Dysfunctional Inflammation in Cystic Fibrosis Airways: From Mechanisms to Novel Therapeutic Approaches

Abstract

Cystic fibrosis (CF) is an inherited disorder caused by mutations in the gene encoding for the cystic fibrosis transmembrane conductance regulator (CFTR) protein, an ATP-gated chloride channel expressed on the apical surface of airway epithelial cells. CFTR absence/dysfunction results in defective ion transport and subsequent airway surface liquid dehydration that severely compromise the airway microenvironment. Noxious agents and pathogens are entrapped inside the abnormally thick mucus layer and establish a highly inflammatory environment, ultimately leading to lung damage. Since chronic airway inflammation plays a crucial role in CF pathophysiology, several studies have investigated the mechanisms responsible for the altered inflammatory/immune response that, in turn, exacerbates the epithelial dysfunction and infection susceptibility in CF patients. In this review, we address the evidence for a critical role of dysfunctional inflammation in lung damage in CF and discuss current therapeutic approaches targeting this condition, as well as potential new treatments that have been developed recently. Traditional therapeutic strategies have shown several limitations and limited clinical benefits. Therefore, many efforts have been made to develop alternative treatments and novel therapeutic approaches, and recent findings have identified new molecules as potential anti-inflammatory agents that may exert beneficial effects in CF patients. Furthermore, the potential anti-inflammatory properties of CFTR modulators, a class of drugs that directly target the molecular defect of CF, also will be critically reviewed. Finally, we also will discuss the possible impact of SARS-CoV-2 infection on CF patients, with a major focus on the consequences that the viral infection could have on the persistent inflammation in these patients.

Keywords: CFTR modulators; anti-inflammatory treatment; cystic fibrosis; inflammation.

Figure 1

Anti-inflammatory properties of CFTR modulators. CF airways are a highly inflammatory environment characterized by infiltration of inflammatory cells, primarily neutrophils, that fail to effectively clear pathogens entrapped in the abnormally thick and sticky mucus layer. Consequently, failed resolution of this indiscriminate and sterile immune response, further fueled by the abnormal intracellular ceramide levels of airway epithelial cells, disrupts the physiological lung barrier, resulting in reduced TEER values. Besides restoring CFTR activity, CFTR modulators exert various anti-inflammatory effects by targeting intracellular processes, such as ceramide accumulation, cytokine transcription, membrane integrity, and macrophage-mediated phagocytosis of bacteria. Red lines represent the damaged plasma membrane. TEER: transepithelial electrical resistance; NE: neutrophil elastase; VX-770: ivacaftor; VX-809: lumacaftor; VX-661: tezacaftor; VX-445: elexacaftor.