular pH increased from 6 to 7.5 [20]. However, pH outside this range reduced CBF. Interestingly, the effect was less prominent in small airway ciliated cells. ##Most studies of airway physiology use proximal (large) airway cells. As CF airway disease involves distal (small) airways, regional differences in pHASL regulation and host defense mechanisms require further attention.

2. H+ and HCO3 Transporters Control pHASL

The balance of acid (H+) and base (HCO3) secretion across the apical membrane determines pHASL [27][28]. In the proximal (cartilaginous) airways, the non-gastric H+/K+-ATPase (ATP12A) is the main route for H+ secretion, and CFTR is the main route for HCO3 secretion. Non-CFTR mechanisms such as calcium-activated Cl channels (CaCC) and solute carrier family 26 (SLC26) transporters are also capable of secreting HCO3, but their overall contribution is small compared to CFTR (Figure 2) [27][29][30][31]. In contrast, in the distal (small) airways, ATP12A is absent, and the vacuolar H+-ATPase (V-ATPase) substitutes as the main H+-secreting mechanism [32]. Both CFTR and CaCC mediate HCO3 secretion across small airway epithelia [33].
Figure 2. Acid–base transporters that control pHASL differ between human and mouse airways. Models show key transport mechanisms that determine pHASL in human and mouse airway epithelia. Left panel (human): (A) a model of non-CF airway epithelium with ASL overlying the apical membrane; (B) loss of CFTR-mediated HCO3 secretion resulting in a lower pHASL; (C) inhibition of basolateral NBC diminishes HCO3 secretion and lowers pHASL despite intact apical CFTR channels. Right panel (mouse): (D) a model of non-CF (wild type) mouse airway epithelium. Note the absence of ATP12A and the expression of non-CFTR (CaCC) HCO3 channels; (E,F) in contrast to humans, loss of CFTR fails to lower pHASL in CF mice, providing one explanation for lack of spontaneous airway disease. However, exogenous ATP12A expression increases H+ secretion and lowers CF mouse pHASL; (G) SLC4A4−/− mice phenocopy human CF. For simplicity, only the chief acid–base transport mechanisms controlling pHASL are shown. It does not show Na+/H+ exchangers, Cl/HCO3 exchangers, Na+ and K+ channels, or Na+/K+-ATPase, which may also influence the movement of acid–base equivalents into or out of ASL. See legend and text for details. CA = carbonic anhydrase.

2.1. Reduced pHASL Disrupts Host Defenses

The normal pHASL is mildly acidic (e.g., 6.9–7.1 in human lower airways) relative to the interstitial fluid [7.4], though it varies considerably between individuals as well as between studies [1][27][28]. Recent reviews provide excellent tables summarizing pHASL variability between studies, including wild type versus CF [27][28]. Absolute pHASL measurements are influenced by technique, model system and airway region. It is also interesting to point out that pH is measured on log scale and a 3/10 increase in pH reflects a doubling of [H+].
Notwithstanding challenges involved in comparing results between studies, recent reports have identified several genetic changes in humans and/or animal models that alter pHASL (Figure 2). These studies provide critical insights into acid–base transport mechanisms that control pHASL and thus airway host defenses.
In humans with CF, the loss of CFTR-mediated HCO3 secretion leaves H+ secretion unbalanced, and hence lowers pHASL [34]. An abnormally acidic pHASL impairs mucociliary clearance, antimicrobial peptide activity against inhaled pathogens, and phagocytic cell function [17][18][21]. Raising pHASL at least partially rescues these impairments and identifies epithelial acid–base transporters as potential therapeutic targets.
The involvement of pHASL in airway host defense has also been tested by disrupting acid–base transporters other than CFTR. For instance, inhibiting basolateral NBC activity in human airway epithelia with normal CFTR channels lowers pHASL [35]. Interestingly, CFTR disruption in mice fails to produce spontaneous airway disease [36][37]. This is partly due to increased expression of non-CFTR HCO3 transporters and lack of expression of the non-gastric H+-pump (ATP12A) in murine airways (see below) [38].
Mutations in carbonic anhydrase isoform 12 (CA12) also phenocopy the loss of CFTR channel activity in human airways [39]. People with CA12 mutations show chronic coughs, airway colonization, bronchiectasis, and elevated sweat [Cl]. Interestingly, CA12 localizes at the apical membrane of airway epithelia. This expression pattern is physiologically relevant because proximal airway CO2 concentration fluctuates during tidal breathing [40]. Thus, pHASL rises during inhalation as airway lumen fills up with inhaled air (low CO2 concentration) but falls during exhalation as alveolar gases (higher CO2 concentration) enter the airways. Tidal pHASL oscillations enhance the epithelial host defense against bacteria.
ASL buffers resist changes in pHASL when H+ ions are added or removed. The main ASL buffer is HCO3 [41]. Accordingly, in Calu-3 epithelia, forskolin stimulation increases and CFTR knockdown decreases buffering capacity of apically secreted fluid. Mucins are negatively charged molecules that can also bind H+ and thus contribute to ASL buffering [42][43]. This effect is dependent on mucin concentration. Mucus accumulation lowers the amplitude of ventilatory pHASL oscillations [40], and dampened oscillations reduce antibacterial host defense, thus providing a potential mechanism by which mucus accumulation may increase susceptibility to respiratory infections.

2.2. pHASL Changes with CF Airway Disease Progression

In vitro studies in human airway epithelia show that pHASL is abnormally acidic in CF [34][38][44], but in vivo studies reveal mixed results. Some studies show a lower pHASL in CF [45][46], whereas others report no difference between CF and non-CF individuals [47][48]. This discrepancy is intriguing, given that CFTR-mediated HCO3 secretion is decreased in both in vitro and in vivo studies.
Most babies with CF develop airway inflammation over the first year of life [49][50][51][52][53]; in some cases, they also develop respiratory infections. Inflammation may induce ASL alkalinization through CFTR-independent mechanisms, and thus conceal the loss of CFTR-mediated HCO3 secretion. Studying initial stages of human CF airway disease might help separate effects due to CFTR loss from those due to inflammation. As inflammation develops early in CF, this approach requires studying ASL from babies soon after birth. In one small pilot study, pHASL in newborn CF babies (<four weeks of age) was lower compared with non-CF babies [54].

2.3. Inflammatory Cytokines Regulate pHASL

In the absence of rigorous in vivo assessments, the effects of inflammation on pHASL may be investigated in vitro by applying CF-relevant inflammatory stimuli to primary cultures of differentiated human airway epithelia. The cytokine interleukin-17 (IL-17) is an evolutionarily conserved molecule that drives neutrophilic airway inflammation [55][56]. In targeting the airway epithelium, IL-17 acts synergistically with other cytokines such as tumor necrosis factor-α (TNFα), IL-1β, etc. [57]. These proinflammatory molecules are increased in established CF airway disease [58][59].

2.4. H+ Secretion

Inflammation may alter acid secretion into ASL. One study reported increased expression of ATP12A in CF airways with established disease [60]. Exposure of airway epithelia to IL-4 or IL-13 also increased ATP12A expression, and thus H+ secretion [61][62]. TNFα exposure had a similar effect, but IL-17 alone or combined IL-17/TNFα did not change H+ secretion [31]. Importantly, inhibiting ATP12A with apical ouabain decreases H+ secretion, lowers ASL viscosity, and increases bacterial killing [34][38][62]. Efforts to identify safer agents that reduce ATP12A activity are underway.
Loss of CFTR function also affects distal (small) airways. Small airway epithelia lack ATP12A, but instead use V-ATPase to secrete H+. Effects of inflammation and infection on small airway H+ secretion remain relatively unexplored. P. aeruginosa infection may reduce V-ATPase-mediated H+ secretion [63][64], or acidify ASL via apically expressed monocarboxylate transporter 2, a H+-lactate cotransporter [65]. Interestingly, Li et al. showed that pHASL regulates membrane localization of V-ATPase in porcine small airway epithelia [32]. At neutral pHASL (7.4), the V-ATPase subunit ATP6V0D2 localizes in the apical membrane of small airway secretory cells.

2.5. HCO3 Secretion

2.5.1. CFTR-Mediated HCO3 Secretion

Several inflammatory cytokines have been shown to alkalinize pHASL. IL-17/TNFα, IL-4, IL-13, and IL-1β increase CFTR expression and activity, and increased CFTR-mediated anion secretion improves respiratory host defenses [31][61][66][67]. In CF epithelia, this component of host response is missing due to mutated, non-functional CFTR proteins. In contrast to above-mentioned cytokines, TGF-β reduces CFTR expression and transport activities in airway epithelia [68][69]. In vivo effects of inflammation are likely to be complex given that several cytokines elevated in CF airways target airway epithelium, alter HCO3 transport, and thus modify pHASL.

2.5.2. Non-CFTR-Mediated HCO3 Secretion

An array of cytokines (IL-17/TNFα, IL-4, and IL-13) induce non-CFTR HCO3 secretion across airway epithelia [30][61][66][70][71]. This is achieved through pendrin, an apical Cl/HCO3 exchanger, encoded by the gene SLC26A4. Several aspects of this transport process are noteworthy. First, pendrin is minimally expressed in airway epithelia under basal conditions but is strongly upregulated by inflammatory cytokines. Second, pendrin is an electroneutral exchanger that does not mediate net anion secretion or absorption or change membrane potential. Third, in the absence of functional CFTR channels, pendrin alone can drive ASL alkalinization, though greater alkalinization is achieved with pendrin plus CFTR [30][31]. Fourth, some reports indicate structural or functional interactions between CFTR and pendrin, resulting in the increased activity of both [70][72].

2.5.3. Paracellular HCO3 Shunt

In addition to secretion by airway epithelial cells, HCO3 can also move between the cells. Very few studies have explored the contribution of the paracellular pathway to pHASL, though it is often mentioned in the context of inflammation. A recent report showed that the paracellular pathway is as permeable to HCO3 as it is to Cl [73]. Under basal conditions, pHASL (6.6) is lower than the pH of the interstitial fluid (7.4) and the paracellular HCO3 flux is towards the lumen; however, the paracellular HCO3 flux decreases or even reverses as pHASL approaches or rises higher than the pH of the interstitial fluid. The paracellular pathway thus acts as a HCO3 shunt that may oppose increased cellular HCO3 secretion in inflamed airway epithelia [74]. Whether paracellular HCO3 permeability can be modulated to support ASL alkalinization is an interesting question and requires further investigation.

2.6. Other Regulatory Mechanisms

Inflammatory cytokines regulate diverse cellular mechanisms involved in HCO3 secretion. In addition to changes in apical HCO3 transporters, cytokines such as IL-17/TNFα, IL-13, or IL-4 also increase transcripts of several carbonic anhydrase and NBC isoforms [30][61]. Additional cytoplasmic mechanisms that regulate epithelial HCO3 secretion also change in the presence of cytokines. The WNK (with-no-lysine [K]) kinases are master-regulators of pancreatic HCO3 secretion [75]. As reported recently, these kinases also control HCO3 secretion across CF and non-CF airway epithelia [76]. Secretory cells, key HCO3 secreting cells in airway epithelia, express two WNK isoforms, WNK1 and WNK2. Reducing WNK kinase activity increases HCO3 secretion, raises pHASL, and enhances CF epithelial host defenses. At a mechanistic level, WNK kinases regulate intracellular [Cl] through their control of the basolateral Na+-K+-2Cl cotransporter (NKCC1). Inhibiting WNK lowers intracellular [Cl], which in turn may act as a signaling ion to stimulate HCO3 transport [77][78]. It is of note that combined IL-17/TNFα reduce WNK2 expression and raise pHASL and inhibiting residual WNK kinase activity further alkalinizes ASL.


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