BMC Pulmonary Medicine | |
Pharmacologic inhibition of S-nitrosoglutathione reductase protects against experimental asthma in BALB/c mice through attenuation of both bronchoconstriction and inflammation | |
Gary J Rosenthal1  Charles Scoggin1  Doug Looker1  Jane P Richards1  Chris Delany1  Kirsten Look1  Michael Suniga1  Ramakrishna Boyanapalli1  Navdeep K Mehra1  Lucia H Green1  Jian Qiu1  Xicheng Sun1  Sarah C Mutka1  Joan P Blonder1  | |
[1] N30 Pharmaceuticals, Inc, 3122 Sterling Circle, Suite 200, Boulder, CO 80301, USA | |
关键词: NFκB; N6022; Nitric oxide; S-nitrosoglutathione; S-nitrosoglutathione reductase; Ovalbumin; Mouse; Inflammation; Asthma; | |
Others : 865456 DOI : 10.1186/1471-2466-14-3 |
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received in 2012-11-01, accepted in 2014-01-03, 发布年份 2014 | |
【 摘 要 】
Background
S-nitrosoglutathione (GSNO) serves as a reservoir for nitric oxide (NO) and thus is a key homeostatic regulator of airway smooth muscle tone and inflammation. Decreased levels of GSNO in the lungs of asthmatics have been attributed to increased GSNO catabolism via GSNO reductase (GSNOR) leading to loss of GSNO- and NO- mediated bronchodilatory and anti-inflammatory actions. GSNOR inhibition with the novel small molecule, N6022, was explored as a therapeutic approach in an experimental model of asthma.
Methods
Female BALB/c mice were sensitized and subsequently challenged with ovalbumin (OVA). Efficacy was determined by measuring both airway hyper-responsiveness (AHR) upon methacholine (MCh) challenge using whole body plethysmography and pulmonary eosinophilia by quantifying the numbers of these cells in the bronchoalveolar lavage fluid (BALF). Several other potential biomarkers of GSNOR inhibition were measured including levels of nitrite, cyclic guanosine monophosphate (cGMP), and inflammatory cytokines, as well as DNA binding activity of nuclear factor kappa B (NFκB). The dose response, onset of action, and duration of action of a single intravenous dose of N6022 given from 30 min to 48 h prior to MCh challenge were determined and compared to effects in mice not sensitized to OVA. The direct effect of N6022 on airway smooth muscle tone also was assessed in isolated rat tracheal rings.
Results
N6022 attenuated AHR (ED50 of 0.015 ± 0.002 mg/kg; Mean ± SEM) and eosinophilia. Effects were observed from 30 min to 48 h after treatment and were comparable to those achieved with three inhaled doses of ipratropium plus albuterol used as the positive control. N6022 increased BALF nitrite and plasma cGMP, while restoring BALF and plasma inflammatory markers toward baseline values. N6022 treatment also attenuated the OVA-induced increase in NFκB activation. In rat tracheal rings, N6022 decreased contractile responses to MCh.
Conclusions
The significant bronchodilatory and anti-inflammatory actions of N6022 in the airways are consistent with restoration of GSNO levels through GSNOR inhibition. GSNOR inhibition may offer a therapeutic approach for the treatment of asthma and other inflammatory lung diseases. N6022 is currently being evaluated in clinical trials for the treatment of inflammatory lung disease.
【 授权许可】
2014 Blonder et al.; licensee BioMed Central Ltd.
【 预 览 】
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