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β2-adrenoceptor activation modulates skin wound healing processes to reduce scarring.

Le Provost GS, Pullar CE - J. Invest. Dermatol. (2014)

Bottom Line: Here we identify a β2AR-mediated mechanism for scar reduction. β2ARag significantly reduced HDF differentiation, via multiple cAMP and/or fibroblast growth factor 2 or basic FGF (FGF2)-dependent mechanisms, in the presence of transforming growth factor betaβ1, reduced contractile function, and inhibited mRNA expression of a number of profibrotic markers. β2ARag also reduced inflammation and angiogenesis in zebrafish and CAMs in vivo, respectively.In Red Duroc pig full-thickness wounds, β2ARag reduced both scar area and hyperpigmentation by almost 50% and significantly improved scar quality.Both macrophage infiltration and angiogenesis were initially decreased, whereas DF function was impaired in the β2ARag-treated porcine wound bed.

View Article: PubMed Central - PubMed

Affiliation: Department of Cell Physiology and Pharmacology, University of Leicester, Leicester, UK.

ABSTRACT
During wound healing, excessive inflammation, angiogenesis, and differentiated human dermal fibroblast (HDF ) function contribute to scarring, whereas hyperpigmentation negatively affects scar quality. Over 100 million patients heal with a scar every year. To investigate the role of the beta 2 adrenergic receptor (β2AR) in wound scarring, the ability of beta 2 adrenergic receptor agonist (β2ARag) to alter HDF differentiation and function, wound inflammation, angiogenesis, and wound scarring was explored in HDFs, zebrafish, chick chorioallantoic membrane assay (CAM), and a porcine skin wound model, respectively. Here we identify a β2AR-mediated mechanism for scar reduction. β2ARag significantly reduced HDF differentiation, via multiple cAMP and/or fibroblast growth factor 2 or basic FGF (FGF2)-dependent mechanisms, in the presence of transforming growth factor betaβ1, reduced contractile function, and inhibited mRNA expression of a number of profibrotic markers. β2ARag also reduced inflammation and angiogenesis in zebrafish and CAMs in vivo, respectively. In Red Duroc pig full-thickness wounds, β2ARag reduced both scar area and hyperpigmentation by almost 50% and significantly improved scar quality. Indeed, mechanisms delineated in vitro and in other in vivo models were evident in the β2ARag-treated porcine scars in vivo. Both macrophage infiltration and angiogenesis were initially decreased, whereas DF function was impaired in the β2ARag-treated porcine wound bed. These data collectively reveal the potential of β2ARag to improve skin scarring.

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Related in: MedlinePlus

β2AR agonist (β2ARag) altered the open wound area within the first 14 days of wound healing but did not affect the re-epithelialization of full-thickness Red Duroc pig wounds. (a) Calibrated photographs of wounds per position were analyzed and wound area was measured at days 0, 7, 14, and 28 in a double-blind manner, as described in the Methods. (b) Percentage of re-epithelialization was determined at days 14 and 28 in a double-blind manner, as described in Materials and Methods. Values presented are means±SEM (10 wounds/animal; N=5, *P<0.05; **P<0.01; ***P<0.001). NS, not significant.
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fig3: β2AR agonist (β2ARag) altered the open wound area within the first 14 days of wound healing but did not affect the re-epithelialization of full-thickness Red Duroc pig wounds. (a) Calibrated photographs of wounds per position were analyzed and wound area was measured at days 0, 7, 14, and 28 in a double-blind manner, as described in the Methods. (b) Percentage of re-epithelialization was determined at days 14 and 28 in a double-blind manner, as described in Materials and Methods. Values presented are means±SEM (10 wounds/animal; N=5, *P<0.05; **P<0.01; ***P<0.001). NS, not significant.

Mentions: Calibrated digital wound pictures were used to determine the open wound area. β2ARag-treated open wound area was 11% smaller and appeared less red and swollen than controls, at 7 days post wounding (Figure 3a). After 14 days, β2ARag-treated open wound area was 23% larger, but there was no significant difference in the open wound area after 28 days, when wounds were almost completely healed (Figure 3a). Re-epithelialization rates could not be assessed 7 days post wounding, but they were similar in both groups after 14 or 28 days and almost all wounds were completely re-epithelialized by 28 days post wounding (Figure 3b).


β2-adrenoceptor activation modulates skin wound healing processes to reduce scarring.

Le Provost GS, Pullar CE - J. Invest. Dermatol. (2014)

β2AR agonist (β2ARag) altered the open wound area within the first 14 days of wound healing but did not affect the re-epithelialization of full-thickness Red Duroc pig wounds. (a) Calibrated photographs of wounds per position were analyzed and wound area was measured at days 0, 7, 14, and 28 in a double-blind manner, as described in the Methods. (b) Percentage of re-epithelialization was determined at days 14 and 28 in a double-blind manner, as described in Materials and Methods. Values presented are means±SEM (10 wounds/animal; N=5, *P<0.05; **P<0.01; ***P<0.001). NS, not significant.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4263603&req=5

fig3: β2AR agonist (β2ARag) altered the open wound area within the first 14 days of wound healing but did not affect the re-epithelialization of full-thickness Red Duroc pig wounds. (a) Calibrated photographs of wounds per position were analyzed and wound area was measured at days 0, 7, 14, and 28 in a double-blind manner, as described in the Methods. (b) Percentage of re-epithelialization was determined at days 14 and 28 in a double-blind manner, as described in Materials and Methods. Values presented are means±SEM (10 wounds/animal; N=5, *P<0.05; **P<0.01; ***P<0.001). NS, not significant.
Mentions: Calibrated digital wound pictures were used to determine the open wound area. β2ARag-treated open wound area was 11% smaller and appeared less red and swollen than controls, at 7 days post wounding (Figure 3a). After 14 days, β2ARag-treated open wound area was 23% larger, but there was no significant difference in the open wound area after 28 days, when wounds were almost completely healed (Figure 3a). Re-epithelialization rates could not be assessed 7 days post wounding, but they were similar in both groups after 14 or 28 days and almost all wounds were completely re-epithelialized by 28 days post wounding (Figure 3b).

Bottom Line: Here we identify a β2AR-mediated mechanism for scar reduction. β2ARag significantly reduced HDF differentiation, via multiple cAMP and/or fibroblast growth factor 2 or basic FGF (FGF2)-dependent mechanisms, in the presence of transforming growth factor betaβ1, reduced contractile function, and inhibited mRNA expression of a number of profibrotic markers. β2ARag also reduced inflammation and angiogenesis in zebrafish and CAMs in vivo, respectively.In Red Duroc pig full-thickness wounds, β2ARag reduced both scar area and hyperpigmentation by almost 50% and significantly improved scar quality.Both macrophage infiltration and angiogenesis were initially decreased, whereas DF function was impaired in the β2ARag-treated porcine wound bed.

View Article: PubMed Central - PubMed

Affiliation: Department of Cell Physiology and Pharmacology, University of Leicester, Leicester, UK.

ABSTRACT
During wound healing, excessive inflammation, angiogenesis, and differentiated human dermal fibroblast (HDF ) function contribute to scarring, whereas hyperpigmentation negatively affects scar quality. Over 100 million patients heal with a scar every year. To investigate the role of the beta 2 adrenergic receptor (β2AR) in wound scarring, the ability of beta 2 adrenergic receptor agonist (β2ARag) to alter HDF differentiation and function, wound inflammation, angiogenesis, and wound scarring was explored in HDFs, zebrafish, chick chorioallantoic membrane assay (CAM), and a porcine skin wound model, respectively. Here we identify a β2AR-mediated mechanism for scar reduction. β2ARag significantly reduced HDF differentiation, via multiple cAMP and/or fibroblast growth factor 2 or basic FGF (FGF2)-dependent mechanisms, in the presence of transforming growth factor betaβ1, reduced contractile function, and inhibited mRNA expression of a number of profibrotic markers. β2ARag also reduced inflammation and angiogenesis in zebrafish and CAMs in vivo, respectively. In Red Duroc pig full-thickness wounds, β2ARag reduced both scar area and hyperpigmentation by almost 50% and significantly improved scar quality. Indeed, mechanisms delineated in vitro and in other in vivo models were evident in the β2ARag-treated porcine scars in vivo. Both macrophage infiltration and angiogenesis were initially decreased, whereas DF function was impaired in the β2ARag-treated porcine wound bed. These data collectively reveal the potential of β2ARag to improve skin scarring.

Show MeSH
Related in: MedlinePlus