Cigarette smoke reversibly activates hypoxia-inducible factor 1 in a reactive oxygen species-dependent manner.
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.
Department of Anesthesia, Kyoto University Hospital, Kyoto, Japan.
Hiroki
H
Daijo
Department of Respiratory Medicine, Kyoto University Hospital, Kyoto, Japan.
Yuma
Y
Hoshino
Department of Anesthesiology, Kansai Medical University, Hirakata, Japan.
Shinichi
S
Kai
Department of Anesthesiology, Kansai Medical University, Hirakata, Japan.
Kengo
K
Suzuki
Department of Anesthesiology, Kansai Medical University, Hirakata, Japan.
Kenichiro
K
Nishi
Department of Anesthesiology, Kansai Medical University, Hirakata, Japan.
Yoshiyuki
Y
Matsuo
Laboratory of Cancer Cell Biology, Radiation Biology Center, Kyoto University, Kyoto, Japan.|Precursory Research for Embryonic Science and Technology (PRESTO), Japan Science and Technology Agency (JST), Saitama, Japan.
Hiroshi
H
Harada
Department of Anesthesiology, Kansai Medical University, Hirakata, Japan.
Kiichi
K
Hirota
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