cathepsin-g and Bronchiectasis

Brensocatib is an investigational, first-in-class, selective, and reversible dipeptidyl peptidase 1 inhibitor that blocks activation of neutrophil serine proteases (NSPs). The NSPs neutrophil elastase, cathepsin G, and proteinase 3 are believed to be central to the pathogenesis of several chronic inflammatory diseases, including bronchiectasis. In a phase II study, oral brensocatib 10 mg and 25 mg reduced sputum neutrophil elastase activity and prolonged the time to pulmonary exacerbation in patients with non-cystic fibrosis bronchiectasis (NCFBE). A population pharmacokinetic (PPK) model was developed to characterize brensocatib exposure, determine potential relationships between brensocatib exposure and efficacy and safety measures, and inform dose selection in clinical studies.. Pharmacokinetic (PK) data pooled from a phase I study of once-daily brensocatib (10, 25, and 40 mg) in healthy adults and a phase II study of once-daily brensocatib (10 mg and 25 mg) in adults with NCFBE were used to develop a PPK model and to evaluate potential covariate effects on brensocatib pharmacokinetics. PK-efficacy relationships for sputum neutrophil elastase below the level of quantification (BLQ) and reduction in pulmonary exacerbation and PK-safety relationships for adverse events of special interest (AESIs; periodontal disease, hyperkeratosis, and infections other than pulmonary infections) were evaluated based on model-predicted brensocatib exposure. A total of 1284 steady-state brensocatib concentrations from 225 individuals were included in the PPK data set; 241 patients with NCFBE from the phase II study were included in the pharmacodynamic (PD) population for the PK/PD analyses.. The PPK model that best described the observed data consisted of two distributional compartments and linear clearance. Two significant covariates were found: age on volume of distribution and renal function on apparent oral clearance. PK-efficacy analysis revealed a threshold brensocatib exposure (area under the concentration-time curve) effect for attaining sputum neutrophil elastase BLQ and a strong relationship between sputum neutrophil elastase BLQ and reduction in pulmonary exacerbations. A PK-safety evaluation showed no noticeable trends between brensocatib exposure and the incidence of AESIs. Based on the predicted likelihood of clinical outcomes for sputum neutrophil elastase BLQ and pulmonary exacerbations, brensocatib doses of 10 mg and 25 mg once daily were selected for a phase III clinical trial in patients with NCFBE (ClinicalTrials.gov identifier: NCT04594369).. PPK results revealed that age and renal function have a moderate effect on brensocatib exposure. However, this finding does not warrant dose adjustments based on age or in those with mild or moderate renal impairment. The PK/PD evaluation demonstrated the clinically meaningful relationship between suppression of neutrophil elastase activity and reduction in exacerbations in brensocatib-treated patients with NCFBE, supporting further development of brensocatib for bronchiectasis.

Topics: Adult; Benzoxazoles; Bronchiectasis; Cathepsin G; Cystic Fibrosis; Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; Fibrosis; Humans; Leukocyte Elastase; Myeloblastin; Oxazepines; Serine Proteases

We attempted to study the possible relationships between neutrophil-type procollagenase/pro-matrix metalloproteinase (MMP-8) and the serine proteinases plasmin, cathepsin G and tryptase in bronchiectasis. The presence of the plasmin/plasminogen system and plasmin-, cathepsin G- and tryptase-like activities were compared to the activity of endogenously activated MMP-8 in bronchoalveolar lavage (BAL) fluid in 38 bronchiectasis patients and in 14 healthy controls by means of immunohistochemistry, Western-blot and substrate-based functional assays. In contrast to cathepsin G- and tryptase-like activities, the plasmin/plasminogen activator system in BAL fluid was observed to have a relatively weak activation stage and no correlation with disease severity. Neither plasmin-like activities nor concentrations of plasminogen activators from the bronchiectatic patients differed significantly from the values of healthy controls. Immunolocation of plasminogen activator inhibitor-1 showed a marked, but not significant, increase in bronchiectatic lung as compared to controls. In contrast to cathepsin G- and tryptase-like activities, with their strong and significant correlation with endogenously activated collagenase (r=0.9; p=0.0001; and r=0.6; p=0.03, respectively), no correlations were observed between plasmin-like and endogenously activated collagenase (r=0.3; p=0.2) in bronchiectasis. These findings suggest that cathepsin G- and tryptase-like activities may act as potent pro-matrix metalloproteinase-8 activators in patients with bronchiectasis, whereas the plasminogen activator/plasmin cascade was shown to be down-regulated.

Topics: Adolescent; Adult; Analysis of Variance; Biopsy; Blotting, Western; Bronchiectasis; Bronchoalveolar Lavage Fluid; Cathepsin G; Cathepsins; Chymases; Collagenases; Down-Regulation; Female; Fibrinolysin; Humans; Immunohistochemistry; In Vitro Techniques; Inflammation Mediators; Lung; Male; Matrix Metalloproteinase 8; Neutrophil Activation; Serine Endopeptidases; Tryptases

The presence, activities, and molecular forms of the serine proteinases, elastase, and cathepsin G, and their endogenous inhibitors, alpha 1-antitrypsin and alpha 1-antichymotrypsin, were investigated in bronchoalveolar lavage (BAL) fluid of bronchiectasis patients divided into mild, moderate, and severe disease subgroups and compared to BAL fluid from healthy controls. Immunochemical characterization and quantitation were performed by Western immunoblot. The activities of elastase and cathepsin G were recorded spectrophotometrically using synthetic substrates. The results showed a significant difference in elastase and cathepsin G activities in BAL fluid of the three subgroups, revealing the following data--mild subgroup, 0.21 +/- 0.09 mU/g and 57.35 +/- 20.9 U/g; moderate subgroup, 1.87 +/- 1.12 mU/g and 89.24 +/- 31.4 U/g; and severe subgroup, 2.64 +/- 1.63 mU/g and 139.18 +/- 58.3 U/g, respectively--compared to those of the healthy control group, 0.09 +/- 0.03 mU/g and 50.96 +/- 16.5 U/g. Evidently, the protective shield of plasma-derived antiproteinases was sufficient in healthy subjects and, also, in mild cases of bronchiectasis, but not in cases of severe and moderate forms of bronchiectasis, in which free and catalytically active elastase and cathepsin G were detected. The serine proteinases inhibitors (serpins), alpha 1-antitrypsin and alpha 1-antichymotrypsin, have evidently been oxidized and/or proteolytically cleaved in the cases of moderate and severe bronchiectasis. The results indicate that insufficient endogenous downregulation of catalytically active elastase and cathepsin G in BALF leads to tissue injury, resulting in alterative and deformative processes in the bronchiectasis lung.

Topics: Adolescent; Adult; alpha 1-Antichymotrypsin; alpha 1-Antitrypsin; Blotting, Western; Bronchiectasis; Bronchoalveolar Lavage Fluid; Cathepsin G; Cathepsins; Child; Electrophoresis, Polyacrylamide Gel; Female; Humans; Leukocyte Elastase; Male; Neutrophils; Pancreatic Elastase; Serine Endopeptidases

To investigate the role of neutrophil proteases in the pathogenesis of mucus hypersecretion in bronchiectasis, we collected sputum samples from seven patients with bronchiectasis and measured their secretagogue activity by examining secretion of radiolabeled macromolecules by bovine airway submucosal gland cells incubated with sputum supernatants. There was marked secretagogue activity in bronchiectasis sputum, reaching a maximum of 1,963 +/- 292% (mean +/- SEM) above baseline at 1:15 dilution. Addition of ICI 200,355 (10(-5) M), a selective human neutrophil elastase inhibitor, decreased the secretory response markedly (72.53 +/- 5.89% reduction). The combination of aprotinin, an inhibitor of cathepsin G, and ICI 200,355 caused significantly more reduction in the secretory response than ICI 200,355 alone (89.12 +/- 3.8 versus 72.53 +/- 5.89% reduction, p < 0.05). We conclude that bronchiectasis sputum causes a large secretory response from tracheal submucosal glands due mostly to neutrophil proteases.

Topics: Adult; Aged; Animals; Aprotinin; Bronchiectasis; Cathepsin G; Cathepsins; Cattle; Cells, Cultured; Female; Humans; Leukocyte Elastase; Macromolecular Substances; Male; Middle Aged; Mucus; Oligopeptides; Pancreatic Elastase; Serine Endopeptidases; Sputum; Trachea