Abstract:
AIMS:Cigarette smoke (CS)-mediated acquired cystic fibrosis transmembrane conductance regulator (CFTR)-dysfunction, autophagy-impairment, and resulting inflammatory-oxidative/nitrosative stress leads to chronic obstructive pulmonary disease (COPD)-emphysema pathogenesis. Moreover, nitric oxide (NO) signaling regulates lung function decline, and low serum NO levels that correlates with COPD severity. Hence, we aim to evaluate here the effects and mechanism(s) of S-nitrosoglutathione (GSNO) augmentation in regulating inflammatory-oxidative stress and COPD-emphysema pathogenesis. RESULTS:Our data shows that cystic fibrosis transmembrane conductance regulator (CFTR) colocalizes with aggresome bodies in the lungs of COPD subjects with increasing emphysema severity (Global Initiative for Chronic Obstructive Lung Disease [GOLD] I - IV) compared to nonemphysema controls (GOLD 0). We further demonstrate that treatment with GSNO or S-nitrosoglutathione reductase (GSNOR)-inhibitor (N6022) significantly inhibits cigarette smoke extract (CSE; 5%)-induced decrease in membrane CFTR expression by rescuing it from ubiquitin (Ub)-positive aggresome bodies (p < 0.05). Moreover, GSNO restoration significantly (p < 0.05) decreases CSE-induced reactive oxygen species (ROS) activation and autophagy impairment (decreased accumulation of ubiquitinated proteins in the insoluble protein fractions and restoration of autophagy flux). In addition, GSNO augmentation inhibits protein misfolding as CSE-induced colocalization of ubiquitinated proteins and LC3B (in autophagy bodies) is significantly reduced by GSNO/N6022 treatment. We verified using the preclinical COPD-emphysema murine model that chronic CS (Ch-CS)-induced inflammation (interleukin [IL]-6/IL-1β levels), aggresome formation (perinuclear coexpression/colocalization of ubiquitinated proteins [Ub] and p62 [impaired autophagy marker], and CFTR), oxidative/nitrosative stress (p-Nrf2, inducible nitric oxide synthase [iNOS], and 3-nitrotyrosine expression), apoptosis (caspase-3/7 activity), and alveolar airspace enlargement (Lm) are significantly (p < 0.05) alleviated by augmenting airway GSNO levels. As a proof of concept, we demonstrate that GSNO augmentation suppresses Ch-CS-induced perinuclear CFTR protein accumulation (p < 0.05), which restores both acquired CFTR dysfunction and autophagy impairment, seen in COPD-emphysema subjects. INNOVATION:GSNO augmentation alleviates CS-induced acquired CFTR dysfunction and resulting autophagy impairment. CONCLUSION:Overall, we found that augmenting GSNO levels controls COPD-emphysema pathogenesis by reducing CS-induced acquired CFTR dysfunction and resulting autophagy impairment and chronic inflammatory-oxidative stress. Antioxid. Redox Signal. 27, 433-451.
journal_name
Antioxid Redox Signaljournal_title
Antioxidants & redox signalingauthors
Bodas M,Silverberg D,Walworth K,Brucia K,Vij Ndoi
10.1089/ars.2016.6895subject
Has Abstractpub_date
2017-09-01 00:00:00pages
433-451issue
7eissn
1523-0864issn
1557-7716journal_volume
27pub_type
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journal_title:Antioxidants & redox signaling
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journal_title:Antioxidants & redox signaling
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journal_title:Antioxidants & redox signaling
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journal_title:Antioxidants & redox signaling
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journal_title:Antioxidants & redox signaling
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journal_title:Antioxidants & redox signaling
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journal_title:Antioxidants & redox signaling
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journal_title:Antioxidants & redox signaling
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journal_title:Antioxidants & redox signaling
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journal_title:Antioxidants & redox signaling
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journal_title:Antioxidants & redox signaling
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journal_title:Antioxidants & redox signaling
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journal_title:Antioxidants & redox signaling
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journal_title:Antioxidants & redox signaling
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更新日期:2012-04-01 00:00:00
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journal_title:Antioxidants & redox signaling
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journal_title:Antioxidants & redox signaling
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更新日期:2008-12-01 00:00:00
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journal_title:Antioxidants & redox signaling
pub_type: 杂志文章,评审
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journal_title:Antioxidants & redox signaling
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journal_title:Antioxidants & redox signaling
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journal_title:Antioxidants & redox signaling
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journal_title:Antioxidants & redox signaling
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journal_title:Antioxidants & redox signaling
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journal_title:Antioxidants & redox signaling
pub_type: 杂志文章
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更新日期:2019-07-20 00:00:00
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journal_title:Antioxidants & redox signaling
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更新日期:2019-04-10 00:00:00
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journal_title:Antioxidants & redox signaling
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更新日期:2014-07-10 00:00:00
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journal_title:Antioxidants & redox signaling
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更新日期:2008-11-01 00:00:00
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journal_title:Antioxidants & redox signaling
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更新日期:2009-08-01 00:00:00
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journal_title:Antioxidants & redox signaling
pub_type: 杂志文章
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更新日期:2020-05-10 00:00:00
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journal_title:Antioxidants & redox signaling
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