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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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Impairment of the 12-HHT/BLT2 axis delays wound healing and attenuates re-epithelialization in mice. (A–C) Wound closure rate after skin punch in BLT2 WT and BLT2 KO mice with or without aspirin (0.18 mg/ml) in the drinking water (n = 5–6 mice per group). The experiments were performed in parallel. (D and E) Morphometric analyses of wounded skin. Re-epithelialization, wound length, and keratinocyte proliferation (as assessed by Ki67 staining) were evaluated in HE-stained tissue sections from BLT2 WT or BLT2 KO mice (D) and from WT mice with or without aspirin treatment (E) at the indicated days after punch (n = 5 mice per group, two sites per mouse). (F and G) Representative HE-stained sections of the wounds at 3 d after skin punching in BLT2 WT and BLT2 KO mice (F) and in WT mice with or without aspirin treatment (G). Arrows, wound margin; arrowheads, epithelial leading edge. Bars, 100 µm. (H and I) Representative Masson’s trichrome–stained sections of the wounds from BLT2 WT and BLT2 KO mice (H, day 5; n = 5 mice per group), control and aspirin-treated WT mice (I, day 5; n = 5 mice per group). Bars, 100 µm. Data represent the mean ± SEM. **, P < 0.01; *, P < 0.05; N.S., not significant (A–C, two-way ANOVA; D and E, unpaired Student’s t test). All the results are representative of at least two independent experiments.
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fig2: Impairment of the 12-HHT/BLT2 axis delays wound healing and attenuates re-epithelialization in mice. (A–C) Wound closure rate after skin punch in BLT2 WT and BLT2 KO mice with or without aspirin (0.18 mg/ml) in the drinking water (n = 5–6 mice per group). The experiments were performed in parallel. (D and E) Morphometric analyses of wounded skin. Re-epithelialization, wound length, and keratinocyte proliferation (as assessed by Ki67 staining) were evaluated in HE-stained tissue sections from BLT2 WT or BLT2 KO mice (D) and from WT mice with or without aspirin treatment (E) at the indicated days after punch (n = 5 mice per group, two sites per mouse). (F and G) Representative HE-stained sections of the wounds at 3 d after skin punching in BLT2 WT and BLT2 KO mice (F) and in WT mice with or without aspirin treatment (G). Arrows, wound margin; arrowheads, epithelial leading edge. Bars, 100 µm. (H and I) Representative Masson’s trichrome–stained sections of the wounds from BLT2 WT and BLT2 KO mice (H, day 5; n = 5 mice per group), control and aspirin-treated WT mice (I, day 5; n = 5 mice per group). Bars, 100 µm. Data represent the mean ± SEM. **, P < 0.01; *, P < 0.05; N.S., not significant (A–C, two-way ANOVA; D and E, unpaired Student’s t test). All the results are representative of at least two independent experiments.

Mentions: We next determined the impact of BLT2 deficiency and/or aspirin treatment on skin wound healing in vivo. Full-thickness 3-mm punch biopsy wounds were made in the dorsal skin of BLT2 WT and BLT2 KO mice with or without aspirin treatment. The wound closure rate was then assessed via daily measurement of the wound area for 8 d, and the kinetics of wound closure were evaluated as percentage of original wound areas (Fig. 2, A–C). BLT2 KO mice exhibited significantly delayed wound closure compared with BLT2 WT mice (Fig. 2 A). Aspirin treatment (at a therapeutic high dose of 0.18 mg/ml in the drinking water) significantly delayed wound closure only in BLT2 WT mice (Fig. 2 B), but no further effects were observed in BLT2 KO mice in response to aspirin administration (Fig. 2 C).


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)

Impairment of the 12-HHT/BLT2 axis delays wound healing and attenuates re-epithelialization in mice. (A–C) Wound closure rate after skin punch in BLT2 WT and BLT2 KO mice with or without aspirin (0.18 mg/ml) in the drinking water (n = 5–6 mice per group). The experiments were performed in parallel. (D and E) Morphometric analyses of wounded skin. Re-epithelialization, wound length, and keratinocyte proliferation (as assessed by Ki67 staining) were evaluated in HE-stained tissue sections from BLT2 WT or BLT2 KO mice (D) and from WT mice with or without aspirin treatment (E) at the indicated days after punch (n = 5 mice per group, two sites per mouse). (F and G) Representative HE-stained sections of the wounds at 3 d after skin punching in BLT2 WT and BLT2 KO mice (F) and in WT mice with or without aspirin treatment (G). Arrows, wound margin; arrowheads, epithelial leading edge. Bars, 100 µm. (H and I) Representative Masson’s trichrome–stained sections of the wounds from BLT2 WT and BLT2 KO mice (H, day 5; n = 5 mice per group), control and aspirin-treated WT mice (I, day 5; n = 5 mice per group). Bars, 100 µm. Data represent the mean ± SEM. **, P < 0.01; *, P < 0.05; N.S., not significant (A–C, two-way ANOVA; D and E, unpaired Student’s t test). All the results are representative of at least two independent experiments.
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fig2: Impairment of the 12-HHT/BLT2 axis delays wound healing and attenuates re-epithelialization in mice. (A–C) Wound closure rate after skin punch in BLT2 WT and BLT2 KO mice with or without aspirin (0.18 mg/ml) in the drinking water (n = 5–6 mice per group). The experiments were performed in parallel. (D and E) Morphometric analyses of wounded skin. Re-epithelialization, wound length, and keratinocyte proliferation (as assessed by Ki67 staining) were evaluated in HE-stained tissue sections from BLT2 WT or BLT2 KO mice (D) and from WT mice with or without aspirin treatment (E) at the indicated days after punch (n = 5 mice per group, two sites per mouse). (F and G) Representative HE-stained sections of the wounds at 3 d after skin punching in BLT2 WT and BLT2 KO mice (F) and in WT mice with or without aspirin treatment (G). Arrows, wound margin; arrowheads, epithelial leading edge. Bars, 100 µm. (H and I) Representative Masson’s trichrome–stained sections of the wounds from BLT2 WT and BLT2 KO mice (H, day 5; n = 5 mice per group), control and aspirin-treated WT mice (I, day 5; n = 5 mice per group). Bars, 100 µm. Data represent the mean ± SEM. **, P < 0.01; *, P < 0.05; N.S., not significant (A–C, two-way ANOVA; D and E, unpaired Student’s t test). All the results are representative of at least two independent experiments.
Mentions: We next determined the impact of BLT2 deficiency and/or aspirin treatment on skin wound healing in vivo. Full-thickness 3-mm punch biopsy wounds were made in the dorsal skin of BLT2 WT and BLT2 KO mice with or without aspirin treatment. The wound closure rate was then assessed via daily measurement of the wound area for 8 d, and the kinetics of wound closure were evaluated as percentage of original wound areas (Fig. 2, A–C). BLT2 KO mice exhibited significantly delayed wound closure compared with BLT2 WT mice (Fig. 2 A). Aspirin treatment (at a therapeutic high dose of 0.18 mg/ml in the drinking water) significantly delayed wound closure only in BLT2 WT mice (Fig. 2 B), but no further effects were observed in BLT2 KO mice in response to aspirin administration (Fig. 2 C).

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