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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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β2AR agonist (β2ARag) reduces scar area and improves the appearance of Red Duroc scars. (a) Twenty 2 × 2 cm2 full-thickness wounds were photographed (7, 14, 21, 28, and 42 days post wounding (gray columns)); four 6-mm punch biopsies (dotted circles) were collected from each edge of two wounds for histology. At day 56, the remaining scars (positions 1–10) were photographed and, after euthanasia, excised for histology (dotted squares). (b) Representative pictures shown, closest to mean scar area at positions 1–10, in the absence (left)/presence (right) of a mask delineating scar area and used for measurement (N=5). Scale bar=1 cm. (c, d) Scar areas were measured 28, 42, and 56 days post wounding from calibrated pictures, in a double-blind manner. (d) Scar area/position is presented 56 days post wounding. (e,f,g) 56 Days post wounding; representative calibrated pictures of the three least hyperpigmented scars/group, position 10 are presented. Scale bar=1 cm (e). Scar characteristics were double-blind scored, using a porcine scar scale, Supplementary Table S1 online (f). Hyperpigmentation scores are presented per position (g). Data presented are means±SEM (10 scars/animal; N=5, *P<0.05; **P<0.01; ***P<0.001).
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fig4: β2AR agonist (β2ARag) reduces scar area and improves the appearance of Red Duroc scars. (a) Twenty 2 × 2 cm2 full-thickness wounds were photographed (7, 14, 21, 28, and 42 days post wounding (gray columns)); four 6-mm punch biopsies (dotted circles) were collected from each edge of two wounds for histology. At day 56, the remaining scars (positions 1–10) were photographed and, after euthanasia, excised for histology (dotted squares). (b) Representative pictures shown, closest to mean scar area at positions 1–10, in the absence (left)/presence (right) of a mask delineating scar area and used for measurement (N=5). Scale bar=1 cm. (c, d) Scar areas were measured 28, 42, and 56 days post wounding from calibrated pictures, in a double-blind manner. (d) Scar area/position is presented 56 days post wounding. (e,f,g) 56 Days post wounding; representative calibrated pictures of the three least hyperpigmented scars/group, position 10 are presented. Scale bar=1 cm (e). Scar characteristics were double-blind scored, using a porcine scar scale, Supplementary Table S1 online (f). Hyperpigmentation scores are presented per position (g). Data presented are means±SEM (10 scars/animal; N=5, *P<0.05; **P<0.01; ***P<0.001).

Mentions: Scars were visible from day 28 onward, and scar area was measured from calibrated digital pictures in a double-blind manner. One scar (1–10, control/β2ARag, Figure 4a), closest to the average scar area at that position, is presented alongside a mask delineating scar area (Figure 4b). β2ARag reduced scar area by 34, 38, and 47%, 28, 42, and 56 days post wounding, respectively (Figure 4c). Tension worsens scarring (Ogawa et al., 2011) and varies along the porcine back, with the highest tension most caudally (positions 9/10). Indeed, wounds in positions 9/10 had scars almost twice the size of wounds in the most cranial positions, 1/2 (Figure 4b and d). Moreover, β2ARag reduced scar area by 50% in the highest tension positions (9/10) (Figure 4d).


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

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

β2AR agonist (β2ARag) reduces scar area and improves the appearance of Red Duroc scars. (a) Twenty 2 × 2 cm2 full-thickness wounds were photographed (7, 14, 21, 28, and 42 days post wounding (gray columns)); four 6-mm punch biopsies (dotted circles) were collected from each edge of two wounds for histology. At day 56, the remaining scars (positions 1–10) were photographed and, after euthanasia, excised for histology (dotted squares). (b) Representative pictures shown, closest to mean scar area at positions 1–10, in the absence (left)/presence (right) of a mask delineating scar area and used for measurement (N=5). Scale bar=1 cm. (c, d) Scar areas were measured 28, 42, and 56 days post wounding from calibrated pictures, in a double-blind manner. (d) Scar area/position is presented 56 days post wounding. (e,f,g) 56 Days post wounding; representative calibrated pictures of the three least hyperpigmented scars/group, position 10 are presented. Scale bar=1 cm (e). Scar characteristics were double-blind scored, using a porcine scar scale, Supplementary Table S1 online (f). Hyperpigmentation scores are presented per position (g). Data presented are means±SEM (10 scars/animal; N=5, *P<0.05; **P<0.01; ***P<0.001).
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Related In: Results  -  Collection

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fig4: β2AR agonist (β2ARag) reduces scar area and improves the appearance of Red Duroc scars. (a) Twenty 2 × 2 cm2 full-thickness wounds were photographed (7, 14, 21, 28, and 42 days post wounding (gray columns)); four 6-mm punch biopsies (dotted circles) were collected from each edge of two wounds for histology. At day 56, the remaining scars (positions 1–10) were photographed and, after euthanasia, excised for histology (dotted squares). (b) Representative pictures shown, closest to mean scar area at positions 1–10, in the absence (left)/presence (right) of a mask delineating scar area and used for measurement (N=5). Scale bar=1 cm. (c, d) Scar areas were measured 28, 42, and 56 days post wounding from calibrated pictures, in a double-blind manner. (d) Scar area/position is presented 56 days post wounding. (e,f,g) 56 Days post wounding; representative calibrated pictures of the three least hyperpigmented scars/group, position 10 are presented. Scale bar=1 cm (e). Scar characteristics were double-blind scored, using a porcine scar scale, Supplementary Table S1 online (f). Hyperpigmentation scores are presented per position (g). Data presented are means±SEM (10 scars/animal; N=5, *P<0.05; **P<0.01; ***P<0.001).
Mentions: Scars were visible from day 28 onward, and scar area was measured from calibrated digital pictures in a double-blind manner. One scar (1–10, control/β2ARag, Figure 4a), closest to the average scar area at that position, is presented alongside a mask delineating scar area (Figure 4b). β2ARag reduced scar area by 34, 38, and 47%, 28, 42, and 56 days post wounding, respectively (Figure 4c). Tension worsens scarring (Ogawa et al., 2011) and varies along the porcine back, with the highest tension most caudally (positions 9/10). Indeed, wounds in positions 9/10 had scars almost twice the size of wounds in the most cranial positions, 1/2 (Figure 4b and d). Moreover, β2ARag reduced scar area by 50% in the highest tension positions (9/10) (Figure 4d).

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