Inhibition of 12-O-Tetradecanoylphorbol-13-Acetate-lnduced Increase in Vascular Permeability in Mouse Skin by Lipoxygenase Inhibitors

Nakadate, Teruo; Yamamoto, Shozo; Aizu, Eriko; Kato, Ryuichi

doi:10.1254/jjp.38.161

Cited by 35 publications

(20 citation statements)

References 33 publications

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“…The results are consistent with our previous observation, i.e. possible involvement of lipoxygenase prod uces) in the mechanism of the TPA-induced inflammation [15]. Both TMK688 and TMK777 have a struc ture of diphenylpyraline in their moiety (see fig.…”

Section: Discussionsupporting

confidence: 93%

“…It is well known that a topi cal application of a potent skin tumor promo tor, TPA, to mouse skin induces a nonallergic inflammation, i.e. an increase in vascular per meability and neutrophil infiltration [12,14,15]. In the present study, we demonstrated that both oral and topical administration of TMK688 inhibited TPA-induced inflamma tion, i.e.…”

Section: Discussionsupporting

confidence: 65%

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Anti-Inflammatory Action of Orally Active 5-Lipoxygenase Inhibitor TMK688

Yamamoto

Jiang²,

Kato³

1994

Pharmacology

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A topical application of 12-0-tetradecanoylphorbol-13-acetate (TPA) to mouse ear surface induces nonallergic inflammation, i.e. ear edema. Oral administration of 3-30 mg/kg of l-{[5’-(3”-methoxy-4”-ethoxycarbonyloxyphenyl)-2’,4’-pentadienoyl]aminoethyl}-4-diphenylmethoxypiperidine (TMK 688), a potent 5-lipoxygenase inhibitor with antihistamine activity, inhibited TPA-induced ear edema in a dose-dependent manner. TMK688 inhibited not only 5-lipoxygenase activity but also epidermal cyclooxygenase activity. 1 – {[ 5 ‘ (3 “ methoxy – 4”-hy droxyphenyl) – 2’, 4’- pentadienoyl] -aminoethyl}-4-diphenylmethoxypiperidine (TMK777), an active metabolite of TMK688, had more potent 5-lipoxygenase inhibitory activity but less potent cyclooxygenase inhibitory activity than TMK688. Oral administration of TMK688 (30 mg/kg) markedly inhibited TPA-stimulated LTB₄ formation in mouse skin but TPA-stimulated PGE₂ formation only slightly. Our experimental results suggest that both cyclooxygenase inhibitory activity and antihistamine activity of TMK688 are not essential to its anti-inflammatory action. The anti-inflammatory effect of orally administered TMK688 is due most probably to the anti-5-lipoxygenase activity of TMK688 and its active metabolite TMK777.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionsupporting

confidence: 65%

Anti-Inflammatory Action of Orally Active 5-Lipoxygenase Inhibitor TMK688

Yamamoto

Jiang²,

Kato³

1994

Pharmacology

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“…Two additional experiments were performed to further characterize the importance of HIF-2α in mediating acute inflammatory responses in vivo. First we induced acute cutaneous inflammation (73,74) by painting ear skin with the TPA. After 24 hours, ears were harvested and analyzed for edema and leukocyte infiltration.…”

Section: Figurementioning

confidence: 99%

Hypoxia-inducible factor 2α regulates macrophage function in mouse models of acute and tumor inflammation

Imtiyaz¹,

Williams²,

Hickey³

et al. 2010

J. Clin. Invest.

411

406

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Hypoxia-inducible factor 1α (HIF-1α) and HIF-2α display unique and sometimes opposing activities in regulating cellular energy homeostasis, cell fate decisions, and oncogenesis. Macrophages exposed to hypoxia accumulate both HIF-1α and HIF-2α, and overexpression of HIF-2α in tumor-associated macrophages (TAMs) is specifically correlated with high-grade human tumors and poor prognosis. However, the precise role of HIF-2α during macrophage-mediated inflammatory responses remains unclear. To fully characterize cellular hypoxic adaptations, distinct functions of HIF-1α versus HIF-2α must be elucidated. We demonstrate here that mice lacking HIF-2α in myeloid cells (Hif2a Δ/Δ mice) are resistant to lipopolysaccharide-induced endotoxemia and display a marked inability to mount inflammatory responses to cutaneous and peritoneal irritants. Furthermore, HIF-2α directly regulated proinflammatory cytokine/chemokine expression in macrophages activated in vitro. Hif2a Δ/Δ mice displayed reduced TAM infiltration in independent murine hepatocellular and colitisassociated colon carcinoma models, and this was associated with reduced tumor cell proliferation and progression. Notably, HIF-2α modulated macrophage migration by regulating the expression of the cytokine receptor M-CSFR and the chemokine receptor CXCR4, without altering intracellular ATP levels. Collectively, our data identify HIF-2α as an important regulator of innate immunity, suggesting it may be a useful therapeutic target for treating inflammatory disorders and cancer.

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“…Acetone (1.4 mL) was added to extract the dye overnight in capped tubes, and the absorbance of the dye was determined spectrophotometrically at 620 nm. This assay is a modi®cation of that used by Nakadate et al [16].…”

Section: Proliferation and Vascular Permeabilitymentioning

confidence: 99%

Chemopreventive activity of celecoxib, a specific cyclooxygenase-2 inhibitor, and indomethacin against ultraviolet light-induced skin carcinogenesis

Fischer

Gordon³

et al. 1999

Mol. Carcinog.

363

234

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Epidemiological and dietary studies suggest that nonsteroidal anti-inflammatory drugs (NSAIDs) reduce the risk of colon cancer, possibly through a mechanism involving inhibition of cyclooxygenase (COX)-2, which is overexpressed in premalignant adenomatous polyps and colon cancer. Because ultraviolet light (UV) can induce COX-2 and nonspecific NSAIDs can decrease UV-induced skin cancer, we evaluated the ability of two compounds, celecoxib (a specific COX-2 inhibitor) and indomethacin (a nonspecific NSAID), to block UV-induced skin tumor development in SKH:HR-1-hrBr hairless mice. Mice fed 150 or 500 ppm celecoxib showed a dose-dependent reduction (60% and 89%, respectively) in tumor yield. Indomethacin (4ppm) reduced tumor yield by 78%. Although both acute and chronic UV exposure increased cell proliferation and edema, neither compound reduced these parameters. In contrast, UV-induced prostaglandin synthesis in the epidermis was effectively blocked by both compounds. UV-induced increases in COX-2 expression in skin were also not altered in any of the treatment groups. Similarly, tumors that constitutively express high levels of COX-2 displayed no reduction by treatment with celecoxib or indomethacin. The dramatic protective effects of celecoxib suggests that specific COX-2 inhibitors may offer a way to safely reduce the risk of skin cancer in humans.

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Inhibition of 12-O-Tetradecanoylphorbol-13-Acetate-lnduced Increase in Vascular Permeability in Mouse Skin by Lipoxygenase Inhibitors

Abstract: Abstract-The painting of mouse dorsal skin with 12-O-tetradecanoylphorbol-

Cited by 35 publications

References 33 publications

Anti-Inflammatory Action of Orally Active 5-Lipoxygenase Inhibitor TMK688

Anti-Inflammatory Action of Orally Active 5-Lipoxygenase Inhibitor TMK688

Hypoxia-inducible factor 2α regulates macrophage function in mouse models of acute and tumor inflammation

Chemopreventive activity of celecoxib, a specific cyclooxygenase-2 inhibitor, and indomethacin against ultraviolet light-induced skin carcinogenesis

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