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

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  • Yang Bi-cheng
    Dalian Institute of Chemical Physics, Chinese Academy of Sciences,China Zhengzhou Tobacco Research Institute of CNTC, China
  • Pan Xiu-jie
    Department of Radiation Toxicology and Oncology, Beijing Institute of Radiation Medicine, China
  • Yang Zhi-hua
    Department of Radiation Toxicology and Oncology, Beijing Institute of Radiation Medicine, China
  • Xiao Feng-jun
    Department of Radiation Toxicology and Oncology, Beijing Institute of Radiation Medicine, China
  • Liu Xing-yu
    Beijing Work Station, Technology Center of Shanghai Tobacco Corporation, China
  • Zhu Mao-xiang
    Department of Radiation Toxicology and Oncology, Beijing Institute of Radiation Medicine, China
  • Xie Jian-ping
    Zhengzhou Tobacco Research Institute of CNTC, China

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Crotonaldehyde, a highly electrophilic α, β-unsaturated aldehyde, is a ubiquitous environmental pollutant and a risk factor for multiple respiratory diseases. Crotonaldehyde is highly volatile and hydrophilic, so it is efficiently absorbed in the respiratory tract. Alveolar macrophages are major effector cells of the nonspecific host defence in the lung. The aim of this study was to investigate the molecular mechanisms and signaling pathways responsible for cell death of alveolar macrophage induced by crotonaldehyde. Our results show that crotonaldehyde induces apoptosis in alveolar macrophages, as indicated by phosphatidylserine externalization and DNA fragmentation. Pretreatment of alveolar macrophages with N-acetylcysteine, ascorbic acid, α-tocopherol, superoxide dismutase inhibited crotonaldehyde-induced apoptosis. Crotonaldehyde-induced apoptosis was characterized by ROS generation, GSH depletion, loss of mitochondrial membrane potential (ΔΨm), the release of cytochrome c from mitochondria, caspase-3/7 and caspase-9 activation, elevation of intracellular Ca2+ concentration and the increase of p53 expression. Furthermore, pretreatment with either p53 inhibitor pifithrin-α or calcium chelator BAPTA-AM effectively attenuated apoptosis induced by crotonaldehyde. Taken together, our results showed that crotonaldehyde induce apoptosis in alveolar macrophages through intracellular calcium, mitochondria and p53 signaling pathways. These results would help to illustrate the mechanism of toxicity induced by crotonaldehyde and to look for a novel treatment for diseases induced by exposure to crotonaldehyde-rich pollutants such as cigarette smoke.

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