Altered Nrf2/Keap1-Bach1 equilibrium in pulmonary emphysema

Abstract

Background: Oxidative stress, resulting from the increased oxidative burden and decreased level of antioxidant proteins, plays a role in the pathophysiology of smoking-related pulmonary emphysema. Expression of several antioxidant proteins, such as heme oxygenase-1 (HO-1), glutathione peroxidase 2 (GPX2) and NAD(P)H:quinone oxidoreductase 1 (NQO1), results from an equilibrium created by positive or negative regulation by the transcription factors Nrf2, Keap1 and Bach1, respectively. However, whether the expression of these transcription factors is altered in emphysema and could account for decreased expression of antioxidant proteins is not known. A study was undertaken to investigate the expression and subcellular localisation of Nrf2, Keap1 and Bach1 as potential regulators of HO-1, GPX2 and NQO1 in alveolar macrophages, a key cell in oxidative stress, in lung surgical specimens from non-smokers without emphysema and smokers with and without emphysema. Methods and results: Western blot, immunohistochemical and laser scanning confocal analysis revealed that the Nrf2 protein level decreased significantly in whole lung tissue and alveolar macrophages (cytosol and nucleus) in patients with emphysema compared with those without emphysema. Conversely, Bach1 and Keap1 levels were increased in patients with emphysema. These modifications were associated with a parallel decrease in the expression of HO-1, GPX2 and NQO1 at the cellular level, which was inversely correlated with airway obstruction and distension indexes, and increased macrophage expression of the lipid peroxidation product 4-hydroxy-2-nonenal. Silencing RNA experiments in vitro in THP-1 cells were performed to confirm the cause-effect relation between the loss of Nrf2 and the decrease in HO-1, NQO1 and GPX2 expression. Nrf2/Keap1-Bach1 equilibrium was altered in alveolar macrophages in pulmonary emphysema, which points to a decreased stress response phenotype. Conclusions: This finding opens a new view of the pathophysiology of emphysema and could provide the basis for new therapeutic approaches based on preservation and/or restoration of such equilibrium.Chronic cigarette smoking is the most important risk factor for lung emphysema, a major component of morbidity and mortality in chronic obstructive pulmonary disease (COPD).1 Several mechanisms by which chronic exposure to cigarette smoke (CS) leads to emphysema include lung inflammation and imbalance in level of proteases/ antiproteases and oxidants/antioxidants (namely, oxidative stress).2 However, the precise nature of these alterations is still unknown. Alveolar macrophages are important components of lung inflammation in emphysema. Studies of emphysematous lung tissue from human subjects have shown a direct relation between alveolar macrophage density in the parenchyma and severity of lung destruction. 3 Moreover, in the emphysematous lung, alveolar macrophages can release an array of matrix metalloprotease enzymes and reactive oxygen species involved in protease/antiprotease imbalance and...

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

“…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.…”

Sulforaphane inhibitsde novosynthesis of IL-8 and MCP-1 in human epithelial cells generated by cigarette smoke extract

“…NRF2 pathway activation has also been shown to be important in COPD patients. Lung samples from COPD patients have a significantly reduced NRF2 activity that correlates to disease severity (Goven et al, 2008;Malhotra et al, 2008;Suzuki et al, 2008). Therefore, if deficiencies in the NRF2 pathways are associated with COPD pathogenesis, therapies directed toward enhancing the expression of NRF2-regulated antioxidants may be a novel strategy for attenuating the effects of inflammation in the pathogenesis of COPD.…”

Experimental Therapeutics of Nrf2 as a Target for Prevention of Bacterial Exacerbations in COPD

“…The Nrf2-directed antioxidant response decreases in peripheral lung tissue and alveolar macrophages in patients with COPD compared with that in patients without COPD. A decrease in Nrf2 activity with progression of COPD was linked to a decrease in Nrf2 protein and is related to changes in the activity of its positive regulator, DJ-1 and negative regulators, Keap1 and BACH1 (34)(35)(36). Nrf2 activity showed an inverse correlation with markers of oxidative damage in COPD (35).…”