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Augmentation of S-Nitrosoglutathione Controls Cigarette Smoke-Induced Inflammatory-Oxidative Stress and Chronic Obstructive Pulmonary Disease-Emphysema Pathogenesis by Restoring Cystic Fibrosis Transmembrane Conductance Regulator Function.
Antioxid Redox Signal. 2017 Sep 01; 27(7):433-451.AR

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.

Authors+Show Affiliations

1 College of Medicine, Central Michigan University , Mt. Pleasant, Michigan.1 College of Medicine, Central Michigan University , Mt. Pleasant, Michigan.1 College of Medicine, Central Michigan University , Mt. Pleasant, Michigan.1 College of Medicine, Central Michigan University , Mt. Pleasant, Michigan.1 College of Medicine, Central Michigan University , Mt. Pleasant, Michigan. 2 Department of Pediatrics and Pulmonary Medicine, The Johns Hopkins University School of Medicine , Baltimore, Maryland.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

28006950

Citation

Bodas, Manish, et al. "Augmentation of S-Nitrosoglutathione Controls Cigarette Smoke-Induced Inflammatory-Oxidative Stress and Chronic Obstructive Pulmonary Disease-Emphysema Pathogenesis By Restoring Cystic Fibrosis Transmembrane Conductance Regulator Function." Antioxidants & Redox Signaling, vol. 27, no. 7, 2017, pp. 433-451.
Bodas M, Silverberg D, Walworth K, et al. Augmentation of S-Nitrosoglutathione Controls Cigarette Smoke-Induced Inflammatory-Oxidative Stress and Chronic Obstructive Pulmonary Disease-Emphysema Pathogenesis by Restoring Cystic Fibrosis Transmembrane Conductance Regulator Function. Antioxid Redox Signal. 2017;27(7):433-451.
Bodas, M., Silverberg, D., Walworth, K., Brucia, K., & Vij, N. (2017). Augmentation of S-Nitrosoglutathione Controls Cigarette Smoke-Induced Inflammatory-Oxidative Stress and Chronic Obstructive Pulmonary Disease-Emphysema Pathogenesis by Restoring Cystic Fibrosis Transmembrane Conductance Regulator Function. Antioxidants & Redox Signaling, 27(7), 433-451. https://doi.org/10.1089/ars.2016.6895
Bodas M, et al. Augmentation of S-Nitrosoglutathione Controls Cigarette Smoke-Induced Inflammatory-Oxidative Stress and Chronic Obstructive Pulmonary Disease-Emphysema Pathogenesis By Restoring Cystic Fibrosis Transmembrane Conductance Regulator Function. Antioxid Redox Signal. 2017 Sep 1;27(7):433-451. PubMed PMID: 28006950.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Augmentation of S-Nitrosoglutathione Controls Cigarette Smoke-Induced Inflammatory-Oxidative Stress and Chronic Obstructive Pulmonary Disease-Emphysema Pathogenesis by Restoring Cystic Fibrosis Transmembrane Conductance Regulator Function. AU - Bodas,Manish, AU - Silverberg,David, AU - Walworth,Kyla, AU - Brucia,Kathryn, AU - Vij,Neeraj, Y1 - 2017/02/07/ PY - 2016/12/23/pubmed PY - 2018/3/13/medline PY - 2016/12/24/entrez KW - CFTR KW - COPD KW - GSNO KW - GSNOR KW - NO KW - emphysema SP - 433 EP - 451 JF - Antioxidants & redox signaling JO - Antioxid Redox Signal VL - 27 IS - 7 N2 - 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. SN - 1557-7716 UR - https://www.unboundmedicine.com/medline/citation/28006950/Augmentation_of_S_Nitrosoglutathione_Controls_Cigarette_Smoke_Induced_Inflammatory_Oxidative_Stress_and_Chronic_Obstructive_Pulmonary_Disease_Emphysema_Pathogenesis_by_Restoring_Cystic_Fibrosis_Transmembrane_Conductance_Regulator_Function_ L2 - https://www.liebertpub.com/doi/10.1089/ars.2016.6895?url_ver=Z39.88-2003&amp;rfr_id=ori:rid:crossref.org&amp;rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -