The Role of Neutrophil Elastase Inhibitors in Lung Diseases

Polverino, Eva; Rosales-Mayor, Edmundo; Dale, Glenn E.; Dembowsky, Klaus; Torres, Antoni

doi:10.1016/j.chest.2017.03.056

Cited by 180 publications

(132 citation statements)

References 67 publications

(74 reference statements)

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“…134 Pharmacologic inhibition of neutrophil elastase attenuates ALI in several mouse models. [135][136][137] Results of human studies, however, are inconsistent, 138,139 likely because extracellular release of hundreds of enzymes during exocytosis are redundant mediators of cell injury. Mice deficient in MMP3 show reduced neutrophil recruitment and lung injury, while MMP9 depletion inhibits ALI without altering neutrophil recruitment.…”

Section: Sepsis and Ischemia-reperfusion Injurymentioning

confidence: 99%

Therapeutic targeting of neutrophil exocytosis

Catz

McLeish

2020

Journal of Leukocyte Biology

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Dysregulation of neutrophil activation causes disease in humans. Neither global inhibition of neutrophil functions nor neutrophil depletion provides safe and/or effective therapeutic approaches. The role of neutrophil granule exocytosis in multiple steps leading to recruitment and cell injury led each of our laboratories to develop molecular inhibitors that interfere with specific molecular regulators of secretion. This review summarizes neutrophil granule formation and contents, the role granule cargo plays in neutrophil functional responses and neutrophil‐mediated diseases, and the mechanisms of granule release that provide the rationale for development of our exocytosis inhibitors. We present evidence for the inhibition of granule exocytosis in vitro and in vivo by those inhibitors and summarize animal data indicating that inhibition of neutrophil exocytosis is a viable therapeutic strategy.

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Section: Sepsis and Ischemia-reperfusion Injurymentioning

confidence: 99%

Therapeutic targeting of neutrophil exocytosis

Catz

McLeish

2020

Journal of Leukocyte Biology

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“…13 Targeting NSP activation is therefore an interesting therapeutic opportunity for the treatment of several potentially neutrophil-driven lung diseases, including COPD and bronchiectasis, but also alpha1-antitrypsin deficiency and cystic fibrosis. 14,15 AZD7986 is a small-molecule, competitive, and reversible inhibitor of DPP1, with high potency and selectivity as measured in vitro. 16 In human primary bone marrow-derived CD34 1 neutrophil progenitor cells, AZD7986 has been shown to completely inhibit activation of all three NSPs (NE, Pr3, and CatG) in a similar concentration-dependent manner (IC 50 , 60-200 nM, Hill coefficient, 0.65).…”

Section: Study Highlightsmentioning

confidence: 99%

“…Furthermore, elevated sputum NE activity has been associated with exacerbations and lung function decline in patients with bronchiectasis . Targeting NSP activation is therefore an interesting therapeutic opportunity for the treatment of several potentially neutrophil‐driven lung diseases, including COPD and bronchiectasis, but also alpha1‐antitrypsin deficiency and cystic fibrosis …”

mentioning

confidence: 99%

Dipeptidyl Peptidase 1 Inhibitor AZD7986 Induces a Sustained, Exposure‐Dependent Reduction in Neutrophil Elastase Activity in Healthy Subjects

Palmer

Mäenpää

Jauhiainen

et al. 2018

Clin Pharma and Therapeutics

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Neutrophil serine proteases (NSPs), such as neutrophil elastase (NE), are activated by dipeptidyl peptidase 1 (DPP1) during neutrophil maturation. High NSP levels can be detrimental, particularly in lung tissue, and inhibition of NSPs is therefore an interesting therapeutic opportunity in multiple lung diseases, including chronic obstructive pulmonary disease (COPD) and bronchiectasis. We conducted a randomized, placebo‐controlled, first‐in‐human study to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of single and multiple oral doses of the DPP1 inhibitor AZD7986 in healthy subjects. Pharmacokinetic and pharmacodynamic data were analyzed using nonlinear mixed effects modeling and showed that AZD7986 inhibits whole blood NE activity in an exposure‐dependent, indirect manner—consistent with in vitro and preclinical predictions. Several dose‐dependent, possibly DPP1‐related, nonserious skin findings were observed, but these were not considered to prevent further clinical development. Overall, the study results provided confidence to progress AZD7986 to phase II and supported selection of a clinically relevant dose.

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“…We found the non-survivors of ARDS had higher levels of phenylacetylglutamine than survivors, the mechanisms underlying may be related to the roles of phenylacetylglutamine in modulating platelets and thrombosis. In the last decades, a broad range of drug therapies emerged for improving ARDS, but none showed efficacy in phase II and III trials [26][27][28][29][30][31]. Given the high mortality rate of ARDS, even a small improvement can save many lives.…”

Section: Discussionmentioning

confidence: 99%

Increased mortality of acute respiratory distress syndrome was associated with high levels of plasma phenylalanine

Pan

et al. 2020

Respir Res

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Background: There is a dearth of drug therapies available for the treatment of acute respiratory distress syndrome (ARDS). Certain metabolites play a key role in ARDS and could serve as potential targets for developing therapies against this respiratory disorder. The present study was designed to determine such "functional metabolites" in ARDS using metabolomics and in vivo experiments in a mouse model.Methods: Metabolomic profiles of blood plasma from 42 ARDS patients and 28 healthy controls were captured using Ultra-high performance liquid chromatography tandem mass spectrometry (UHPLC-MS/MS) assay. Univariate and multivariate statistical analysis were performed on metabolomic profiles from blood plasma of ARDS patients and healthy controls to screen for "functional metabolites", which were determined by variable importance in projection (VIP) scores and P value. Pathway analysis of all the metabolites was performed. The mouse model of ARDS was established to investigate the role of "functional metabolites" in the lung injury and mortality caused by the respiratory disorder. Results: The metabolomic profiles of patients with ARDS were significantly different from healthy controls, difference was also observed between metabolomic profiles of the non-survivors and the survivors among the ARDS patient pool. Levels of Phenylalanine, D-Phenylalanine and Phenylacetylglutamine were significantly increased in non-survivors compared to the survivors of ARDS. Phenylalanine metabolism was the most notably altered pathway between the non-survivors and survivors of ARDS patients. In vivo animal experiments demonstrated that high levels of Phenylalanine might be associated with the severer lung injury and increased mortality of ARDS. Conclusion: Increased mortality of acute respiratory distress syndrome was associated with high levels of plasma Phenylalanine.

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The Role of Neutrophil Elastase Inhibitors in Lung Diseases

Cited by 180 publications

References 67 publications

Therapeutic targeting of neutrophil exocytosis

Therapeutic targeting of neutrophil exocytosis

Dipeptidyl Peptidase 1 Inhibitor AZD7986 Induces a Sustained, Exposure‐Dependent Reduction in Neutrophil Elastase Activity in Healthy Subjects

Increased mortality of acute respiratory distress syndrome was associated with high levels of plasma phenylalanine

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