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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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A synthetic BLT2 agonist accelerates wound healing and enhances re-epithelialization in C57BL/6J and db/db mice. DMSO vehicle or a synthetic BLT2 agonist (10 µM in Vaseline) was applied daily to the skin wounds of C57BL/6J (B6) mice (A–E) and db/db mice (F–J). (A and F) Wound closure rate in C57BL/6J (A, n = 3 mice per group) and db/db (F, n = 8–10 mice per group) mice. (B and G) Gross appearance of the wounds in C57BL/6J mice on day 6 (B, n = 3 mice per group) and db/db mice at the indicated days (G, n = 8–10 mice per group). Bar, 1 mm. (C and H) Morphometric analysis of wounded skin. Re-epithelialization (top), wound length (middle), and Ki67-positive keratinocyte proliferation (bottom; n = 5 mice per group, two sites per mouse) were evaluated in HE-stained tissue sections. (D and I) Representative HE-stained sections of the wounds at 3 d after skin punching. Arrows, wound margin; arrowheads, epithelial leading edge. Bars, 100 µm. (E and J) Representative Masson’s trichrome–stained sections of the wounds (E, day 6; J, day 7; n = 5 mice per group). Bars, 100 µm. Data represent the mean ± SEM. **, P < 0.01; *, P < 0.05; N.S., not significant (A and F, two-way ANOVA; C and H, unpaired Student’s t test). All the results are representative of at least two independent experiments.
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fig9: A synthetic BLT2 agonist accelerates wound healing and enhances re-epithelialization in C57BL/6J and db/db mice. DMSO vehicle or a synthetic BLT2 agonist (10 µM in Vaseline) was applied daily to the skin wounds of C57BL/6J (B6) mice (A–E) and db/db mice (F–J). (A and F) Wound closure rate in C57BL/6J (A, n = 3 mice per group) and db/db (F, n = 8–10 mice per group) mice. (B and G) Gross appearance of the wounds in C57BL/6J mice on day 6 (B, n = 3 mice per group) and db/db mice at the indicated days (G, n = 8–10 mice per group). Bar, 1 mm. (C and H) Morphometric analysis of wounded skin. Re-epithelialization (top), wound length (middle), and Ki67-positive keratinocyte proliferation (bottom; n = 5 mice per group, two sites per mouse) were evaluated in HE-stained tissue sections. (D and I) Representative HE-stained sections of the wounds at 3 d after skin punching. Arrows, wound margin; arrowheads, epithelial leading edge. Bars, 100 µm. (E and J) Representative Masson’s trichrome–stained sections of the wounds (E, day 6; J, day 7; n = 5 mice per group). Bars, 100 µm. Data represent the mean ± SEM. **, P < 0.01; *, P < 0.05; N.S., not significant (A and F, two-way ANOVA; C and H, unpaired Student’s t test). All the results are representative of at least two independent experiments.

Mentions: Finally, to address the clinical relevance of our observations, the therapeutic effects of a BLT2 agonist were determined on wound healing in C57BL/6J and db/db mice. The db/db mouse is an animal model of diabetes and exhibits impaired wound closure (Greenhalgh et al., 1990). Topical application of a BLT2 agonist accelerated wound closure by enhancing re-epithelialization in both C57BL/6J mice (Fig. 9, A–E) and db/db mice (Fig. 9, F–J) but not by promoting contraction (Fig. 9, C [middle] and H [middle]), keratinocyte proliferation (Fig. 9, C [bottom] and H [bottom]), or collagen deposition (Fig. 9, E and J). Furthermore, a BLT2 agonist did not influence skin inflammation either (unpublished data). Thus, BLT2 activation in keratinocytes accelerates wound healing by enhancing keratinocyte migration.


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)

A synthetic BLT2 agonist accelerates wound healing and enhances re-epithelialization in C57BL/6J and db/db mice. DMSO vehicle or a synthetic BLT2 agonist (10 µM in Vaseline) was applied daily to the skin wounds of C57BL/6J (B6) mice (A–E) and db/db mice (F–J). (A and F) Wound closure rate in C57BL/6J (A, n = 3 mice per group) and db/db (F, n = 8–10 mice per group) mice. (B and G) Gross appearance of the wounds in C57BL/6J mice on day 6 (B, n = 3 mice per group) and db/db mice at the indicated days (G, n = 8–10 mice per group). Bar, 1 mm. (C and H) Morphometric analysis of wounded skin. Re-epithelialization (top), wound length (middle), and Ki67-positive keratinocyte proliferation (bottom; n = 5 mice per group, two sites per mouse) were evaluated in HE-stained tissue sections. (D and I) Representative HE-stained sections of the wounds at 3 d after skin punching. Arrows, wound margin; arrowheads, epithelial leading edge. Bars, 100 µm. (E and J) Representative Masson’s trichrome–stained sections of the wounds (E, day 6; J, day 7; n = 5 mice per group). Bars, 100 µm. Data represent the mean ± SEM. **, P < 0.01; *, P < 0.05; N.S., not significant (A and F, two-way ANOVA; C and H, unpaired Student’s t test). All the results are representative of at least two independent experiments.
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fig9: A synthetic BLT2 agonist accelerates wound healing and enhances re-epithelialization in C57BL/6J and db/db mice. DMSO vehicle or a synthetic BLT2 agonist (10 µM in Vaseline) was applied daily to the skin wounds of C57BL/6J (B6) mice (A–E) and db/db mice (F–J). (A and F) Wound closure rate in C57BL/6J (A, n = 3 mice per group) and db/db (F, n = 8–10 mice per group) mice. (B and G) Gross appearance of the wounds in C57BL/6J mice on day 6 (B, n = 3 mice per group) and db/db mice at the indicated days (G, n = 8–10 mice per group). Bar, 1 mm. (C and H) Morphometric analysis of wounded skin. Re-epithelialization (top), wound length (middle), and Ki67-positive keratinocyte proliferation (bottom; n = 5 mice per group, two sites per mouse) were evaluated in HE-stained tissue sections. (D and I) Representative HE-stained sections of the wounds at 3 d after skin punching. Arrows, wound margin; arrowheads, epithelial leading edge. Bars, 100 µm. (E and J) Representative Masson’s trichrome–stained sections of the wounds (E, day 6; J, day 7; n = 5 mice per group). Bars, 100 µm. Data represent the mean ± SEM. **, P < 0.01; *, P < 0.05; N.S., not significant (A and F, two-way ANOVA; C and H, unpaired Student’s t test). All the results are representative of at least two independent experiments.
Mentions: Finally, to address the clinical relevance of our observations, the therapeutic effects of a BLT2 agonist were determined on wound healing in C57BL/6J and db/db mice. The db/db mouse is an animal model of diabetes and exhibits impaired wound closure (Greenhalgh et al., 1990). Topical application of a BLT2 agonist accelerated wound closure by enhancing re-epithelialization in both C57BL/6J mice (Fig. 9, A–E) and db/db mice (Fig. 9, F–J) but not by promoting contraction (Fig. 9, C [middle] and H [middle]), keratinocyte proliferation (Fig. 9, C [bottom] and H [bottom]), or collagen deposition (Fig. 9, E and J). Furthermore, a BLT2 agonist did not influence skin inflammation either (unpublished data). Thus, BLT2 activation in keratinocytes accelerates wound healing by enhancing keratinocyte migration.

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