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12-Hydroxyheptadecatrienoic acid promotes epidermal wound healing by accelerating keratinocyte migration via the BLT2 receptor.

Liu M, Saeki K, Matsunobu T, Okuno T, Koga T, Sugimoto Y, Yokoyama C, Nakamizo S, Kabashima K, Narumiya S, Shimizu T, Yokomizo T - J. Exp. Med. (2014)

Bottom Line: Leukotriene B4 (LTB4) receptor type 2 (BLT2) is a G protein-coupled receptor (GPCR) for 12(S)-hydroxyheptadeca-5Z,8E,10E-trienoic acid (12-HHT) and LTB4.Despite the well-defined proinflammatory roles of BLT1, the in vivo functions of BLT2 remain elusive.These results identify a novel mechanism underlying the action of the 12-HHT/BLT2 axis in epidermal keratinocytes and accordingly suggest the use of BLT2 agonists as therapeutic agents to accelerate wound healing, particularly for intractable wounds, such as diabetic ulcers.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Biochemistry, Juntendo University School of Medicine, Tokyo 113-8421, Japan Department of Medical Biochemistry, Kyushu University, Fukuoka 812-8582, Japan.

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The TxA2/TP axis and BLT1 are not involved in wound healing. (A–D) Wound closure rate in TxA2S WT and TxA2S KO mice (A, n = 5–6 mice per group), WT and TP KO mice (B, n = 5 mice per group), BLT1 WT and BLT1 KO mice (C, n = 5 mice per group), and vehicle and celecoxib-treated WT mice (D, n = 6–7 mice per group). In D, vehicle (0.5% methyl cellulose) or celecoxib (25 mg/kg body weight) was administrated by gavage to the mice (male C57BL/6J, 8 wk old) every day. Celecoxib treatment started 48 h before skin punching. (E) MDA adduct levels were measured in mouse skin samples from WT mice with or without aspirin treatment (n = 4 mice per group). Aspirin treatment (0.18 mg/ml in the drinking water) was initiated at 2 d before the biopsy. A 5-mm punch biopsy sample was used to assess the presence of MDA adducts via ELISA. Data represent the mean ± SEM. **, P < 0.01; N.S., not significant (A–D, two-way ANOVA; E, unpaired Student’s t test). All the results are representative of at least two independent experiments.
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fig4: The TxA2/TP axis and BLT1 are not involved in wound healing. (A–D) Wound closure rate in TxA2S WT and TxA2S KO mice (A, n = 5–6 mice per group), WT and TP KO mice (B, n = 5 mice per group), BLT1 WT and BLT1 KO mice (C, n = 5 mice per group), and vehicle and celecoxib-treated WT mice (D, n = 6–7 mice per group). In D, vehicle (0.5% methyl cellulose) or celecoxib (25 mg/kg body weight) was administrated by gavage to the mice (male C57BL/6J, 8 wk old) every day. Celecoxib treatment started 48 h before skin punching. (E) MDA adduct levels were measured in mouse skin samples from WT mice with or without aspirin treatment (n = 4 mice per group). Aspirin treatment (0.18 mg/ml in the drinking water) was initiated at 2 d before the biopsy. A 5-mm punch biopsy sample was used to assess the presence of MDA adducts via ELISA. Data represent the mean ± SEM. **, P < 0.01; N.S., not significant (A–D, two-way ANOVA; E, unpaired Student’s t test). All the results are representative of at least two independent experiments.

Mentions: Because aspirin treatment inhibits both 12-HHT and TxA2 production (Fig. 1 E), reduced TxA2 levels might also be involved in the deleterious effects of aspirin. To investigate this hypothesis, we performed a punch assay in the dorsal skin of mice lacking TxA2S, the terminal enzyme required for the production of TxA2 and 12-HHT, and mice lacking the TxA2 receptor (TP). TxA2S deficiency delayed wound closure (Fig. 4 A), whereas wound closure was normal in TP KO mice (Fig. 4 B). These findings indicate that a reduction in TxA2 is not responsible for the aspirin-dependent delay in skin wound healing. Wound closure was also normal in mice deficient in BLT1 (Yokomizo et al., 1997), a high-affinity LTB4 receptor (Fig. 4 C), also ruling out the involvement of BLT1 in wound healing. The effect of a COX2 selective inhibitor, celecoxib, on wound healing was also studied. Celecoxib treatment (25 mg/kg body weight) had no effect on wound closure in WT mice (Fig. 4 D). We also measured 12-HHT production in both mouse serum and wound fluid, which was not affected by celecoxib treatment (unpublished data).


12-Hydroxyheptadecatrienoic acid promotes epidermal wound healing by accelerating keratinocyte migration via the BLT2 receptor.

Liu M, Saeki K, Matsunobu T, Okuno T, Koga T, Sugimoto Y, Yokoyama C, Nakamizo S, Kabashima K, Narumiya S, Shimizu T, Yokomizo T - J. Exp. Med. (2014)

The TxA2/TP axis and BLT1 are not involved in wound healing. (A–D) Wound closure rate in TxA2S WT and TxA2S KO mice (A, n = 5–6 mice per group), WT and TP KO mice (B, n = 5 mice per group), BLT1 WT and BLT1 KO mice (C, n = 5 mice per group), and vehicle and celecoxib-treated WT mice (D, n = 6–7 mice per group). In D, vehicle (0.5% methyl cellulose) or celecoxib (25 mg/kg body weight) was administrated by gavage to the mice (male C57BL/6J, 8 wk old) every day. Celecoxib treatment started 48 h before skin punching. (E) MDA adduct levels were measured in mouse skin samples from WT mice with or without aspirin treatment (n = 4 mice per group). Aspirin treatment (0.18 mg/ml in the drinking water) was initiated at 2 d before the biopsy. A 5-mm punch biopsy sample was used to assess the presence of MDA adducts via ELISA. Data represent the mean ± SEM. **, P < 0.01; N.S., not significant (A–D, two-way ANOVA; E, unpaired Student’s t test). All the results are representative of at least two independent experiments.
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fig4: The TxA2/TP axis and BLT1 are not involved in wound healing. (A–D) Wound closure rate in TxA2S WT and TxA2S KO mice (A, n = 5–6 mice per group), WT and TP KO mice (B, n = 5 mice per group), BLT1 WT and BLT1 KO mice (C, n = 5 mice per group), and vehicle and celecoxib-treated WT mice (D, n = 6–7 mice per group). In D, vehicle (0.5% methyl cellulose) or celecoxib (25 mg/kg body weight) was administrated by gavage to the mice (male C57BL/6J, 8 wk old) every day. Celecoxib treatment started 48 h before skin punching. (E) MDA adduct levels were measured in mouse skin samples from WT mice with or without aspirin treatment (n = 4 mice per group). Aspirin treatment (0.18 mg/ml in the drinking water) was initiated at 2 d before the biopsy. A 5-mm punch biopsy sample was used to assess the presence of MDA adducts via ELISA. Data represent the mean ± SEM. **, P < 0.01; N.S., not significant (A–D, two-way ANOVA; E, unpaired Student’s t test). All the results are representative of at least two independent experiments.
Mentions: Because aspirin treatment inhibits both 12-HHT and TxA2 production (Fig. 1 E), reduced TxA2 levels might also be involved in the deleterious effects of aspirin. To investigate this hypothesis, we performed a punch assay in the dorsal skin of mice lacking TxA2S, the terminal enzyme required for the production of TxA2 and 12-HHT, and mice lacking the TxA2 receptor (TP). TxA2S deficiency delayed wound closure (Fig. 4 A), whereas wound closure was normal in TP KO mice (Fig. 4 B). These findings indicate that a reduction in TxA2 is not responsible for the aspirin-dependent delay in skin wound healing. Wound closure was also normal in mice deficient in BLT1 (Yokomizo et al., 1997), a high-affinity LTB4 receptor (Fig. 4 C), also ruling out the involvement of BLT1 in wound healing. The effect of a COX2 selective inhibitor, celecoxib, on wound healing was also studied. Celecoxib treatment (25 mg/kg body weight) had no effect on wound closure in WT mice (Fig. 4 D). We also measured 12-HHT production in both mouse serum and wound fluid, which was not affected by celecoxib treatment (unpublished data).

Bottom Line: Leukotriene B4 (LTB4) receptor type 2 (BLT2) is a G protein-coupled receptor (GPCR) for 12(S)-hydroxyheptadeca-5Z,8E,10E-trienoic acid (12-HHT) and LTB4.Despite the well-defined proinflammatory roles of BLT1, the in vivo functions of BLT2 remain elusive.These results identify a novel mechanism underlying the action of the 12-HHT/BLT2 axis in epidermal keratinocytes and accordingly suggest the use of BLT2 agonists as therapeutic agents to accelerate wound healing, particularly for intractable wounds, such as diabetic ulcers.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Biochemistry, Juntendo University School of Medicine, Tokyo 113-8421, Japan Department of Medical Biochemistry, Kyushu University, Fukuoka 812-8582, Japan.

Show MeSH
Related in: MedlinePlus