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Changes of vitamin D receptors (VDR) and MAPK activation in cytoplasmic and nuclear fractions following exposure to cigarette smoke with or without filter in rats.

ABSTRACT: Cigarette smoke (CS) is a major cause of obstructive lung disease which is associated with significant disability and mortality. Vitamin D receptor (VDR) together with, mitogen activated protein kinases (MAPKs; ERK, JNK and p38) are the cellular transmission signals that mechanistically respond to CS and are recently found to have a role in lung pathogenesis. There are a few in vitro studies on subcellular VDR distribution involved MAPK but in vivo effects of cigarette smoke exposure with and without filter on this complex remain unclear. This study investigated subcellular VDR distribution and MAPK expression at early stages of both types of cigarette smoke exposure (CSE) in a rat model. Male Wistar rats were randomly divided into no-filter, filter and control groups. After 7 and 14 days of CSE, lung tissues were obtained to determine histopathology and protein expression. Cytoplasmic and nuclear VDR distribution significantly decreased on both CSE groups and corresponded with immunohistochemistry detection. The ratio of phosphorylated ERK to total ERK significantly increased in cytoplasm of both CSE on day 7. In particular, nuclear ERK MAPK significantly escalated in the filter group on day 14. In consistent with changes in intracellular markers, histopathological examination in both CSE groups showed significant increases in tracheal and peribronchiolar epithelial proliferation, alveolar macrophages and an increased trend of parenchymal infiltration. In summary, the evidence of lung injuries along with VDR depletion and MAPK activation observed in both CSE types indicated that there was no benefit of using cigarette filter to prevent protein damage or protect cells against cigarette smoke exposure in this model.

SUBMITTER: Okrit F

PROVIDER: S-EPMC7851787 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:The WHO study group on tobacco product regulation (TobReg) advised regulating and lowering toxicant levels in cigarette smoke. Aldehydes are one of the chemical classes on the TobReg smoke toxicants priority list. To provide insight in factors determining aldehyde yields, the levels of 12 aldehydes in mainstream cigarette smoke of 11 Dutch brands were quantified. Variations in smoking behavior and cigarette design affecting human exposure to aldehydes were studied by using four different machine testing protocols. Machine smoking was based on the International Standardization Organization (ISO) and Health Canada Intense (HCI) regime, both with and without taping the filter vents. The 11 cigarette brands differed in (i) design and blend characteristics; (ii) tar, nicotine, and carbon monoxide (TNCO) levels; (iii) popularity; and (iv) manufacturer. Cigarette smoke was trapped on a Cambridge filter pad and carboxen cartridge. After being dissolved in methanol/CS2 and derivatization with DNPH, the aldehyde yields were determined using HPLC-DAD. Using an intense smoking regime (increased puff volume, shorter puff interval) significantly increased aldehyde yields, following the pattern: ISO < ISO-taped < HCI-untaped < HCI. For all of the regimes, acetaldehyde and acrolein yields were strongly correlated ( r = 0.804). The difference in TNCO and aldehyde levels between regular and highly ventilated low-TNCO cigarettes (as measured using ISO) diminished when smoking intensely; this effect is stronger when combined with taping filter vents. The highly ventilated low-TNCO brands showed six times more aldehyde production per mg nicotine for the intense smoking regimes. In conclusion, acetaldehyde and acrolein can be used as representatives for the class of volatile aldehydes for the different brands and smoking regimes. The aldehyde-to-nicotine ratio increased when highly ventilated cigarettes were smoked intensely, similar to real smokers. Thus, a smoker of highly ventilated low-TNCO cigarettes has an increased potential for higher aldehyde exposures compared to a smoker of regular cigarettes.

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.

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Changes of vitamin D receptors (VDR) and MAPK activation in cytoplasmic and nuclear fractions following exposure to cigarette smoke with or without filter in rats.

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