Journal
JOURNAL OF INVESTIGATIVE DERMATOLOGY
Volume 135, Issue 1, Pages 279-288Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/jid.2014.312
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Funding
- Wellcome Trust [82586, G0901844, 9295]
- MRC [MC_PC_14117, G0901844] Funding Source: UKRI
- Medical Research Council [MC_PC_14117, G0901844] Funding Source: researchfish
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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 (beta 2AR) in wound scarring, the ability of beta 2 adrenergic receptor agonist (beta 2ARag) 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 PAR-mediated mechanism for scar reduction. beta 2ARag 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 beta beta 1, reduced contractile function, and inhibited mRNA expression of a number of profibrotic markers. beta 2ARag also reduced inflammation and angiogenesis in zebrafish and CAMs in vivo, respectively. In Red Duroc pig full-thickness wounds, beta 2ARag 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 beta 2ARag-treated porcine scars in vivo. Both macrophage infiltration and angiogenesis were initially decreased, whereas DF function was impaired in the beta 2ARag-treated porcine wound bed. These data collectively reveal the potential of beta 2ARag to improve skin scarring.
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