Knowledge on the mechanisms of acid and base secretion in airways has progressed recently. The aim of this review is to summarize the known mechanisms of airway surface liquid (ASL) pH regulation and their implication in lung diseases. Normal ASL is slightly acidic relative to the interstitium, and defects in ASL pH regulation are associated with various respiratory diseases, such as cystic fibrosis. Basolateral bicarbonate (HCO₃⁻) entry occurs via the electrogenic, coupled transport of sodium (Na⁺) and HCO₃⁻, and, together with carbonic anhydrase enzymatic activity, provides HCO₃⁻ for apical secretion. The latter mainly involves CFTR, the apical chloride/bicarbonate exchanger pendrin and paracellular transport. Proton (H⁺) secretion into ASL is crucial to maintain its relative acidity compared to the blood. This is enabled by H⁺ apical secretion, mainly involving H⁺/K⁺ ATPase and vacuolar H⁺-ATPase that carry H⁺ against the electrochemical potential gradient. Paracellular HCO₃⁻ transport, the direction of which depends on the ASL pH value, acts as an ASL protective buffering mechanism. How the transepithelial transport of H⁺ and HCO₃⁻ is coordinated to tightly regulate ASL pH remains poorly understood, and should be the focus of new studies.

The mammalian kidney is particularly vulnerable to hypoperfusion, because the O₂supply to the renal medulla barely exceeds its O₂requirements. In this study, we examined the impact of the complex structural organization of the rat outer medulla (OM) on O₂distribution. We extended the region-based mathematical model of the rat OM developed by Layton and Layton ( Am J Physiol Renal Physiol 289: F1346–F1366, 2005) to incorporate the transport of RBCs, Hb, and O₂. We considered basal cellular O₂consumption and O₂consumption for active transport of NaCl across medullary thick ascending limb epithelia. Our model predicts that the structural organization of the OM results in significant Po₂gradients in the axial and radial directions. The segregation of descending vasa recta, the main supply of O₂, at the center and immediate periphery of the vascular bundles gives rise to large radial differences in Po₂between regions, limits O₂reabsorption from long descending vasa recta, and helps preserve O₂delivery to the inner medulla. Under baseline conditions, significantly more O₂is transferred radially between regions by capillary flow, i.e., advection, than by diffusion. In agreement with experimental observations, our results suggest that 79% of the O₂supplied to the medulla is consumed in the OM and that medullary thick ascending limbs operate on the brink of hypoxia.

We used a mathematical model of O₂transport and the urine concentrating mechanism of the outer medulla of the rat kidney to study the effects of blood pH and medullary blood flow on O₂availability and Na⁺reabsorption. The model predicts that in vivo paracellular Na⁺fluxes across medullary thick ascending limbs (mTALs) are small relative to transcellular Na⁺fluxes and that paracellular fluxes favor Na⁺reabsorption from the lumen along most of the mTAL segments. In addition, model results suggest that blood pH has a significant impact on O₂transport and Na⁺reabsorption owing to the Bohr effect, according to which a lower pH reduces the binding affinity of hemoglobin for O₂. Thus our model predicts that the presumed greater acidity of blood in the interbundle regions, where mTALs are located, relative to that in the vascular bundles, facilitates the delivery of O₂to support the high metabolic requirements of the mTALs and raises the concentrating capability of the outer medulla. Model results also suggest that increases in vascular and tubular flow rates result in disproportional, smaller increases in active O₂consumption and mTAL active Na⁺transport, despite the higher delivery of O₂and Na⁺. That is, at a sufficiently high medullary O₂supply, O₂demand in the outer medulla does not adjust precisely to changes in O₂delivery.

We extended the region-based mathematical model of the urine-concentrating mechanism in the rat outer medulla (OM) developed by Layton and Layton ( Am J Physiol Renal Physiol 289: F1346–F1366, 2005) to examine the impact of the complex structural organization of the OM on O₂transport and distribution. In the present study, we investigated the sensitivity of predicted Po₂profiles to several parameters that characterize the degree of OM regionalization, boundary conditions, structural dimensions, transmural transport properties, and relative positions and distributions of tubules and vessels. Our results suggest that the fraction of O₂supplied to descending vasa recta (DVR) that reaches the inner medulla, i.e., a measure of the axial Po₂gradient in the OM, is insensitive to parameter variations as a result of the sequestration of long DVR in the vascular bundles. In contrast, O₂distribution among the regions surrounding the vascular core strongly depends on the radial positions of medullary thick ascending limbs (mTALs) relative to the vascular core, the degree of regionalization, and the distribution of short DVR along the corticomedullary axis. Moreover, if it is assumed that the mTAL active Na⁺transport rate decreases when mTAL Po₂falls below a critical level, O₂availability to mTALs has a significant impact on the concentrating capability of the model OM. The model also predicts that when the OM undergoes hypertrophy, its concentrating capability increases significantly only when anaerobic metabolism supports a substantial fraction of the mTAL active Na⁺transport and is otherwise critically reduced by low interstitial and mTAL luminal Po₂in a hypertrophied OM.