ABSTRACT
Inflammation is a key driver in the pathogenesis of cystic fibrosis (CF). We assessed the effectiveness of elexacaftor/tezacaftor/ivacaftor (ETI) therapy on downregulating systemic and immune cell-derived inflammatory cytokines. We also monitored the impact of ETI therapy on clinical outcome. Adults with CF, heterozygous for F508del (n = 19), were assessed at baseline, one month and three months following ETI therapy, and clinical outcomes were measured, including sweat chloride, lung function, weight, neutrophil count and C-reactive protein (CRP). Cytokine quantifications were measured in serum and following stimulation of peripheral blood mononuclear cells (PBMCs) with lipopolysaccharide (LPS) and adenosine triphosphate and analysed using LEGEND plex™ Human Inflammation Panel 1 by flow cytometry (n = 19). ASC specks were measured in serum and caspase-1 activity and mRNA levels determined from stimulated PBMCs were determined. Patients remained stable over the study period. ETI therapy resulted in decreased sweat chloride concentrations (p < 0.0001), CRP (p = 0.0112) and neutrophil count (p = 0.0216) and increased percent predicted forced expiratory volume (ppFEV1) (p = 0.0399) from baseline to three months, alongside a trend increase in weight. Three months of ETI significantly decreased IL-18 (p< 0.0011, p < 0.0001), IL-1ß (p<0.0013, p = 0.0476), IL-6 (p = 0.0109, p = 0.0216) and TNF (p = 0.0028, p = 0.0033) levels in CF serum and following PBMCs stimulation respectively. The corresponding mRNA levels were also found to be reduced in stimulated PBMCs, as well as reduced ASC specks and caspase-1 levels, indicative of NLRP3-mediated production of pro-inflammatory cytokines, IL-1ß and IL-18. While ETI therapy is highly effective at reducing sweat chloride and improving lung function, it also displays potent anti-inflammatory properties, which are likely to contribute to improved long-term clinical outcomes.
Subject(s)
Aminophenols , Anti-Inflammatory Agents , Benzodioxoles , Cystic Fibrosis Transmembrane Conductance Regulator , Cystic Fibrosis , Cytokines , Indoles , Quinolones , Humans , Cystic Fibrosis/drug therapy , Cystic Fibrosis/genetics , Benzodioxoles/therapeutic use , Benzodioxoles/pharmacology , Adult , Aminophenols/therapeutic use , Female , Indoles/therapeutic use , Indoles/pharmacology , Male , Cystic Fibrosis Transmembrane Conductance Regulator/genetics , Quinolones/therapeutic use , Anti-Inflammatory Agents/therapeutic use , Anti-Inflammatory Agents/pharmacology , Cytokines/metabolism , Cytokines/blood , Pyrazoles/therapeutic use , Pyrazoles/pharmacology , Young Adult , Pyridines/therapeutic use , Pyridines/pharmacology , Leukocytes, Mononuclear/metabolism , Leukocytes, Mononuclear/drug effects , C-Reactive Protein/metabolism , Pyrroles/therapeutic use , Pyrroles/pharmacology , Sweat/chemistry , Sweat/metabolism , PyrrolidinesABSTRACT
The aetiology of increased serum bicarbonate and metabolic alkalosis in CF is complex and appears to be driven, at least in part, by renal tubular CFTR dysfunction https://bit.ly/3NFPkUu.
