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

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)-1ß 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.

Airway Inflammation and Host Responses in the Era of CFTR Modulators.

The arrival of cystic fibrosis transmembrane conductance regulator (CFTR) modulators as a new class of treatment for cystic fibrosis (CF) in 2012 represented a pivotal advance in disease management, as these small molecules directly target the upstream underlying protein defect. Further advancements in the development and scope of these genotype-specific therapies have been transformative for an increasing number of people with CF (PWCF). Despite clear improvements in CFTR function and clinical endpoints such as lung function, body mass index (BMI), and frequency of pulmonary exacerbations, current evidence suggests that CFTR modulators do not prevent continued decline in lung function, halt disease progression, or ameliorate pathogenic organisms in those with established lung disease. Furthermore, it remains unknown whether their restorative effects extend to dysfunctional CFTR expressed in phagocytes and other immune cells, which could modulate airway inflammation. In this review, we explore the effects of CFTR modulators on airway inflammation, infection, and their influence on the impaired pulmonary host defences associated with CF lung disease. We also consider the role of inflammation-directed therapies in light of the widespread clinical use of CFTR modulators and identify key areas for future research.

SLPI deficiency alters airway protease activity and induces cell recruitment in a model of muco-obstructive lung disease.

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.

Ontario family justice in "lockdown": Early pandemic cases and professional experience.

The COVID-19 pandemic has profoundly affected families and children involved in Ontario's family justice system as well as family justice professionals in the province. In a span of two years, Ontario's family justice system has been fundamentally transformed, from a paper-based, in-person system to a paperless system in which many services, including judicial proceedings, continue to be largely delivered remotely. We report on the findings of two studies on the impact of the COVID-19 pandemic on Ontario family justice: (1) an analysis of early pandemic court decisions; and (2) a survey of family justice professionals about their experiences during the early pandemic. We describe how the pandemic has exacerbated access to justice issues for certain groups, including families experiencing high conflict, victims of intimate partner violence, families involved in child welfare proceedings, and self-represented litigants, while improving access to justice for others by improving efficiency and reducing legal costs. As Ontario moves past the pandemic, the family justice system will need to ensure that technological advances improve access to justice for all court-involved families.

The role of inflammation in cystic fibrosis pulmonary exacerbations.

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.