Deregulation of apoptosis mediators' p53 and bcl2 in lung tissue of COPD patients

Siganaki, Marianna; Koutsopoulos, Anastasios; Neofytou, Eirini; Vlachaki, Eleni; Psarrou, Maria; Soulitzis, Nikolaos; Pentilas, Nikolaos; Schiza, Sophia; Siafakas, Nikolaos M.; Tzortzaki, Eleni G.

doi:10.1186/1465-9921-11-46

Cited by 56 publications

(50 citation statements)

References 35 publications

(62 reference statements)

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“…As shown in Figures 7B and 7C, both were elevated in COPD tissue relative to control and expression increased with worsening severity. This is consistent with previously published data showing increased p53 protein levels in lungs of smokers with COPD compared with lungs of smokers without COPD (23,50).…”

Section: Dna Damage Is Increased In Copdsupporting

confidence: 93%

“…For instance, p53 is increased in type II pneumocytes of smokers with COPD relative to smokers without COPD (23), and patients with COPD have shortened telomeres in peripheral blood compared with control subjects, independent of smoking history (24). This may be caused by dysregulated antioxidant defense mechanisms (24) or repeated cycles of lymphocyte activation and proliferation (25), but a third possibility is that these individuals have impaired ability to repair double-strand DNA breaks resulting in premature telomere shortening (26).…”

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confidence: 99%

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Retinoic Acid–related Orphan Receptor-α Is Induced in the Setting of DNA Damage and Promotes Pulmonary Emphysema

Shi

Cao

Gao

et al. 2012

Am J Respir Crit Care Med

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Rationale: The discovery that retinoic acid-related orphan receptor (Rora)-a is highly expressed in lungs of patients with COPD led us to hypothesize that Rora may contribute to the pathogenesis of emphysema. Objectives: To determine the role of Rora in smoke-induced emphysema. Methods: Cigarette smoke extract in vitro and elastase or cigarette smoke exposure in vivo were used to model smoke-related cell stress and airspace enlargement. Lung tissue from patients undergoing lung transplantation was examined for markers of DNA damage and Rora expression. Measurements and Main Results: Rora expression was induced by cigarette smoke in mice and in cell culture. Gene expression profiling of Rora-null mice exposed to cigarette smoke demonstrated enrichment for genes involved in DNA repair. Rora expression increased and Rora translocated to the nucleus after DNA damage. Inhibition of ataxia telangiectasia mutated decreased the induction of Rora. Gene silencing of Rora attenuated apoptotic cell death in response to cigarette smoke extract, whereas overexpression of Rora enhanced apoptosis. Rora-deficient mice were protected from elastase and cigarette smoke induced airspace enlargement. Finally, lungs of patients with COPD showed evidence of increased DNA damage even in the absence of active smoking. Conclusions: Taken together, these findings suggest that DNA damage may contribute to the pathogenesis of emphysema, and that Rora has a previously unrecognized role in cellular responses to genotoxicity. These findings provide a potential link between emphysema and features of premature ageing, including enhanced susceptibility to lung cancer.Keywords: chronic obstructive pulmonary disease; p53; retinoic acidrelated orphan receptor-a; senescence; apoptosis Retinoic acid-related orphan receptor-a (Rora) is a nuclear hormone receptor named for its sequence homology with the retinoic acid receptor; its designation as "orphan" indicates that its natural ligand is unknown. We discovered that Rora expression is robustly increased in lungs of patients with chronic obstructive pulmonary disease (COPD), and this led us to examine whether Rora contributes to the pathogenesis of this disease. Little is known about the role of Rora in the lung, although its absence had been reported to lead paradoxically to increased LPS-induced lung inflammation (1) and decreased allergic inflammation (2). Outside the lung, Rora has been implicated in processes as diverse as osteogenic differentiation (3), circadian rhythm (4), apolipoprotein transcription (5), and Purkinje cell development (6). Gene expression profiling in Rora-null mice led us to the hypothesis that this nuclear receptor is involved in responses to DNA damage.Although the contribution of DNA damage to COPD has not been examined in detail, there are theoretical reasons to believe that genotoxicity could be involved in the pathogenesis of emphysema. Compromised DNA damage repair is known to result in accelerated ageing, as occurs in progeroid syndromes (7). Individuals with these syn...

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Section: Dna Damage Is Increased In Copdsupporting

confidence: 93%

mentioning

confidence: 99%

Retinoic Acid–related Orphan Receptor-α Is Induced in the Setting of DNA Damage and Promotes Pulmonary Emphysema

Shi

Cao

Gao

et al. 2012

Am J Respir Crit Care Med

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“…Given that hMSC have been shown to mediate anti-inflammatory effects8, reduce oxidative stress, reduce fibrosis and enhance repair30 it seems logical that hMSC might represent a suitable and efficacious therapy for COPD. Key pathological mechanisms of epithelial damage and wound formation occur in COPD, eventually leading to development of emphysema3132. This study has shown that hMSC possess potent cytoprotective and reparative abilities that may limit these activities.…”

Section: Discussionmentioning

confidence: 84%

Human mesenchymal stromal cells exert HGF dependent cytoprotective effects in a human relevant pre-clinical model of COPD

Kennelly

Mahon

English

2016

Sci Rep

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Bone-marrow derived mesenchymal stromal cells (MSCs) have potent immunomodulatory and tissue reparative properties, which may be beneficial in the treatment of inflammatory diseases such as COPD. This study examined the mechanisms by which human MSCs protect against elastase induced emphysema. Using a novel human relevant pre-clinical model of emphysema the efficacy of human MSC therapy and optimal cell dose were investigated. Protective effects were examined in the lung through histological examination. Further in vivo experiments examined the reparative abilities of MSCs after tissue damage was established and the role played by soluble factors secreted by MSCs. The mechanism of MSC action was determined in using shRNA gene knockdown. Human MSC therapy and MSC conditioned media exerted significant cytoprotective effects when administered early at the onset of the disease. These protective effects were due to significant anti-inflammatory, anti-fibrotic and anti-apoptotic mechanisms, mediated in part through MSC production of hepatocyte growth factor (HGF). When MSC administration was delayed, significant protection of the lung architecture was observed but this was less extensive. MSC cell therapy was more effective than MSC conditioned medium in this emphysema model.

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“…It has been reported that the classic anti-apoptotic protein, Bcl-2, might present protective potential for emphysema. 8,[11][12][13] whereas the pro-apoptotic protein, Bax, might contribute to emphysema progress. [14][15][16] Some studies described methylation, an important epigenetic event, participated in regulation of Bcl-2 and apoptosis.…”

Section: Introductionmentioning

confidence: 99%

Involvement of B-cell CLL/lymphoma 2 promoter methylation in cigarette smoke extract-induced emphysema

Zeng

Shi

Kong

et al. 2016

Exp Biol Med (Maywood)

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Abnormal apoptotic events play an important role in the pathogenesis of emphysema. The B-cell CLL/lymphoma 2 (Bcl-2) family proteins are essential and critical regulators of apoptosis. We determined whether the anti-apoptotic Bcl-2 play a role in the cigarette smoke extract (CSE)-induced emphysema. Furthermore, given the involvement of epigenetics in chronic obstructive pulmonary disease, we hypothesized that the deregulation of Bcl-2 might be caused by gene methylation. The emphysema in BALB/C mice was established by intraperitoneally injection of CSE. 5-aza-2 0 -deoxycytidine (AZA; a demethylation reagent) and phosphate-buffered saline were also administered intraperitoneally as CSE. TUNEL assay was used to assess apoptotic index of pulmonary cells. The methylation status of CpG dinucleotides within the Bcl-2 promoter was observed in all groups by bisulfite sequencing PCR. Pulmonary expression of Bcl-2, Bax, and cytochrome C were measured after four weeks of treatment. The apoptotic index of pulmonary cells in CSE injection group was much higher than control ((25.88 AE 7.55)% vs. (6.28 AE 2.96)%). Compared to control mice, decreased expression of Bcl-2 and high methylation of Bcl-2 promoter was observed in CSE injected mice (0.88 AE 0.08 vs. 0.49 AE 0.11, (3.82 AE 1.34)% vs. (35.68 AE 5.99)%, P < 0.01).CSE treatment induced lung cell apoptosis and decreased lung function. AZA treatment increased Bcl-2 expression with Bcl-2 promoter demethylation. AZA also alleviated the lung cell apoptosis and function failure caused by CSE treatment. The decreased expression of antiapoptotic Bcl-2 might account for the increased apoptosis in CSE induced-emphysema. Apparently, epigenetic alternation played a role in this deregulation of Bcl-2 expression, and it might support the involvement of epigenetic events in the pathogenesis of emphysema.

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Deregulation of apoptosis mediators' p53 and bcl2 in lung tissue of COPD patients

Cited by 56 publications

References 35 publications

Retinoic Acid–related Orphan Receptor-α Is Induced in the Setting of DNA Damage and Promotes Pulmonary Emphysema

Retinoic Acid–related Orphan Receptor-α Is Induced in the Setting of DNA Damage and Promotes Pulmonary Emphysema

Human mesenchymal stromal cells exert HGF dependent cytoprotective effects in a human relevant pre-clinical model of COPD

Involvement of B-cell CLL/lymphoma 2 promoter methylation in cigarette smoke extract-induced emphysema

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