Diminished airway host innate response in people with cystic fibrosis who experience frequent pulmonary exacerbations.

Pulmonary exacerbations (PEx) are clinically impactful events that accelerate cystic fibrosis (CF) lung disease progression. The pathophysiological mechanisms underlying an increased frequency of PEx have not been explored. To compare host immune response during intravenous antibiotic treatment of PEx in people with CF who have a history of frequent Adults with CF were recruited at onset of antibiotic treatment of a PEx and were categorized as infrequent or frequent exacerbators based on their PEx frequency in the previous 12 months. Clinical parameters, sputum bacterial load and sputum inflammatory markers were measured on day 0, day 5 and at the end of treatment. Shotgun proteomic analysis was performed on sputum using liquid chromatography-mass spectrometry. Many sputum proteins were differentially enriched between infrequent and frequent exacerbators (day 0=23 and day 5=31). The majority of these proteins had a higher abundance in infrequent exacerbators and were secreted innate host defence proteins with antimicrobial, antiprotease and immunomodulatory functions. Several differentially enriched proteins were validated by ELISA and Western blot including SLPI, lipocalin-1 and cystatin SA. Sputum from frequent exacerbators demonstrated potent ability to cleave exogenous recombinant SLPI in an NE-dependent manner. Frequent exacerbators had increased sputum inflammatory markers (IL-1β and IL-8) and total bacterial load compared to infrequent exacerbators. A diminished innate host protein defence may play a role in the pathophysiological mechanisms of frequent CF PEx. Frequent exacerbators may benefit from therapies targeting this dysregulated host immune response.

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