Abstract
Cigarette smoke (CS) is a major contributor to the development of a large number of fatal and debilitating disorders. However, the precise molecular mechanisms underlying the effects of CS in lung disease are largely unknown. To elucidate these pathophysiological processes, we examined the in vitro and in vivo effects of CS extract (CSE) and CS on the transcription factor, hypoxia-inducible factor 1 (HIF-1). CSE induced concentration- and time-dependent accumulation of HIF-1α protein in human lung epithelial-like cells under non-hypoxic conditions. Genes upregulated by HIF-1, including vascular endothelial growth factor and regulated in development and DNA damage response 1, both of which are involved in smoking-induced emphysematous changes, were increased by CSE treatment under non-hypoxic conditions in vitro and in vivo. Further investigation revealed that reactive oxygen species were generated in cells exposed to CSE and were required for CSE-mediated induction of HIF-1α protein, as was activation of phosphoinositide 3-kinase and mitogen-activated protein kinase pathways. In conclusion, we demonstrated that CSE and CS induced HIF-1 activation in vitro and in vivo, respectively. The evidence warrants further investigation to indicate that HIF-1 plays an important role in CS-induced gene expression, which is deeply involved in pulmonary cellular stress and small airway remodelling.
Highlights
Cigarette smoking is a major contributing factor in the development of a large number of fatal and debilitating disorders, including degenerative diseases and cancers
We found that CS extract (CSE) increased reactive oxygen species (ROS) levels and stimulated HIF-1αprotein translation in alveolar and bronchial epithelium-derived cells and that Cigarette smoke (CS) induced hypoxia-inducible factor 1 (HIF-1)-dependent gene expression in the lung tissues of mice under non-hypoxic conditions in a concentration- and time-dependent manner
The present study has provided a novel insight into the regulatory mechanisms underlying CS-induced HIF-1 activation
Summary
Cigarette smoking is a major contributing factor in the development of a large number of fatal and debilitating disorders, including degenerative diseases and cancers. The expression levels of VEGF, REDD1 (Rtp801), MMP-9, and HO-1 are reported to be regulated by the transcription factor, hypoxia-inducible factor 1 (HIF-1). We found that CSE increased reactive oxygen species (ROS) levels and stimulated HIF-1αprotein translation in alveolar and bronchial epithelium-derived cells and that CS induced HIF-1-dependent gene expression in the lung tissues of mice under non-hypoxic conditions in a concentration- and time-dependent manner. These results indicate that HIF-1 may play an important role in CS exposure-induced cellular stress, inflammation, and remodeling of the alveolar and bronchial epithelium
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