Discussion
bronchiectasis, bacterial infection, reductions in airway inflammation, inflammatory disorder, A1AT, reductions in lung inflammation
LUNG INFLAMMATION, BRONCHIECTASIS, INFLAMMATORY RESPONSE, BACTERIAL INFECTION, RECRUITMENT, INFLAMMATORY DISORDER, AIRWAY DISEASE, BRONCHIECTASIS
Bronchiectasis is an inflammatory disorder and neutrophils dominate the airway inflammatory profile in the majority of bronchiectasis patients. NSPs such as NE, PR3 and CatG are released from neutrophil granules when neutrophils are activated and during the formation of neutrophil extracellular traps [There are currently no approved treatments for bronchiectasis, and there is a need for non-antibiotic treatments that can reduce lung inflammation. To that end, inhibition of DPP-1 represents a novel therapeutic strategy to reduce NSP activity and lung inflammation [Interestingly, a greater reduction of NE activity was observed in sputum than in WBCs (Table There are several plausible explanations for a greater effect in the lung than in the circulation. Reduced NSP activity may directly or indirectly reduce neutrophil recruitment to the lung, or the inflammatory stimulus for NSP release including potentially impacting bacterial infection through restoration of antimicrobial peptides. This theoretically generates a “virtuous cycle”, the counterpoint to the vicious cycle, whereby reductions in lung inflammation improve other aspects of airway disease, leading to larger and more sustained reductions in airway inflammation. These reductions in NSP activity in the lung may allow for a return to homeostatic balance of NSPs with their inhibitors: alpha-1 antitrypsin (A1AT), elafin and secretory leukocyte peptidase inhibitor (SLPI).The positing of a virtuous cycle in response to brensocatib suggests that once brensocatib treatment is removed, NSP activities in the lung may take longer to return to baseline levels than for those in the circulation (i.e., WBC extracts). Indeed, four weeks after termination of brensocatib treatment, NE activity in the WBCs returned to baseline levels, while NE, PR3 and CatG activities in sputum did not.Sputum NE, PR3 and CatG activities were strongly correlated at baseline and positive correlations were observed on study treatment at all timepoints, suggesting that brensocatib’s effect on all three NSP activities is interrelated. This does not appear to be a surprising result given that the mechanism of action of DPP-1 is to activate all three NSPs. However, while the NSP correlations remained positive on treatment, the strength of those correlations decreased somewhat for those on brensocatib, and more so for those on the higher 25 mg dose of brensocatib. The explanation may be related to the differential reduction in the NSP activities to brensocatib treatment, with CatG being reduced to the greatest extent, followed closely by NE, with a lower reduction in PR3 activity in sputum. Thus, it may not be unexpected that the very strong correlation between NE and CatG at baseline showed the least change in response to brensocatib treatment, since both biomarkers were more likely to have been reduced comparably. In contrast, the positive correlations between PR3 and both NE and CatG declined on brensocatib treatment (but not on placebo), which may be explained by the lower reduction in PR3 activity relative to both NE and CatG. The residual reductions in the NSP correlations that cannot be explained by differential impact of brensocatib on the individual NSP biomarkers may be related to the increased appearance of NSP activity values below the quantification limit. Notably, four weeks after the end of brensocatib treatment, the sputum NSP correlations all recovered close to their initial values.DPP-1 inhibition with brensocatib had the greatest effect in reducing CatG activity in sputum and the least effect on PR3 activity. There may be multiple factors accounting for the differential response in NSP activity to DPP-1 inhibition. In the absence of a DPP-1 inhibitor, nearly all of the NSPs zymogens are converted to active forms during neutrophil maturation [Brensocatib reduced all three NSP biomarkers in sputum illustrating the unique mechanism of action of DPP-1 inhibitors that simultaneously reduce several key inflammatory mediators linked to exacerbation. In contrast, specific inhibitors to NE ([The thesis that PR3 and CatG are also important regulators of the local inflammatory response is supported by the literature [