Crotonaldehyde induces apoptosis in alveolar macrophages through intracellular calcium, mitochondria and p53 signaling pathways

Yang, Bicheng; Pan, Xiujie; Yang, Zhihua; Xiao, Fengjun; Liu, Xingyu; Zhu, Man; Xie, Jianping

doi:10.2131/jts.38.225

Cited by 18 publications

(9 citation statements)

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“…Based on reports that cigarette smoke increases oxidative stress levels in the lung [ 35 , 36 ], we hypothesized that CRO may have similar effects on the human distal lung cells. Therefore, we treated H441 cells with CRO at 0, 2, 8 and 24 h, and intracellular ROS levels were then detected by the dichlorofluorescein assay.…”

Section: Resultsmentioning

confidence: 99%

“…We found that CRO can inhibit the amiloride-sensitive Isc of H441 cell monolayers dose-dependently, strongly suggesting that CRO inhibits Na + transport via suppressing lung ENaC. In our study, 80 μM CRO was chosen based on previous studies [ 36 , 42 ] and from the IC 50 value calculated in our Ussing chamber results, which amounts to one or two 2R4F Kentucky reference cigarettes [ 43 ]. We were excited to discover that both α- and γ-ENaC expression decreased at the protein and transcriptional level after CRO exposure.…”

Section: Discussionmentioning

confidence: 99%

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Novel mechanisms for crotonaldehyde-induced lung edema

Chang

Cui

et al. 2017

Oncotarget

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BackgroundCrotonaldehyde is a highly noxious α,β-unsaturated aldehyde in cigarette smoke that causes edematous acute lung injury.ObjectiveTo understand how crotonaldehyde impairs lung function, we examined its effects on human epithelial sodium channels (ENaC), which are major contributors to alveolar fluid clearance.MethodsWe studied alveolar fluid clearance in C57 mice and ENaC activity was examined in H441 cells. Expression of α- and γ-ENaC was measured at protein and mRNA levels by western blot and real-time PCR, respectively. Intracellular ROS levels were detected by the dichlorofluorescein assay. Heterologous αβγ-ENaC activity was observed in an oocyte model.ResultsOur results showed that crotonaldehyde reduced transalveolar fluid clearance in mice. Furthermore, ENaC activity in H441 cells was inhibited by crotonaldehyde dose-dependently. Expression of α- and γ-subunits of ENaC was decreased at the protein and mRNA level in H441 cells exposed to crotonaldehyde, which was probably mediated by the increase in phosphorylated extracellular signal-regulated protein kinases 1 and 2. ROS levels increased time-dependently in cells exposed to crotonaldehyde. Heterologous αβγ-ENaC activity was rapidly eliminated by crotonaldehyde.ConclusionOur findings suggest that crotonaldehyde causes edematous acute lung injury by eliminating ENaC activity at least partly via facilitating the phosphorylation of extracellular signal-regulated protein kinases 1 and 2 signal molecules. Long-term exposure may decrease the expression of ENaC subunits and damage the cell membrane integrity, as well as increase the levels of cellular ROS products.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Novel mechanisms for crotonaldehyde-induced lung edema

Chang

Cui

et al. 2017

Oncotarget

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“…The primary sources of TCA include lipid peroxidation in mitochondria in vivo 13 , 14 , tobacco tar 15 , and environmental pollution in vitro , etc 16 . In search of how to eliminate the mutagenic action of TCA, it was accidentally discovered that the maximum UV-vis peak at 301 nm of TCA was red-shifted by EtOH.…”

Section: Introductionmentioning

confidence: 99%

Influences of ethanol on the structure of toxic trans-crotonaldehyde in mitochondria coming from rat myocardium

et al. 2017

Sci Rep

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Inappropriate use of ethanol (EtOH) had led to noticeable health problems, but a beneficial phenomenon was found that EtOH displayed unique influences for toxic trans-crotonaldehyde (TCA) derived from mitochondrial lipid peroxidation. The influences of EtOH on the structure of TCA were systematically probed by UV-vis & Raman spectroscopy in the absence and presence of mitochondria, respectively. The maximum UV-vis peak at 301 nm of TCA was red shifted by hydroxyl (-OH) and methyl (-CH3) of EtOH, respectively. Raman stretching band of aldehyde (-CH=O) of TCA (TCA-CH=O) was split by the -CH3 of EtOH. The -CH3 increased TCA-CH=O stretching frequency while the -OH induced it. The more exposed -OH, the less stretching frequency. The ectopic -CH3 red shifted the UV-vis peak at 301 nm and Raman band of TCA-CH=O. In mitochondria, EtOH red shifted Raman stretching band of TCA-CH=O. Raman stretching bands of C-H, C-O and C-C of EtOH were red shifted, while Raman stretching bands of -CH2 and C-C-O of EtOH disappeared. The paper unearths the influences of EtOH to trap and transform the structure of TCA-CH=O. This discovery has an important contribution to eliminate TCA in order to protect and repair mtDNA by means of the decrease of 8-oxoG.

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“…Crotonaldehyde could induce oxidative stress, caspase-dependent apoptosis and alter gene expression profile in the genome-wide transcriptional in human bronchial epithelial cells (Liu et al, 2010a(Liu et al, , 2010b. Crotonaldehyde induces apoptosis, immunosuppression and IL-8 release in alveolar macrophages (Yang et al, 2012(Yang et al, , 2013a(Yang et al, and 2013b. Recent studies have reported that crotonaldehyde-induced HO-1 expression is mediated by the PKC-δ-p38MAPK-Nrf2-HO-1 pathway in human umbilical vein endothelial cells, which is an adaptive response to oxidative stress (Lee et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

Transcript profiling analysis of <i>in vitro</i> cultured THP-1 cells after exposure to crotonaldehyde

Yang

Pan

et al. 2014

J. Toxicol. Sci.

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-Crotonaldehyde, a highly toxic α, β-unsaturated aldehyde, is a major component of cigarette smoke and a ubiquitous environmental pollutant. Crotonaldehyde exposure is known to have adverse effects on respiratory health, but the underlying mechanisms remain obscure. As alveolar macrophages display important immunological and inflammatory properties in response to extraneous substances in the lung, we aimed at gaining more insight in changes of human macrophage-like cells transcriptome in response to crotonaldehyde. In vitro cultures of human THP-1 cells (a human monocytic leukemia cell line) were differentiated into macrophage-like cells treated by PMA (phorbol 12-myristate 13-acetate) and be exposed crotonaldehyde. Using RNA-seq technology such as digital gene expression, the global changes in transcriptional level were analyzed. Real-time quantitative polymerase chain reaction (qPCR) was performed to validate RNA-seq data. The differential regulated genes in many biological processes were dysregulated, including in antigen processing and presentation, oxidative stress, inflammation, cytokine signaling, and apoptosis. Collectively, our study demonstrated that crotonaldehyde altered gene expression profile in the genome-wide transcriptional level in human macrophage-like cells, and many of them may represent potential mechanisms of crotonaldehyde causing cytotoxicity and tissue injury in the human lung.

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Crotonaldehyde induces apoptosis in alveolar macrophages through intracellular calcium, mitochondria and p53 signaling pathways

Cited by 18 publications

References 50 publications

Novel mechanisms for crotonaldehyde-induced lung edema

Novel mechanisms for crotonaldehyde-induced lung edema

Influences of ethanol on the structure of toxic trans-crotonaldehyde in mitochondria coming from rat myocardium

Transcript profiling analysis of <i>in vitro</i> cultured THP-1 cells after exposure to crotonaldehyde

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