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Previous data identified increased mast cell number and activation state in keloids suggesting a role in disease progression. The major eicosanoid secreted by mast cells is prostaglandin D2 (<jats:styled-content style=\"fixed-case\">PGD<\/jats:styled-content>2), a relatively unstable pro\u2010inflammatory mediator which can be spontaneously converted to 15\u2010deoxy\u2010(Delta12,14)\u2010prostaglandin J2(15d\u2010PGJ2) or enzymatically metabolized to 9\u03b1,11\u03b2\u2010<jats:styled-content style=\"fixed-case\">PGF<\/jats:styled-content>2 by aldo\u2010keto reductase 1C3 (<jats:styled-content style=\"fixed-case\">AKR<\/jats:styled-content>1C3). In this work, we investigated the possible role of <jats:styled-content style=\"fixed-case\">PGD<\/jats:styled-content>2 and its metabolites in keloids using <jats:styled-content style=\"fixed-case\">CRL<\/jats:styled-content>1762 keloid fibroblasts (<jats:styled-content style=\"fixed-case\">KF<\/jats:styled-content>) and immunohistochemical staining. Our data suggested approximately 3\u2010fold increase of tryptase\u2010positive mast cell count in keloids compared with normal skin. Furthermore, <jats:styled-content style=\"fixed-case\">AKR<\/jats:styled-content>1C3 was overexpressed in the fibrotic area of keloids while relatively weak staining detected in normal skin. Metabolism of <jats:styled-content style=\"fixed-case\">PGD<\/jats:styled-content>2 to 9<jats:italic>\u03b1<\/jats:italic>,11<jats:italic>\u03b2<\/jats:italic>\u2010<jats:styled-content style=\"fixed-case\">PGF<\/jats:styled-content>2 by both, <jats:styled-content style=\"fixed-case\">KF<\/jats:styled-content> and normal fibroblasts, was dependent on <jats:styled-content style=\"fixed-case\">AKR<\/jats:styled-content>1C3 as this reaction was attenuated in the presence of the <jats:styled-content style=\"fixed-case\">AKR<\/jats:styled-content>1C3 inhibitor, 2\u2032\u2010hydroxyflavanone, or in cells with decreased <jats:styled-content style=\"fixed-case\">AKR<\/jats:styled-content>1C3 expression. 15d\u2010<jats:styled-content style=\"fixed-case\">PGJ<\/jats:styled-content>2, but not the other tested <jats:styled-content style=\"fixed-case\">PG<\/jats:styled-content>s, inhibited <jats:styled-content style=\"fixed-case\">KF<\/jats:styled-content> proliferation, attenuated <jats:styled-content style=\"fixed-case\">KF<\/jats:styled-content>\u2010mediated collagen gel contraction and increased caspase\u20103 activation. In addition, treatment with 15d\u2010<jats:styled-content style=\"fixed-case\">PGJ<\/jats:styled-content>2 activated P38\u2010<jats:styled-content style=\"fixed-case\">MAPK<\/jats:styled-content>, induced reactive oxygen species and upregulated superoxide dismutase\u20101 (<jats:styled-content style=\"fixed-case\">SOD<\/jats:styled-content>\u20101). Finally, inhibition of P38\u2010<jats:styled-content style=\"fixed-case\">MAPK<\/jats:styled-content> further augmented 15d\u2010<jats:styled-content style=\"fixed-case\">PGJ<\/jats:styled-content>2\u2010induced caspase\u20103 cleavage and attenuated its effect on <jats:styled-content style=\"fixed-case\">SOD<\/jats:styled-content>\u20101 transcription. This work suggests that localized dual inhibition of <jats:styled-content style=\"fixed-case\">AKR<\/jats:styled-content>1C3 and P38\u2010<jats:styled-content style=\"fixed-case\">MAPK<\/jats:styled-content> may inhibit keloid progression. Inhibiting <jats:styled-content style=\"fixed-case\">AKR<\/jats:styled-content>1C3 activity may generate oxidative environment due to redirection of <jats:styled-content style=\"fixed-case\">PGD<\/jats:styled-content>2 metabolism towards 15d\u2010<jats:styled-content style=\"fixed-case\">PGJ<\/jats:styled-content>2 while inhibition of P38\u2010<jats:styled-content style=\"fixed-case\">MAPK<\/jats:styled-content> will sensitize keloid cells to <jats:styled-content style=\"fixed-case\">ROS<\/jats:styled-content>\u2010induced apoptosis.<\/jats:p>","DOI":"10.1111\/exd.12854","type":"journal-article","created":{"date-parts":[[2015,8,26]],"date-time":"2015-08-26T13:31:18Z","timestamp":1440595878000},"page":"38-43","source":"Crossref","is-referenced-by-count":12,"title":["The role of aldo\u2010keto reductase 1<scp>C<\/scp>3 (<scp>AKR<\/scp>1<scp>C<\/scp>3)\u2010mediated prostaglandin <scp>D<\/scp>2 (<scp>PGD<\/scp>2) metabolism in keloids"],"prefix":"10.1111","volume":"25","author":[{"given":"Alon","family":"Mantel","sequence":"first","affiliation":[{"name":"Hampton University Skin of Color Research Institute (HUSCRI) Hampton VA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Austin","family":"Newsome","sequence":"additional","affiliation":[{"name":"Hampton University Skin of Color Research Institute (HUSCRI) Hampton VA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Theresa","family":"Thekkudan","sequence":"additional","affiliation":[{"name":"Hampton University Skin of Color Research Institute (HUSCRI) Hampton VA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert","family":"Frazier","sequence":"additional","affiliation":[{"name":"Leroy T. Canoles Jr. Cancer Research Center Eastern Virginia Medical School (EVMS) Norfolk VA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meena","family":"Katdare","sequence":"additional","affiliation":[{"name":"Hampton University Skin of Color Research Institute (HUSCRI) Hampton VA USA"},{"name":"Department of Dermatology Eastern Virginia Medical School (EVMS) Norfolk VA 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