Abstract Rationale Neutrophil-dominated airway inflammation drives progressive tissue damage in both cystic fibrosis (CF) and non CF bronchiectasis (NCFB), primarily through excessive protease activity that overwhelms antiprotease defenses and leads to progressive decline in lung function. Elexacaftor/tezacaftor/ivacaftor (ETI) markedly improves clinical outcomes in CF, however its longer term effects on airway protease-antiprotease balance remain incompletely defined. We aimed to characterize airway and systemic protease and antiprotease activity in people with CF (PWCF) before and 4-5 years after initiating ETI and to compare these profiles to individuals with NCFB. METHOD: Adults with CF established on ETI therapy (n = 50) underwent bronchoscopy with bronchoalveolar lavage (BAL) and time matched blood sampling. A comparator NCFB cohort (n = 20) underwent matched sampling. BAL and plasma were analyzed for neutrophil elastase (NE), cathepsin G (CatG), proteinase 3 (PR3) activity using fluorometric assays and ELISA. Antiprotease concentrations and activity (alpha-1 antitrypsin A1AT, secretory leukoprotease inhibitor SLPI, elafin) were measured by activity assay and Western blot. Inflammatory cytokines (IL-8, TNF receptor, IL-1β) were quantified to contextualize protease activity in both BAL and plasma. Pre-ETI blood and sputum samples were analyzed for longitudinal comparison. Clinical parameters (FEV1, BMI, exacerbations) were recorded pre and post ETI. Results Following 4-5 years of ETI, median FEV1 increased by 17.5% (0.0001), BMI improved and, exacerbation frequency declined. BAL total cells and neutrophil counts remained higher in PWCF compared with NCFB (p = 0.0435), and BAL NE levels correlated with total BAL cell burden (r = 0.78). However, BAL NE activity decreased to levels comparable to NCFB (p = 0.0966). A1AT and SLPI concentrations increased significantly in PWCF post-ETI, resulting in a marked reduction in the NE:A1AT activity ratio (p 0.0001). Cytokine profiles demonstrated ongoing airway inflammation, though neutrophil activation markers decreased to levels overlapping with NCFB, indicating partial restoration of protease-antiprotease balance but persistent proteolytic potential. Conclusions CF airways exhibit a more profound protease-antiprotease imbalance than NCFB, but ETI substantially ameliorates this disturbance, reducing protease burden and partially restoring antiprotease defenses. Despite clinical and biochemical improvement, residual inflammatory activity persists, suggesting that proteolytic injury remains an important therapeutic target in the modulator era. Comparative BAL profiling provides a valuable platform for mechanistic biomarker discovery and evaluation of adjunctive anti-inflammatory or antiprotease therapies in CF and bronchiectasis. This abstract is funded by: Cystic Fibrosis Foundation
Mullen et al. (Fri,) studied this question.