The intravenous anesthetic propofol inhibits lipopolysaccharide-induced hypoxia-inducible factor 1 activation and suppresses the glucose metabolism in macrophages

Tanaka, Tomoharu; Takabuchi, Satoshi; Nishi, Kenichiro; Oda, Seiko; Wakamatsu, Takuhiko; Daijo, Hiroki; Fukuda, Kazuhiko; Hirota, Kiichi

doi:10.1007/s00540-009-0829-1

Cited by 52 publications

(42 citation statements)

References 31 publications

(46 reference statements)

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“…The authors also demonstrated that propofol does not suppress HIF‐1α mRNA expression; rather, it selectively suppresses the translation of mRNA into protein. A more recent study reported that propofol also inhibits HIF‐1 activation by lipopolysaccharide in macrophages with a resultant reduction in glycolysis‐dependent metabolism 98. This study also concluded that the most likely mechanism behind propofol's inhibitory effect on HIF‐1 was via impaired translation of mRNA.…”

Section: Anesthetics and Direct Effects On Cancer Cell Biologymentioning

confidence: 69%

“…A more recent study reported that propofol also inhibits HIF-1 activation by lipopolysaccharide in macrophages with a resultant reduction in glycolysis-dependent metabolism. 98 This study also concluded that the most likely mechanism behind propofol's inhibitory effect on HIF-1 was via impaired translation of mRNA. Interestingly, there is already evidence that clinical concentrations of propofol produce anticancer effects by modulating the GTPase RhoA, thereby inhibiting cancer cells' capacity for migration and invasion.…”

Section: Anesthetics That Downregulate Hifsmentioning

confidence: 82%

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Cancer recurrence after surgery: Direct and indirect effects of anesthetic agents*

Tavare

Perry

Benzonana

et al. 2011

Intl Journal of Cancer

276

212

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Surgery is of paramount importance in the management of solid tumors as definitive resection can be totally curative. Nonetheless, metastatic recurrence after surgery remains a major cause of morbidity and mortality. Interest in the impact of the perioperative period on cancer recurrence is now growing rapidly, with recent research suggesting that some anesthetics or anesthetic techniques may influence the pathophysiology of postoperative metastatic spread. Our review examines the most widely postulated mechanisms for this, including the impact of anesthesia on neuroendocrine and immune function. We also consider evidence for a direct impact on tumor cell signaling pathways based on findings from organ protection research. These studies have demonstrated that certain volatile anaesthetics confer cytoprotective properties to exposed cells and lead to significant upregulation of Hypoxia Inducible Factor-1a (HIF-1a). This ubiquitous transcription factor exerts many effects in cancer: its activity has been linked with more aggressive phenotypes and poorer clinical prognosis. It is proposed that such an upregulation of HIFs in tumor cells by these anesthetics may contribute to a tumor's recurrence by stimulating cytoprotective or protumorigenic behavior in residual cells. Conversely, other anesthetic agents appear to downregulate HIFs or cause negligible effect and thus may prove more suitable for use in cancer surgery. As anesthetic drugs are given at a point of potentially high vulnerability in terms of dissemination and establishment of metastases, there is an urgent need to determine the most appropriate anesthetic strategy for surgical oncology so that the optimal techniques are used to maximize long-term survival.

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Section: Anesthetics and Direct Effects On Cancer Cell Biologymentioning

confidence: 69%

Section: Anesthetics That Downregulate Hifsmentioning

confidence: 82%

Cancer recurrence after surgery: Direct and indirect effects of anesthetic agents*

Tavare

Perry

Benzonana

et al. 2011

Intl Journal of Cancer

276

212

View full text Add to dashboard Cite

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“…Antagonism of HIF1A and ADORA2B in BMDMs led to decreases in profibrotic mediator production, suggesting new potential targets for halting the progression of pulmonary fibrosis in patients with IPF. Care should be taken when managing patients with IPF with anesthetics given evidence of their impact on HIF1A stabilization (42)(43)(44)(45). Future work will include elucidating the impact of hypoxia-independent pathways, whether stretch induced or metabolite mediated, on upstream HIF1A stabilization.…”

Section: Discussionmentioning

confidence: 99%

HIF1A up‐regulates the ADORA2B receptor on alternatively activated macrophages and contributes to pulmonary fibrosis

et al. 2017

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Idiopathic pulmonary fibrosis (IPF) is a deadly chronic lung disease. Extracellular accumulation of adenosine and subsequent activation of the ADORA2B receptor play important roles in regulating inflammation and fibrosis in IPF. Additionally, alternatively activated macrophages (AAMs) expressing ADORA2B have been implicated in mediating adenosine's effects in IPF. Although hypoxic conditions are present in IPF, hypoxia's role as a direct modulator of macrophage phenotype and identification of factors that regulate ADORA2B expression on AAMs in IPF is not well understood. In this study, an experimental mouse model of pulmonary fibrosis and lung samples from patients with IPF were used to examine the effects and interactions of macrophage differentiation and hypoxia on fibrosis. We demonstrate that hypoxia-inducible factor 1-α (HIF1A) inhibition in late stages of bleomycin-induced injury attenuates pulmonary fibrosis in association, with reductions in ADORA2B expression in AAMs. Additionally, ADORA2B deletion or pharmacological antagonism along with HIF1A inhibition disrupts AAM differentiation and subsequent IL-6 production in cultured macrophages. These findings suggest that hypoxia, through HIF1A, contributes to the development and progression of pulmonary fibrosis through its regulation of ADORA2B expression on AAMs, cell differentiation, and production of profibrotic mediators. These studies support a potential role for HIF1A or ADORA2B antagonists in the treatment of IPF.-Philip, K., Mills, T. W., Davies, J., Chen, N.-Y., Karmouty-Quintana, H., Luo, F., Molina, J. G., Amione-Guerra, J., Sinha, N., Guha, A., Eltzschig, H. K., Blackburn, M. R. HIF1A up-regulates the ADORA2B receptor on alternatively activated macrophages and contributes to pulmonary fibrosis.

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“…Moreover, the substitution between the two isoenzymes is remarkable, and, in fact, the protein levels of L-PFK2 almost disappear and are substituted by the uPFK2 form in the course of TLR-2, -3, -4, or -9 activation, despite the use of nonredundant signaling pathways (i.e., MyD88-dependent and independent pathways). One likely mechanism to explain this switch between PFK2 isoenzymes after classic activation is the rise in the levels of Hif-1a because a functional relationship has been described between the hypoxia-responsive element motifs present in the uPFK2 promoter and the expression of this isoenzyme (16,18,19,22,23,53). Accordingly, experiments in macrophages lacking Hif-1a were carried out with the idea to impair uPFK2 expression.…”

Section: Discussionmentioning

confidence: 99%

Substrate Fate in Activated Macrophages: A Comparison between Innate, Classic, and Alternative Activation

Rodríguez-Prados

Través

Cuenca

et al. 2010

The Journal of Immunology

864

746

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The intravenous anesthetic propofol inhibits lipopolysaccharide-induced hypoxia-inducible factor 1 activation and suppresses the glucose metabolism in macrophages

Cited by 52 publications

References 31 publications

Cancer recurrence after surgery: Direct and indirect effects of anesthetic agents*

Cancer recurrence after surgery: Direct and indirect effects of anesthetic agents*

HIF1A up‐regulates the ADORA2B receptor on alternatively activated macrophages and contributes to pulmonary fibrosis

Substrate Fate in Activated Macrophages: A Comparison between Innate, Classic, and Alternative Activation

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