CFTR as a therapeutic target for severe lung infection

Abstract

Lung infection is one of the leading causes of morbidity and mortality worldwide. Even with appropriate antibiotic and antiviral treatment, mortality in hospitalized patients often exceeds 10%, highlighting the need for the development of new therapeutic strategies. Of late, cystic fibrosis transmembrane conductance regulator (CFTR) is-in addition to its well-established roles in the lung airway and extrapulmonary organs-increasingly recognized as a key regulator of alveolar homeostasis and defense. In the alveolar epithelium, CFTR mediates alveolar fluid secretion and liquid homeostasis; in the microvascular endothelium, CFTR maintains vascular barrier function. CFTR also contributes to alveolar immunity. Yet, in lung infection, diverse molecular mechanisms reduce CFTR abundance and otherwise impair its function, promoting alveolar inflammation, edema, and cell death. Preservation or restoration of CFTR function by CFTR modulator drugs thus presents a promising avenue to combat lung infection in a pathogen-independent manner.

Keywords: CFTR; acute respiratory distress syndrome; host-pathogen interactions; pneumonia; pulmonary alveoli.

Figure 1.. Current conceptual model of alveolar liquid secretion at homeostasis.

Under baseline conditions, activity of the basolateral Na,K-ATPase (NKA) in the alveolar epithelium transports Na⁺ out of the cytosol and into the interstitial space, establishing an outward Na⁺ gradient across basolateral plasma membranes that drives cellular uptake of Na⁺ and Cl⁻ through the basolateral Na⁺-K⁺-Cl⁻ (NKCC) cotransporter. Cl⁻ uptake thus increases intracellular Cl⁻ content in the alveolar epithelium and establishes the Cl⁻ potential gradient that drives Cl⁻ through apical plasma membrane CFTR into airspace lumens. Na⁺ and water follow by transcellular or paracellular pathways to generate the alveolar lining layer (ALL). Na,K-ATPase activity is likely constitutive, since its dysfunction disrupts epithelial tight junctions (135). Although CFTR may regulate ENaC function in some epithelia (136), reports indicate it does not in the alveolar epithelium (17, 25).