Alternative Oxidase Attenuates Cigarette Smoke-induced Lung Dysfunction and Tissue Damage.
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ABSTRACT:
SUBMITTER: Giordano L
PROVIDER: S-EPMC6503618 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:The oxidative stress and cellular apoptosis by environmental factor including cigarette smoke induces alveolar airway remodeling leading to chronic obstructive pulmonary disease (COPD). Recently, the receptor for advanced glycan end products (RAGE) which is highly expressed in alveolar epithelium is emerging as a biomarker for COPD susceptibility or progression. However, it still remains unknown how RAGE plays a role in cigarette smoke extract (CSE)-exposed human alveolar type II epithelial cell line. Therefore, we determined the efficacy of RAGE-specific antagonist FPS-ZM1 in response to CSE-induced lung epithelial cells. CSE induced the elevated generation of RONS and release of pro-inflammatory cytokines, and impaired the cellular antioxidant defense system. Further, CSE induced the alteration of RAGE distribution via the activation of redox-sensitive DAMP (Damage-associated molecular patterns) signaling through Nrf2 in cells. Although pre-treatment with SB202190 (p38 inhibitor) or SP600125 (JNK inhibitor) failed to recover the alteration of RAGE distribution, treatment of FPS-ZM1 significantly exhibited anti-inflammatory and anti-oxidative/nitrosative effects, also inhibited the activation of redox-sensitive DAMP signaling through Nrf2 (nuclear factor erythroid 2-related factor 2) migration in the presence of CSE. Taken together, our data demonstrate that RAGE and Nrf2 play a pivotal role in maintenance of alveolar epithelial integrity.
| S-EPMC6036614 | biostudies-literature
Project description:Chronic obstructive pulmonary disease (COPD) is a prevalent smoking-related disease for which no disease-altering therapies currently exist. As dysregulated TGF-β signaling associates with lung pathology in patients with COPD and in animal models of lung injury induced by chronic exposure to cigarette smoke (CS), we postulated that inhibiting TGF-β signaling would protect against CS-induced lung injury. We first confirmed that TGF-β signaling was induced in the lungs of mice chronically exposed to CS as well as in COPD patient samples. Importantly, key pathological features of smoking-associated lung disease in patients, e.g., alveolar injury with overt emphysema and airway epithelial hyperplasia with fibrosis, accompanied CS-induced alveolar cell apoptosis caused by enhanced TGF-β signaling in CS-exposed mice. Systemic administration of a TGF-β-specific neutralizing antibody normalized TGF-β signaling and alveolar cell death, conferring improved lung architecture and lung mechanics in CS-exposed mice. Use of losartan, an angiotensin receptor type 1 blocker used widely in the clinic and known to antagonize TGF-β signaling, also improved oxidative stress, inflammation, metalloprotease activation and elastin remodeling. These data support our hypothesis that inhibition of TGF-β signaling through angiotensin receptor blockade can attenuate CS-induced lung injury in an established murine model. More importantly, our findings provide a preclinical platform for the development of other TGF-β-targeted therapies for patients with COPD.
| S-EPMC3248282 | biostudies-literature
Project description:Senescent cells accumulate in tissues during aging or pathological settings. The semi-genetic or pharmacological targeting of senescent cells revealed that cellular senescence underlies many aspects of the aging-associated phenotype and diseases. We previously reported that cellular senescence contributes to aging- and disease-associated pulmonary dysfunction. We herein report that the elimination of Arf-expressing cells ameliorates cigarette smoke-induced lung pathologies in mice. Cigarette smoke induced the expression of Ink4a and Arf in lung tissue with concomitant increases in lung tissue compliance and alveolar airspace. The elimination of Arf-expressing cells prior to cigarette smoke exposure protected against these changes. Furthermore, the administration of cigarette smoke extract lead to pulmonary dysfunction, which was ameliorated by subsequent senescent cell elimination. Collectively, these results suggest that senescent cells are a potential therapeutic target for cigarette smoking-associated lung disease.
| S-EPMC7175375 | biostudies-literature
Project description:Background: We found previously that ursolic acid (UA) administration could alleviate cigarette smoke-induced emphysema in rats partly through the unfolded protein response (UPR) PERK-CHOP and Nrf2 pathways, thus alleviating endoplasmic reticulum stress (ERS)-associated oxidative stress and cell apoptosis. We hypothesized that other UPR pathways may play similar roles in cigarette smoke extract (CSE)-induced emphysema. So, we sought to investigate the dynamic changes and effects of UPR and the downstream apoptotic pathways. Further, we investigated whether UA could alleviate CSE-induced emphysema and airway remodelling in rats, whether and when it exerts its effects through UPR pathways as well as Smads pathways. Methods: One hundred eight Sprague Dawley (SD) rats were randomly divided into three groups: Sham group, CSE group, and UA group, and each group was further divided into three subgroups, administered CSE (vehicle) for 2, 3, or 4 weeks; each subgroup had 12 rats. We examined pathological changes, analyzed the three UPR signaling pathways and subsequent ERS, intrinsic and extrinsic apoptotic pathway indicators, as well as activation of Smad2,3 molecules in rat lungs. Results: Exposure to CSE for 3 or 4 weeks could apparently induce emphysema and airway remodeling in rats, including gross and microscopic changes, alteration of mean alveolar number (MAN), mean linear intercept (MLI), and mean airway thickness in lung tissue sections. UA intervention could significantly alleviate CSE-induced emphysema and airway remodeling in rats. UA exerted its effects through ameliorating apoptosis by down regulating UPR signalling pathways and subsequent apoptosis pathways, as well as, downregulating p-Smad2 and p-Smad3 molecules. Conclusions: UA attenuated CSE-induced emphysema and airway remodeling, exerting its effects partly through regulation of three UPR pathways, amelioration downstream apoptotic pathways, and alleviating activation of Smad2 and Smad3.
| S-EPMC6595172 | biostudies-literature
Project description:Exposure to cigarette smoke (CS) is the primary factor associated with the development of chronic obstructive pulmonary disease (COPD). CS increases the level of oxidants in the lungs, resulting in a depletion of antioxidants, which promotes oxidative stress and the destruction of alveolar tissue. In response to CS, pulmonary epithelial cells counteract increased levels of oxidants by activating Nrf2-dependent pathways to augment the expression of detoxification and antioxidant enzymes, thereby protecting the lung from injury. We hypothesize that increasing the pathways activated by Nrf2 will afford protection against CS-induced lung damage. To this end we have developed a novel mouse model in which the cytosolic inhibitor of Nrf2, Keap1, is genetically deleted in Clara cells, which predominate in the upper airways in mice. Deletion of Keap1 in Clara cells resulted in increased expression of Nrf2-dependent genes, such as Nqo1 and Gclm, as determined by microarray analysis and quantitative PCR. Deletion of Keap1 in airway epithelium decreased Keap1 protein levels and significantly increased the total level of glutathione in the lungs. Increased Nrf2 activation protected Clara cells against oxidative stress ex vivo and attenuated oxidative stress and CS-induced inflammation in vivo. Expression of KEAP1 was also decreased in human epithelial cells through siRNA transfection, which increased the expression of Nrf2-dependent genes and attenuated oxidative stress. In conclusion, activating Nrf2 pathways in tissue-specific Keap1 knockout mice represents an important genetic approach against oxidant-induced lung damage.
| S-EPMC2874439 | biostudies-literature
Project description:Chronic obstructive pulmonary disease (COPD), which comprises emphysema and chronic bronchitis resulting from prolonged exposure to cigarette smoke (CS), is a major public health burden with no effective treatment. Emphysema is also associated with pulmonary hypertension, which can progress to right ventricular failure, an important cause of morbidity and mortality among patients with COPD. Nuclear erythroid 2 p45 related factor-2 (Nrf2) is a redox-sensitive transcription factor that up-regulates a battery of antioxidative genes and cytoprotective enzymes that constitute the defense against oxidative stress. Recently, it has been shown that patients with advanced COPD have a decline in expression of the Nrf2 pathway in lungs, suggesting that loss of this antioxidative protective response is a key factor in the pathophysiological progression of emphysema. Furthermore, genetic disruption of Nrf2 in mice causes early-onset and severe emphysema. The present study evaluated whether the strategy of activation of Nrf2 and its downstream network of cytoprotective genes with a small molecule would attenuate CS-induced oxidative stress and emphysema. Nrf2(+/+) and Nrf2(-/-) mice were fed a diet containing the potent Nrf2 activator, 1-[2-cyano-3-,12-dioxooleana-1,9(11)-dien-28-oyl]imidazole (CDDO-Im), while being exposed to CS for 6 months. CDDO-Im significantly reduced lung oxidative stress, alveolar cell apoptosis, alveolar destruction, and pulmonary hypertension in Nrf2(+/+) mice caused by chronic exposure to CS. This protection from CS-induced emphysema depended on Nrf2, as Nrf2(-/-) mice failed to show significant reduction in alveolar cell apoptosis and alveolar destruction after treatment with CDDO-Im. These results suggest that targeting the Nrf2 pathway during the etiopathogenesis of emphysema may represent an important approach for prophylaxis against COPD.
| S-EPMC2629210 | biostudies-literature
Project description:Gastrointestinal (GI) dysfunction is a common comorbidity of chronic obstructive pulmonary disease (COPD) for which a major cause is cigarette smoking (CS). The underlying mechanisms and precise effects of CS on gut contractility, however, are not fully characterised. Therefore, the aim of the present study was to investigate whether CS impacts GI function and structure in a mouse model of CS-induced COPD. We also aimed to investigate GI function in the presence of ebselen, an antioxidant that has shown beneficial effects on lung inflammation resulting from CS exposure. Mice were exposed to CS for 2 or 6 months. GI structure was analysed by histology and immunofluorescence. After 2 months of CS exposure, ex vivo gut motility was analysed using video-imaging techniques to examine changes in colonic migrating motor complexes (CMMCs). CS decreased colon length in mice. Mice exposed to CS for 2 months had a higher frequency of CMMCs and a reduced resting colonic diameter but no change in enteric neuron numbers. Ten days cessation after 2 months CS reversed CMMC frequency changes but not the reduced colonic diameter phenotype. Ebselen treatment reversed the CS-induced reduction in colonic diameter. After 6 months CS, the number of myenteric nitric-oxide producing neurons was significantly reduced. This is the first evidence of colonic dysmotility in a mouse model of CS-induced COPD. Dysmotility after 2 months CS is not due to altered neuron numbers; however, prolonged CS-exposure significantly reduced enteric neuron numbers in mice. Further research is needed to assess potential therapeutic applications of ebselen in GI dysfunction in COPD.
| S-EPMC7676466 | biostudies-literature
Project description:BackgroundCigarette smoke-induced cellular and molecular mechanisms of lung injury are not clear. Cigarette smoke is a complex mixture containing long-lived radicals, including p-benzosemiquinone that causes oxidative damage. Earlier we had reported that oxidative protein damage is an initial event in smoke-induced lung injury. Considering that p-benzosemiquinone may be a causative factor of lung injury, we have isolated p-benzosemiquinone and compared its pathophysiological effects with cigarette smoke. Since vitamin C is a strong antioxidant, we have also determined the modulatory effect of vitamin C for preventing the pathophysiological events.MethodsVitamin C-restricted guinea pigs were exposed to cigarette smoke (5 cigarettes/day; 2 puffs/cigarette) for 21 days with and without supplementation of 15 mg vitamin C/guinea pig/day. Oxidative damage, apoptosis and lung injury were assessed in vitro, ex vivo in A549 cells as well as in vivo in guinea pigs. Inflammation was measured by neutrophilia in BALF. p-Benzosemiquinone was isolated from freshly prepared aqueous extract of cigarette smoke and characterized by various physico-chemical methods, including mass, NMR and ESR spectroscopy. p-Benzosemiquinone-induced lung damage was examined by intratracheal instillation in guinea pigs. Lung damage was measured by increased air spaces, as evidenced by histology and morphometric analysis. Oxidative protein damage, MMPs, VEGF and VEGFR2 were measured by western blot analysis, and formation of Michael adducts using MALDI-TOF-MS. Apoptosis was evidenced by TUNEL assay, activation of caspase 3, degradation of PARP and increased Bax/Bcl-2 ratio using immunoblot analysis and confocal microscopy.ResultsExposure of guinea pigs to cigarette smoke resulted in progressive protein damage, inflammation, apoptosis and lung injury up to 21 days of the experimental period. Administration of 15 mg of vitamin C/guinea pig/day prevented all these pathophysiological effects. p-Benzosemiquinone mimicked cigarette smoke in causing protein modification and apoptosis in vitro and in A549 cells ex vivo as well as apoptosis and lung damage in vivo. All these pathophysiological events were also prevented by vitamin C.Conclusionp-Benzosemiquinone appears to be a major causative factor of cigarette smoke-induced oxidative protein damage that leads to apoptosis and lung injury. The pathophysiological events are prevented by a moderately large dose of vitamin C.
| S-EPMC2615750 | biostudies-literature
Project description:AimTo appraise the efficacy of Vam3 (Amurensis H), a dimeric derivative of resveratrol, at inhibiting cigarette smoke-induced autophagy.MethodsHuman bronchial epithelial cells were treated with cigarette smoke condensates, and a chronic obstructive pulmonary disease (COPD) model was established by exposing male BALB/c mice to cigarette smoke. The protein levels of the autophagic marker microtubule-associated protein 1A/1B-light chain 3 (LC3), Sirtuin 1 (Sirt1), and foxhead box O 3a (FoxO3a) were examined using Western blotting and Immunohistochemistry. LC3 punctae were detected by immunofluorescence. The levels of FoxO3a acetylation were examined by immunoprecipitation. The level of intracellular oxidation was assessed by detecting ROS and GSH-Px.ResultsVam3 attenuated cigarette smoke condensate-induced autophagy in human bronchial epithelial cells, and restored the expression levels of Sirt1 and FoxO3a that had been reduced by cigarette smoke condensates. Similar protective effects of Vam3, reducing autophagy and restoring the levels of Sirt1 and FoxO3a, were observed in the COPD animal model. Additionally, Vam3 also diminished the oxidative stress that was induced by the cigarette smoke condensates.ConclusionVam3 decreases cigarette smoke-induced autophagy via up-regulating/restoring the levels of Sirt1 and FoxO3a and inhibiting the induced oxidative stress.
| S-EPMC4011152 | biostudies-literature
Project description:Chronic obstructive pulmonary disease (COPD) and lung cancer represent two diseases that share a strong risk factor in smoking, and COPD increases risk of lung cancer even after adjusting for the effects of smoking. These diseases not only occur jointly within an individual but also there is evidence of shared occurrence within families. Understanding the genetic contributions to these diseases, both individually and jointly, is needed to identify the highest risk group for screening and targeted prevention, as well as aiding in the development of targeted treatments. The chromosomal regions that have been identified as being associated either jointly or independently with lung cancer, COPD, nicotine addiction, and lung function are presented. Studies jointly measuring genetic variation in lung cancer and COPD have been limited by the lack of detailed COPD diagnosis and severity data in lung cancer populations, the lack of lung cancer-specific phenotypes (histology and tumor markers) in COPD populations, and the lack of inclusion of minorities. African Americans, who smoke fewer cigarettes per day and have different linkage disequilibrium and disease patterns than whites, and Asians, also with different patterns of exposure to lung carcinogens and linkage patterns, will provide invaluable information to better understand shared and independent genetic contributions to lung cancer and COPD to more fully define the highest risk group of individuals who will most benefit from screening and to develop molecular signatures to aid in targeted treatment and prevention efforts.
| S-EPMC3359114 | biostudies-literature