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Secretory leukocyte protease inhibitor (SLPI) is an important cationic protein involved in innate airway immunity and highly expressed in mucosal secretions, shown to target and inhibit neutrophil elastase (NE), cathepsin G and trypsin activity to limit proteolytic activity. In addition to the potent anti-protease activity, SLPI has been demonstrated to exert a direct anti-inflammatory effect, which is mediated via increased inhibition and competitive binding of NF-κB, regulating immune responses through limiting transcription of pro-inflammatory gene targets. In muco-obstructive lung disorders, such as Chronic Obstructive Pulmonary Disease (COPD) and Cystic Fibrosis (CF), there is an observed elevation in airway SLPI protein concentrations as a result of increased lung inflammation and disease progression. However, studies have identified COPD patients presenting with diminished SLPI concentrations. Furthermore, there is a decrease in SLPI concentrations through cleavage and subsequent inactivation by NE degradation in Pseudomonas aeruginosa infected people with CF (pwCF). These observations suggest reduced SLPI protein levels may contribute to the compromising of airway immunity indicating a potential role of decreased SLPI levels in the pathogenesis of muco-obstructive lung disease. The Beta Epithelial Na+ Channel transgenic (ENaC-Tg) mouse model phenotype exhibits characteristics which replicate the pathological features observed in conditions such as COPD and CF, including mucus accumulation, alterations in airway morphology and increased pulmonary inflammation. To evaluate the effect of SLPI in muco-obstructive pulmonary disease, ENaC-Tg mice were crossed with SLPI knock-out (SLPI -/- ) mice, generating a ENaC-Tg/SLPI -/- colony to further investigate the role of SLPI in chronic lung disease and determine the effect of its ablation on disease pathogenesis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Brown, Dougan, Ferris, Delaney, Houston, Rodgers, Downey, Mall, Connolly, Small, Weldon and Taggart.)

Rationale: Pulmonary exacerbations are clinically impactful events that accelerate cystic fibrosis (CF) lung disease progression. The pathophysiological mechanisms underlying an increased frequency of pulmonary exacerbations have not been explored., Objectives: To compare host immune response during intravenous antibiotic treatment of pulmonary exacerbations in people with CF who have a history of frequent versus infrequent exacerbations., Methods: Adults with CF were recruited at onset of antibiotic treatment of a pulmonary exacerbation and were categorised as infrequent or frequent exacerbators based on their pulmonary exacerbation 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., Measurements and Main Results: Many sputum proteins were differentially enriched between infrequent and frequent exacerbators (day 0 n=23 and day 5 n=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 using ELISA and Western blot including secretory leukocyte protease inhibitor (SLPI), lipocalin-1 and cystatin SA. Sputum from frequent exacerbators demonstrated potent ability to cleave exogenous recombinant SLPI in a neutrophil elastase dependent manner. Frequent exacerbators had increased sputum inflammatory markers (interleukin (IL)-1β and IL-8) and total bacterial load compared to infrequent exacerbators., Conclusions: A diminished innate host protein defence may play a role in the pathophysiological mechanisms of frequent CF pulmonary exacerbations. Frequent exacerbators may benefit from therapies targeting this dysregulated host immune response., Competing Interests: Conflict of interest: During the course of the manuscript, funding for C.J. Houston's PhD studentship was received from the Department for the Economy. A. Alkhatib has no potential conflicts of interest to disclose. G.G. Einarsson reports grants from EU/EFPIA (IMI iABC grant number 115721), outside the submitted work. M.M. Tunney reports grants from Novartis, Spexis, Shionogi and NIHR EME, outside the submitted work. C.C. Taggart reports grants from Chiesi Farmaceutici, NICHS, the Medical Research Council and NIHR EME, outside the submitted work. D.G. Downey reports grants from Chiesi Farmaceutici and the CF Foundation, consulting fees from Vertex, lecture honoraria from Gilead, Chiesi, Vertex and Insmed, travel support from the European Cystic Fibrosis Society, advisory board participation with Nomab trial UK and CSL Behring, and a leadership role as Director of European CF Society Clinical Trials Network, outside the submitted work., (Copyright ©The authors 2024.)

Introduction: Cystic Fibrosis pulmonary exacerbations are critical events in the lives of people with CF that have deleterious effects on lung function, quality of life, and life expectancy. There are significant unmet needs in the management of exacerbations. We review here the associated inflammatory changes that underlie these events and are of interest for the development of biomarkers of exacerbation., Areas Covered: Inflammatory responses in CF are abnormal and contribute to a sustained proinflammatory lung microenvironment, abundant in proinflammatory mediators and deficient in counter-regulatory mediators that terminate and resolve inflammation. There is increasing interest in these inflammatory pathways to discover novel biomarkers for pulmonary exacerbation management. In this review, we explore the inflammatory changes occurring during intravenous antibiotic therapy for exacerbation and how they may be applied as biomarkers to guide exacerbation therapy. A literature search was conducted using the PubMed database in February 2020., Expert Opinion: Heterogeneity in inflammatory responses to treatment of a pulmonary exacerbation, a disease process with complex pathophysiology, limits the clinical utility of individual biomarkers. Biomarker panels may be a more successful strategy to capture informative changes within the CF population to improve pulmonary exacerbation management and outcomes.