Hypoxia-Induced Epithelial-To-Mesenchymal Transition Mediates Fibroblast Abnormalities via ERK Activation in Cutaneous Wound Healing

Abstract

Previous studies described the involvement of extracellular signal-related kinase (ERK) in systemic fibrotic diseases, but the role ofERKincutaneousscarring is unknown. Although hypoxia drives tissue fibrosis by activating hypoxia-inducible factor-1α (HIF-1α), the specific roles of hypoxia and associatedERKphosphorylation in abnormalfibroblastactivity duringcutaneousscarring are unclear. Here, we investigated whether pathologic myofibroblast-like keloidfibroblastactivity is promoted byhypoxia-inducedepithelial-mesenchymaltransitionmediated byERKactivation.ERKphosphorylation was significantly increased in keloid tissue and fibroblasts. Human dermal fibroblasts cultured under hypoxia (1% O2) expressed phosphorylatedERKand exhibitedactivationof p38 mitogen-activated protein kinase signaling. Hypoxic human dermal fibroblasts showed increased protein and mRNA levels of epithelial-mesenchymaltransitionmarkers. Furthermore, administration of anERKinhibitor (SCH772984) reduced thehypoxia-inducedelevation of collagen type I levels in human dermal fibroblasts. Therefore,ERKmay be a promising therapeutic target in profibrogenic diseases.