Role of neutrophil elastase in allergen-induced lysozyme secretion in the dog trachea

To test our hypothesis that neutrophil elastase plays a role in airway hypersecretion associated with the allergic late-phase response, using an isolated tracheal segment system in vivo and measuring lysozyme activity in the perfusate of the lumen as a marker of submucosal gland secretion over 8 h, we studied the response of five allergic dogs to ragweed. The dogs were exposed on separate occasions to specific allergen, to allergen vehicle, and to allergen in the presence of a selective neutrophil elastase inhibitor, ICI 200,355. Allergen exposure caused a marked increase in lysozyme secretion that was significantly increased at 4, 6, and 8 h compared with controls and ICI 200,355-treated dogs. Neutrophil elastase appeared in the perfusate after allergen exposure and was positively correlated with lysozyme secretion at 8 h. These findings suggest that neutrophil elastase plays an important role as a secretagogue in the allergic late-phase response.

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Role of neutrophils in xanthine/xanthine oxidase-induced oxidant injury in isolated rabbit lungs

Journal of Applied Physiology ◽

10.1152/jappl.1999.87.6.2319 ◽

1999 ◽

Vol 87 (6) ◽

pp. 2319-2325 ◽

Cited By ~ 12

Author(s):

Masashi Kishi ◽

Lois F. Richard ◽

Robert O. Webster ◽

Thomas E. Dahms

Keyword(s):

Lung Injury ◽

Xanthine Oxidase ◽

Neutrophil Elastase ◽

Weight Ratio ◽

Dry Weight ◽

Neutrophil Elastase Inhibitor ◽

Fluid Filtration ◽

Elastase Inhibitor ◽

Pulmonary Arterial

Reactive oxygen species have been shown to play an important role in the pathogenesis of lung injury. This study was designed to clarify the role of intrapulmonary neutrophils in the development of xanthine/xanthine oxidase (X/XO)-induced lung injury in isolated buffer-perfused rabbit lungs. We measured microvascular fluid filtration coefficient ( K f) and wet-to-dry weight ratio to assess lung injury. X/XO induced a significant increase in K f and wet-to-dry weight ratio in neutrophil-replete lungs, whereas the lung injury was attenuated in neutrophil-depleted lungs. A neutrophil elastase inhibitor, ONO-5046, also attenuated the lung injury. In addition, X/XO induced a transient pulmonary arterial pressure (Ppa) increase. The thromboxane inhibitor OKY-046 attenuated the Ppa increase but did not alter the increase in permeability. Neutrophil depletion reduced the K f increase but had no effect on the Ppa increase. These results suggest that intrapulmonary neutrophils activated by X/XO play a major role in development of the lung injury, that neutrophil elastase is involved in the injury, and that the X/XO-induced vasoconstriction is independent of intrapulmonary neutrophils.

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Novel and Modified Neutrophil Elastase Inhibitor Loaded in Topical Formulations for Psoriasis Management

Pharmaceutics ◽

10.3390/pharmaceutics12040358 ◽

2020 ◽

Vol 12 (4) ◽

pp. 358 ◽

Cited By ~ 1

Author(s):

Andreia Nunes ◽

Joana Marto ◽

Lídia Maria Gonçalves ◽

Sandra Simões ◽

Rita Félix ◽

...

Keyword(s):

Serine Protease ◽

Neutrophil Elastase ◽

In Vitro Cytotoxicity ◽

Human Neutrophil Elastase ◽

Therapeutic Effects ◽

Neutrophil Elastase Inhibitor ◽

Analytical Methodology ◽

Elastase Inhibitor

Human neutrophil elastase (HNE) is a serine protease that degrades matrix proteins. An excess of HNE may trigger several pathological conditions, such as psoriasis. In this work, we aimed to synthesize, characterize and formulate new HNE inhibitors with a 4-oxo-β-lactam scaffold with less toxicity, as well as therapeutic index in a psoriasis context. HNE inhibitors with 4-oxo-β-lactam scaffolds were synthesized and characterized by NMR, FTIR, melting point, mass spectrometry and elemental analysis. In vitro cytotoxicity and serine protease assays were performed. The compound with the highest cell viability (AAN-16) was selected to be incorporated in an emulsion (AAN-16 E) and in a microemulsion (AAN-16 ME). Formulations were characterized in terms of organoleptic properties, pH, rheology, droplet size distribution, in vitro drug release and in vivo psoriatic activity. All compounds were successfully synthesized according to analytical methodology, with good yields. Both formulations presented suitable physicochemical properties. AAN-16 E presented the most promising therapeutic effects in a murine model of psoriasis. Overall, new HNE inhibitors were synthesized with high and selective activity and incorporated into topical emulsions with potential to treat psoriasis.

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In vitro and in vivo characterisation of the novel neutrophil elastase inhibitor BI 1323495

10.1183/13993003.congress-2020.3303 ◽

2020 ◽

Author(s):

Stefan Kreideweiss ◽

Annette Schuler-Metz ◽

Christian Gnamm ◽

Stefan Peters ◽

Thorsten Oost

Keyword(s):

Neutrophil Elastase ◽

The Novel ◽

Neutrophil Elastase Inhibitor ◽

Elastase Inhibitor

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In Vivo Adenovirus-Mediated Expression of Human Pre-Elafin, a Potent Neutrophil Elastase Inhibitor

CHEST Journal ◽

10.1378/chest.111.6_supplement.128s ◽

1997 ◽

Vol 111 (6) ◽

pp. 128S-129S ◽

Cited By ~ 4

Author(s):

Jean-Michel Sallenave ◽

Zhou Xing ◽

Frank Graham ◽

Jack Gauldie

Keyword(s):

Neutrophil Elastase ◽

Neutrophil Elastase Inhibitor ◽

Elastase Inhibitor

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Faculty Opinions recommendation of Phase II study of a neutrophil elastase inhibitor (AZD9668) in patients with bronchiectasis.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.722618726.793557664 ◽

2019 ◽

Author(s):

Mark Metersky

Keyword(s):

Phase Ii ◽

Neutrophil Elastase ◽

Phase Ii Study ◽

Neutrophil Elastase Inhibitor ◽

Elastase Inhibitor

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Decoding the temporal nature of brain GR activity in the NFκB signal transition leading to depressive-like behavior

Molecular Psychiatry ◽

10.1038/s41380-021-01016-1 ◽

2021 ◽

Author(s):

Young-Min Han ◽

Min Sun Kim ◽

Juyeong Jo ◽

Daiha Shin ◽

Seung-Hae Kwon ◽

...

Keyword(s):

Inhibitory Action ◽

Time Course ◽

Molecular Mechanisms ◽

Late Phase ◽

Fine Tuning ◽

Dependent Manner ◽

Middle Phase ◽

Temporal Shift

AbstractThe fine-tuning of neuroinflammation is crucial for brain homeostasis as well as its immune response. The transcription factor, nuclear factor-κ-B (NFκB) is a key inflammatory player that is antagonized via anti-inflammatory actions exerted by the glucocorticoid receptor (GR). However, technical limitations have restricted our understanding of how GR is involved in the dynamics of NFκB in vivo. In this study, we used an improved lentiviral-based reporter to elucidate the time course of NFκB and GR activities during behavioral changes from sickness to depression induced by a systemic lipopolysaccharide challenge. The trajectory of NFκB activity established a behavioral basis for the NFκB signal transition involved in three phases, sickness-early-phase, normal-middle-phase, and depressive-like-late-phase. The temporal shift in brain GR activity was differentially involved in the transition of NFκB signals during the normal and depressive-like phases. The middle-phase GR effectively inhibited NFκB in a glucocorticoid-dependent manner, but the late-phase GR had no inhibitory action. Furthermore, we revealed the cryptic role of basal GR activity in the early NFκB signal transition, as evidenced by the fact that blocking GR activity with RU486 led to early depressive-like episodes through the emergence of the brain NFκB activity. These results highlight the inhibitory action of GR on NFκB by the basal and activated hypothalamic-pituitary-adrenal (HPA)-axis during body-to-brain inflammatory spread, providing clues about molecular mechanisms underlying systemic inflammation caused by such as COVID-19 infection, leading to depression.

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