Dual Inhibition of Cathepsin G and Chymase Is Effective in Animal Models of Pulmonary Inflammation

“…The DCCI used in this study was shown to selectively inhibit Cat.G and chymase in vitro, with little effect on several other serine proteases such as thrombin, factor Xa, trypsin, tryptase, proteinase 3, and elastase [6]. DCCI has been shown to markedly reduce neutrophil influx and nitric oxide levels associated with lipopolysaccharide-induced lung inflammation [23]. In the present study, we describe how DCCI administration to mice subjected to IR injury resulted in reduced myocardial Cat.G and chymase activity and pathologic remodeling associated with IR.…”

Section: Introductionmentioning

confidence: 91%

Dual inhibition of cathepsin G and chymase reduces myocyte death and improves cardiac remodeling after myocardial ischemia reperfusion injury

et al. 2017

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Early reperfusion of ischemic cardiac tissue increases inflammatory cell infiltration which contributes to cardiomyocyte death and loss of cardiac function, referred to as ischemia/reperfusion (IR) injury. Neutrophil- and mast cell-derived proteases, cathepsin G (Cat.G) and chymase, are released early after IR, but their function is complicated by potentially redundant actions and targets. This study investigated whether a dual inhibition of Cat.G and chymase influences cardiomyocyte injury and wound healing after experimental IR in mice. Treatment with a dual Cat.G and chymase inhibitor (DCCI) immediately after reperfusion blocked cardiac Cat.G and chymase activity induced after IR, which resulted in decreased immune response in the infarcted heart. Mice treated with DCCI had less myocardial collagen deposition and showed preserved ventricular function at 1 and 7 days post-IR compared with vehicle-treated mice. DCCI treatment also significantly attenuated focal adhesion (FA) complex disruption and myocyte degeneration after IR. Treatment of isolated cardiomyocytes with Cat.G or chymase significantly promoted FA signaling downregulation, myofibril degeneration and myocyte apoptosis. Conversely, treatment of cardiac fibroblasts with Cat.G or chymase induced FA signaling activation and increased their migration and differentiation to myofibroblasts. These opposite responses in cardiomyocytes and fibroblasts were blocked by treatment with DCCI. These findings show that Cat.G and chymase are key mediators of myocyte apoptosis and fibroblast migration and differentiation that play a role in adverse cardiac remodeling and function post-IR. Thus, dual targeting of neutrophil- and mast cell-derived proteases could be used as a novel therapeutic strategy to reduce post-IR inflammation and improve cardiac remodeling.

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“…Whether the potential safety advantages associated with high selectivity occur at the expense of efficacy is as yet unknown. Pr3 and catG, the two other granule-associated serine proteases in neutrophils, individually have the potential to contribute to human COPD by multiple mechanisms often with significant overlap to NE (Maryanoff et al, 2010), but in contrast to NE, their role in human COPD or the relevant smoke-driven animal models has yet to be demonstrated.…”

Section: Downloaded Frommentioning

confidence: 99%

AZD9668: Pharmacological Characterization of a Novel Oral Inhibitor of Neutrophil Elastase

Stevens

Ekholm²,

Gränse³

et al. 2011

J Pharmacol Exp Ther

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N-{[5-(methanesulfonyl)pyridin-2-yl]methyl}-6-methyl-5-(1-methyl-1H-pyrazol-5-yl)-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide (AZD9668) is a novel, oral inhibitor of neutrophil elastase (NE), an enzyme implicated in the signs, symptoms, and disease progression in NE-driven respiratory diseases such as bronchiectasis and chronic obstructive pulmonary disease via its role in the inflammatory process, mucus overproduction, and lung tissue damage. In vitro and in vivo experiments were done to evaluate the binding kinetics, potency, and selectivity of AZD9668, its effects in whole-blood and cell-based assays, and its efficacy in models of lung inflammation and damage. In contrast to earlier NE inhibitors, the interaction between AZD9668 and NE was rapidly reversible. AZD9668 was also highly selective for NE over other neutrophil-derived serine proteases. In cell-based assays, AZD9668 inhibited plasma NE activity in zymosan-stimulated whole blood. In isolated human polymorphonuclear cells, AZD9668 inhibited NE activity on the surface of stimulated cells and in the supernatant of primed, stimulated cells. AZD9668 showed good crossover potency to NE from other species. Oral administration of AZD9668 to mice or rats prevented human NE-induced lung injury, measured by lung hemorrhage, and an increase in matrix protein degradation products in bronchoalveolar lavage (BAL) fluid. In an acute smoke model, AZD9668 reduced the inflammatory response to cigarette smoke as indicated by a reduction in BAL neutrophils and interleukin-1␤. Finally, AZD9668 prevented airspace enlargement and small airway wall remodeling in guinea pigs in response to chronic tobacco smoke exposure whether dosed therapeutically or prophylactically. In summary, AZD9668 has the potential to reduce lung inflammation and the associated structural and functional changes in human diseases.

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Dual Inhibition of Cathepsin G and Chymase Is Effective in Animal Models of Pulmonary Inflammation

Abstract: The preclinical antiinflammatory effects of RWJ-355871 in these animal models of inflammation indicate that this dual inhibitor may have therapeutic utility for treating airway inflammatory diseases involving mechanisms that depend on Cat G and/or chymase.

Cited by 54 publications

References 49 publications

Functional inhibition of PAR₂ alleviates allergen‐induced airway hyperresponsiveness and inflammation

Functional inhibition of PAR₂ alleviates allergen‐induced airway hyperresponsiveness and inflammation

Dual inhibition of cathepsin G and chymase reduces myocyte death and improves cardiac remodeling after myocardial ischemia reperfusion injury

AZD9668: Pharmacological Characterization of a Novel Oral Inhibitor of Neutrophil Elastase

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Dual Inhibition of Cathepsin G and Chymase Is Effective in Animal Models of Pulmonary Inflammation

Abstract: The preclinical antiinflammatory effects of RWJ-355871 in these animal models of inflammation indicate that this dual inhibitor may have therapeutic utility for treating airway inflammatory diseases involving mechanisms that depend on Cat G and/or chymase.

Cited by 54 publications

References 49 publications

Functional inhibition of PAR2 alleviates allergen‐induced airway hyperresponsiveness and inflammation

Functional inhibition of PAR2 alleviates allergen‐induced airway hyperresponsiveness and inflammation

Dual inhibition of cathepsin G and chymase reduces myocyte death and improves cardiac remodeling after myocardial ischemia reperfusion injury

AZD9668: Pharmacological Characterization of a Novel Oral Inhibitor of Neutrophil Elastase

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Product

Resources

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Functional inhibition of PAR₂ alleviates allergen‐induced airway hyperresponsiveness and inflammation

Functional inhibition of PAR₂ alleviates allergen‐induced airway hyperresponsiveness and inflammation