Decline in NRF2-regulated Antioxidants in Chronic Obstructive Pulmonary Disease Lungs Due to Loss of Its Positive Regulator, DJ-1

Malhotra, Deepti; Thimmulappa, Rajesh K.; Navas‐Acien, Ana; Sandford, Andrew J.; Elliott, Mark; Singh, Anju; Chen, Linan; Zhuang, Xiaoxi; Hogg, James C.; Paré, Peter D.; Tuder, Rubin M.; Biswal, Shyam

doi:10.1164/rccm.200803-380oc

Cited by 342 publications

(338 citation statements)

References 54 publications

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“…Recently, a redox-sensitive transcription factor, Nrf2, has been suggested to be an interesting target to intervene in the progression of experimental COPD/emphysema (43). However, it remains to be seen how effective Nrf2 activators will be in the treatment of COPD/emphysema, as it is posttranslationally modified, destabilized, and degraded in lungs of patients with COPD, and in rodent lungs exposed to CS (44)(45)(46)(47). In light of this, we compared the efficacy of SOD mimetic with NAC on elastase-induced emphysema in WT C57BL/6J and SOD3 KO mice.…”

Section: Discussionmentioning

confidence: 99%

Extracellular superoxide dismutase protects against pulmonary emphysema by attenuating oxidative fragmentation of ECM

Yao

Arunachalam

Hwang

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

175

166

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Extracellular superoxide dismutase (ECSOD or SOD3) is highly expressed in lungs and functions as a scavenger of O 2 • ─ . ECM fragmentation, which can be triggered by oxidative stress, participates in the pathogenesis of chronic obstructive pulmonary disease (COPD) through attracting inflammatory cells into the lungs. The level of SOD3 is significantly decreased in lungs of patients with COPD. However, the role of endogenous SOD3 in the development/progression of emphysema is unknown. We hypothesized that SOD3 protects against emphysema by attenuating oxidative fragmentation of ECM in mice. To test this hypothesis, SOD3-deficient, SOD3-transgenic, and WT C57BL/6J mice were exposed to cigarette smoke (CS) for 3 d (300 mg total particulate matter/m 3 ) to 6 mo (100 mg/m 3 total particulate matter) or by intratracheal elastase injection. Airspace enlargement, lung inflammation, lung mechanical properties, and exercise tolerance were determined at different time points during CS exposure or after elastase administration. CS exposure and elastase administration caused airspace enlargement as well as impaired lung function and exercise capacity in SOD3-null mice, which were improved in mice overexpressing SOD3 and by pharmacological SOD mimetic. These phenomena were associated with SOD3-mediated protection against oxidative fragmentation of ECM, such as heparin sulfate and elastin, thereby attenuating lung inflammatory response. In conclusion, SOD3 attenuates emphysema and reduces oxidative fragmentation of ECM in mouse lung. Thus, pharmacological augmentation of SOD3 in the lung may have a therapeutic potential in the intervention of COPD/emphysema.antioxidants | cigarette smoke | chronic obstructive pulmonary disease | oxidants | glutathione E xtracellular superoxide dismutase (ECSOD or SOD3) is one of the three SOD antioxidant enzyme isoforms, and is highly expressed in lungs and vessels (1, 2). It is located in the ECM, the junctions of airway epithelial cells, the surface of airway smooth muscle, and the lining of vessels of the lung. SOD3 functions as a superoxide anion scavenger, thereby attenuating oxidative stress, which may play an important role in the pathogenesis of chronic obstructive pulmonary disease (COPD). Acute loss of SOD3 in adult mice causes death, whereas low mortality rates are seen in SOD3-overexpressing animals exposed to hyperoxia, suggesting an essential role of SOD3 for survival (3,4). Accumulating evidence shows that SOD3 polymorphism is associated with a decline in lung function in rodents and humans, and susceptibility to COPD, which may be a result of alteration of its encoding protein structure, function, and level (5-14). However, it is unclear whether endogenous SOD3 participates in the development/ progression of the inflammatory response, leading to COPD/ emphysema.Cigarette smoke (CS) is the major etiological factor in the pathogenesis of COPD, which is characterized by chronic lung inflammation, parenchymal destruction (i.e., emphysema), and accelerated decline in lung function....

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Section: Discussionmentioning

confidence: 99%

Extracellular superoxide dismutase protects against pulmonary emphysema by attenuating oxidative fragmentation of ECM

Yao

Arunachalam

Hwang

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

175

166

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“…Pro-inflammatory cytokines may also promote tumour angiogenesis, which accelerates cell growth and metastases. The transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2), which regulates multiple antioxidant and detoxifying genes, is functionally defective in COPD lungs [146] and may contribute to the increased susceptibility of COPD patients to lung cancer, since Nrf2 plays an important role in defence against certain carcinogens in tobacco smoke by regulating the expression of several detoxifying enzymes [147]. Epidermal growth factor receptors (EGFR), which promote epithelial proliferation, show an increased expression in COPD patients [148].…”

Section: Mechanismsmentioning

confidence: 99%

“…A more attractive approach may be to restore the reduced Nrf2 levels in COPD lungs to normal. This has been achieved in vitro and in vivo by isothiocyanate compounds, such as sulforaphane, which occurs naturally in broccoli [146].…”

Section: Antioxidantsmentioning

confidence: 99%

Systemic manifestations and comorbidities of COPD

Barnes¹,

Celli²

2009

Eur Respir J

1,476

1,113

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Increasing evidence indicates that chronic obstructive pulmonary disease (COPD) is a complex disease involving more than airflow obstruction. Airflow obstruction has profound effects on cardiac function and gas exchange with systemic consequences. In addition, as COPD results from inflammation and/or alterations in repair mechanisms, the ''spill-over'' of inflammatory mediators into the circulation may result in important systemic manifestations of the disease, such as skeletal muscle wasting and cachexia. Systemic inflammation may also initiate or worsen comorbid diseases, such as ischaemic heart disease, heart failure, osteoporosis, normocytic anaemia, lung cancer, depression and diabetes. Comorbid diseases potentiate the morbidity of COPD, leading to increased hospitalisations, mortality and healthcare costs. Comorbidities complicate the management of COPD and need to be evaluated carefully. Current therapies for comorbid diseases, such as statins and peroxisome proliferator-activated receptor-agonists, may provide unexpected benefits for COPD patients. Treatment of COPD inflammation may concomitantly treat systemic inflammation and associated comorbidities. However, new broad-spectrum anti-inflammatory treatments, such as phosphodiesterase 4 inhibitors, have significant side-effects so it may be necessary to develop inhaled drugs in the future. Another approach is the reversal of corticosteroid resistance, for example with effective antioxidants. More research is needed on COPD comorbidities and their treatment.

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“…Дефицит пред-ставительства NRF2 сопровождается снижением экспрессии его генов-мишеней, которые коди-руют антиоксидантные протеины гемоксидазы, НАДФН-дегидрогеназу хинон-1 и глутатионпе-роксидазу-2 в альвеолярных макрофагах больных с эмфиземой легкого. Скорее всего, высокая экс-прессия протеина KEAP1, способствуя протеасом-ной деградации NRF2, обусловливает его дефицит и, как следствие, низкую активность антиокси-дантной системы [1,7].…”

Section: хроническая обструктивная болезнь легкихunclassified

Нозоспецифічні Особливості Редокс-Процесів При Бронхіальній Астмі Та Хронічній Обструктивній Хворобі Легень

Babуch¹,

Волосовец²,

Borysovа³

2021

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В огляді літератури викладено сучасні дані щодо специфічних особливостей оксидантного стресу, функціональної активності антиоксидантної системи та розвитку запального процесу при бронхіальній астмі і хронічній обструктивній хворобі легень.

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Decline in NRF2-regulated Antioxidants in Chronic Obstructive Pulmonary Disease Lungs Due to Loss of Its Positive Regulator, DJ-1

Abstract: NRF2-dependent antioxidants and DJ-1 expression was negatively associated with severity of COPD. Therapy directed toward enhancing NRF2-regulated antioxidants may be a novel strategy for attenuating the effects of oxidative stress in the pathogenesis of COPD.

Cited by 342 publications

References 54 publications

Extracellular superoxide dismutase protects against pulmonary emphysema by attenuating oxidative fragmentation of ECM

Extracellular superoxide dismutase protects against pulmonary emphysema by attenuating oxidative fragmentation of ECM

Systemic manifestations and comorbidities of COPD

Нозоспецифічні Особливості Редокс-Процесів При Бронхіальній Астмі Та Хронічній Обструктивній Хворобі Легень

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