CFTR is required for maximal transepithelial liquid transport in pig alveolar epithelia

Abstract

A balance between alveolar liquid absorption and secretion is critical for maintaining optimal alveolar subphase liquid height and facilitating gas exchange in the alveolar space. However, the role of cystic fibrosis transmembrane regulator protein (CFTR) in this homeostatic process has remained elusive. Using a newly developed porcine model of cystic fibrosis, in which CFTR is absent, we investigated ion transport properties and alveolar liquid transport in isolated type II alveolar epithelial cells (T2AECs) cultured at the air-liquid interface. CFTR was distributed exclusively to the apical surface of cultured T2AECs. Alveolar epithelia from CFTR(-/-) pigs failed to increase liquid absorption in response to agents that increase cAMP, whereas cAMP-stimulated liquid absorption in CFTR(+/-) epithelia was similar to that in CFTR(+/+) epithelia. Expression of recombinant CFTR restored stimulated liquid absorption in CFTR(-/-) T2AECs but had no effect on CFTR(+/+) epithelia. In ex vivo studies of nonperfused lungs, stimulated liquid absorption was defective in CFTR(-/-) alveolar epithelia but similar between CFTR(+/+) and CFTR(+/-) epithelia. When epithelia were studied at the air-liquid interface, elevating cAMP levels increased subphase liquid height in CFTR(+/+) but not in CFTR(-/-) T2AECs. Our findings demonstrate that CFTR is required for maximal liquid absorption under cAMP stimulation, but it is not the rate-limiting factor. Furthermore, our data define a role for CFTR in liquid secretion by T2AECs. These insights may help to develop new treatment strategies for pulmonary edema and respiratory distress syndrome, diseases in which lung liquid transport is disrupted.

Inter-α-Inhibitor Blocks Epithelial Sodium Channel Activation and Decreases Nasal Potential Differences in ΔF508 Mice

“…Another study reported that increased functional CFTR decreases ENaC activity by raising intracellular Cl 2 (47). However, studies in newborn pigs with CF disease found no evidence for increased Na 1 reabsorption across airway epithelia (48,49). Herein we report that ΔF508 mice have significantly more negative amiloride-sensitive NPD values (223 vs. 27 mV for wild-type mice), which is in agreement with previous reports in mice (50) and humans with CF (51).…”

Comparative Mammalian Lung Primary Surface Epithelial Cell Culture

“…(Bove et al, 2010) Adult porcine CFTR-mediated transepithelial liquid transport. (Li et al, 2012) ECM, extracellular matrix; KGF, keratinocyte growth factor; SPA, SPB, SPD, surfactant proteins A, B, and D.…”

CFTR and lung homeostasis

“…Using isolated type II alveolar epithelial cells and ex vivo studies of newborn lungs, their data indicated that CFTR was not required for basal liquid absorption but was required for cAMP-stimulated liquid absorption and secretion, suggesting that the apical liquid layer is controlled by a number of ion channels at both the apical and basolateral membranes (47). These results are consistent with previous results of Matthay and coworkers (19,25), who suggested that CFTR is important for apical-basolateral fluid transport in cultured human alveolar epithelial type II cells.…”