The cystic fibrosis transmembrane conductance regulator (CFTR) gene encodes a cAMP-regulated anion channel [1, 11]. CFTR is expressed in many tissues, but it is best known for its detrimental role in the development of cystic fibrosis. Mutations in the CFTR gene result in a lack of functional channels at the plasma membrane of epithelial cells and cause dysfunction of many affected organs such as the lungs, the intestine, and the pancreas [2, 12]. CFTR function, however, may also be impaired in inflammatory or infectious diseases. Rapid loss of functional CFTR has been observed following bacterial or viral infections, and among others, has been linked to pneumonia-induced acute respiratory distress syndrome (ARDS) [7]. ARDS is a syndrome of acute respiratory failure caused by noncardiogenic pulmonary edema. It is characterized by damage to the endothelial and epithelial barriers of the lung. The resulting increase in permeability to liquid and proteins across lung endothelial and epithelial barriers causes protein-rich edema in the lung interstitium and alveoli, respectively [9]. The mechanisms linking infection, loss of CFTR, and barrier dysfunction, however, have been elusive.

In an elegant study published in the Science Translational Medicine, Erfinanda and colleagues now identified an important pathomechanism that links infection to loss of functional CFTR from pulmonary endothelial cells, lung barrier failure, and development of pneumonia-induced ARDS [4]. First, they confirmed that CFTR expression is downregulated in human and murine lung tissue following infection with S. pneumoniae or P. aeruginosa. Of note, CFTR was also lost from endothelial cells treated with plasma from COVID patients (personal communication). In elaborate experiments, they further showed that loss of CFTR function increased endothelial permeability and edema formation in isolated perfused rat lungs. This is linked to an increase in intracellular Cl− and Ca2+ levels within the endothelial cells. They then went on to fully delineate the molecular pathways that link loss of CFTR function to endothelial barrier failure. CFTR acts as an active ion channel in pulmonary endothelial cells and loss of CFTR reduces Cl− conductance across the plasma membrane which results in an increase in the intracellular Cl− concentration [Cl−]i. Counterintuitively, the authors found that inhibition of CFTR also leads to membrane depolarization, opening of voltage-gated calcium channels (VGCCs), and an increase in the intracellular Ca2+ concentration in endothelial cells. Since inhibition of a Cl− conductance in a cell, where Cl− is not passively distributed, will rather cause membrane hyperpolarization, the authors aimed at unraveling this conundrum. They found that the increase in [Cl−]i inhibits the serine-threonine kinase with-no-lysine kinase 1 (WNK1). Inhibition of WNK1 causes endothelial Ca2+ influx via activation of the polymodal cation channel transient receptor potential vanilloid 4 (TRPV4), a known regulator of lung endothelial barrier function [10] (Fig. 1). TRPV4-deficient (Trpv4−/−) mice have reduced permeability-type lung edema upon S. pneumoniae infection, confirming TRPV4 as a downstream effector of endothelial barrier failure after CFTR and subsequent WNK1 inhibition.

Fig. 1
figure 1

Permeability to liquid and proteins across the endothelial and epithelial barriers is tightly regulated in the healthy lung (left). This prevents formation of pulmonary edema and is critical for adequate gas exchange in the lung. Barrier-damage-induced pulmonary edema is a key feature of ARDS. Erfinanda and colleagues have now unraveled an important pathomechanism for lung barrier failure and development of pneumonia-induced ARDS. Infection causes a loss of CFTR from pulmonary endothelial cells resulting in an increase in intracellular Cl− levels. High Cl− levels inhibit WNK1, which in turn leads to activation (disinhibition) of TRPV4. This raises intracellular Ca2+ levels and leads to increased endothelial permeability and formation of pulmonary edema (right). Rescuing CFTR function with ivacaftor, a clinically approved CFTR potentiator, prevents barrier failure and edema

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Finally, the translational potential of these findings was convincingly demonstrated in vitro and in vivo. Ivacaftor, a clinically approved CFTR potentiator [3], stabilizes endothelial CFTR expression and function, prevents endothelial barrier failure and edema, and improves survival in mice with S. pneumoniae–induced pneumonia. The relevance of these findings is supported by a very recent report, showing that SARS-CoV and SARS-CoV-2 cause a loss of CFTR expression and increased edema accumulation in lungs of mice which is rescued by ivacaftor [5].

Overall, the study of Erfinanda and colleagues presents a possible therapeutic strategy in people suffering from ARDS due to severe pneumonia. Such treatment is urgently needed. Despite five decades of basic and clinical research, there is still no effective pharmacotherapy for ARDS and the treatment remains primarily supportive [6]. Furthermore, these findings can expand the success story of the highly effective CFTR-directed therapeutics that are already a life-changing treatment for up to 90% of people with cystic fibrosis who carry responsive CFTR mutations [8].