cathepsin-g and Fibrosis

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

Interleukin (IL)-36 is a recently described cytokine with well-known functions in the regulation of multiple inflammatory diseases. Since no data exists on how this cytokine regulates adipose tissue (AT) homeostasis, we aimed to explore the function of a specific isoform, IL-36γ, an agonist, in human obesity and obesity-associated type 2 diabetes as well as in AT inflammation and fibrosis. Plasma IL-36γ was measured in 91 participants in a case-control study and the effect of weight loss was evaluated in 31 patients with severe obesity undergoing bariatric surgery. Gene expression levels of

Topics: Adipocytes; Adipose Tissue; Animals; Case-Control Studies; Cathepsin G; Cytokines; Diabetes Mellitus, Type 2; Fibrosis; Humans; Inflammation; Interleukin-1; Interleukins; Leukocytes, Mononuclear; Macrophages; Mice; Obesity

Neutrophil activation to release granules containing proteases and other enzymes is a primary cause of tissue damage during ischemia/reperfusion injury. Because the contribution of specific granule enzymes to this injury remains poorly defined, the role of cathepsin G in renal ischemia/reperfusion injury was tested. Bilateral renal ischemia led to the expiration of 64% of wild-type mice within 4 days of reperfusion, whereas all cathepsin G-deficient mice survived. Serum creatinine increased to similar levels at 24 hours after reperfusion and then decreased to background in both groups of mice. Ischemic kidneys from both groups had similar levels of neutrophil infiltration and of CXCL1, CXCL2, and myeloperoxidase protein 9 hours after reperfusion, but at 24 hours, these acute inflammatory response components were decreased more than 50% in kidneys from cathepsin G-deficient versus wild-type mice. Ischemic kidneys from surviving wild-type mice had severe tubular necrosis and tubular cell apoptosis 24 hours after reperfusion with subsequent development of fibrosis 30 days later. In contrast, ischemic kidneys from cathepsin G-deficient mice had a 70% decrease in tubular cell apoptosis with little detectable collagen deposition. These data identify cathepsin G as a critical component sustaining neutrophil-mediated acute tissue pathology and subsequent fibrosis after renal ischemia/reperfusion injury.

Topics: Animals; Apoptosis; Cathepsin G; Cathepsins; Chemokine CXCL1; Chemokines, CXC; Creatinine; Enzyme-Linked Immunosorbent Assay; Fibrosis; In Situ Nick-End Labeling; Inflammation; Kidney; Mice; Neutrophil Infiltration; Peroxidase; Reperfusion Injury; Serine Endopeptidases

In human kidney transplantation the main cause of declining long-term graft function is chronic allograft nephropathy (CAN). Recent studies have implicated human mast cells (MC) in chronic inflammation and fibrosis, MC can be subtyped according to protease content: MC(T) containing tryptase only and MC(TC) containing both tryptase and chymase. We investigated immunohistochemically whether numbers and subtypes of MC in biopsy specimens 100 d after transplantation could predict subsequent fibrosis and graft dysfunction. The total number of MC/high-power field at 100 d after transplantation correlated significantly with change in creatinine clearance (DeltaCcr), defined as (Ccr at 100 d) - (Ccr at 3 yr) (R = 0.597, p = 0.0021); fibrosis index (FI) at 100 d (R = 0.583, p = 0.0066); and DeltaFI, defined as (FI at 3 yr) - (FI at 100 d) (R = 0.406, p < 0.05). The ratio of MC(TC) to total MC at 100 d also correlated with DeltaCcr (R = 0.491, p = 0.0148), FI at 100 d (R = 0.527, p = 0.0081), and DeltaFI (R = 0.417, p < 0.05). Thus, increases in number of total MC and the ratio of MC(TC) to total MC in early biopsy specimens were related to decline of long-term graft function and fibrosis.

Topics: Biopsy; Cathepsin G; Cathepsins; Cell Count; Chymases; Fibrosis; Graft Rejection; Humans; Immunohistochemistry; Kidney; Kidney Transplantation; Living Donors; Mast Cells; Postoperative Period; Serine Endopeptidases; Time Factors; Tryptases

The mast cell populations in the human testis were examined using immunohistochemical techniques in five fertile volunteers and 12 patients with obstructive azoospermia, seven patients with idiopathic azoospermia, and 30 patients with varicocele. The number of mast cells per seminiferous tubular section was significantly increased (P < 0.05) in the men with idiopathic azoospermia. In the normal testes, mast cells containing only tryptase were the predominant subtype. In the patient groups, the predominant subtype of mast cell was shifted to that containing both tryptase and chymase. The average number of mast cells containing both tryptase and chymase per seminiferous tubular section was significantly increased (P < 0.05) compared with the controls in patients with obstructive azoospermia, idiopathic azoospermia, and varicocele. The number of mast cells containing only tryptase was not increased in infertile men. The selective expansion of the mast cell population containing both tryptase and chymase may be related to spermatogenetic disorders and testicular fibrosis.

Topics: Adult; Cathepsin G; Cathepsins; Chymases; Fibrosis; Follicle Stimulating Hormone; Humans; Infertility, Male; Luteinizing Hormone; Male; Mast Cells; Middle Aged; Oligospermia; Reference Values; Sclerosis; Seminiferous Tubules; Serine Endopeptidases; Testis; Tryptases; Varicocele