Abstract
Previous studies described the involvement of extracellular signal-related kinase (ERK) in systemic fibrotic diseases, but the role of ERK in cutaneous scarring is unknown. Although hypoxia drives tissue fibrosis by activating hypoxia-inducible factor-1α (HIF-1α), the specific roles of hypoxia and associated ERK phosphorylation in abnormal fibroblast activity during cutaneous scarring are unclear. Here, we investigated whether pathologic myofibroblast-like keloid fibroblast activity is promoted by hypoxia-induced epithelial–mesenchymal transition mediated by ERK activation. ERK phosphorylation was significantly increased in keloid tissue and fibroblasts. Human dermal fibroblasts cultured under hypoxia (1% O2) expressed phosphorylated ERK and exhibited activation of p38 mitogen-activated protein kinase signaling. Hypoxic human dermal fibroblasts showed increased protein and mRNA levels of epithelial–mesenchymal transition markers. Furthermore, administration of an ERK inhibitor (SCH772984) reduced the hypoxia-induced elevation of collagen type I levels in human dermal fibroblasts. Therefore, ERK may be a promising therapeutic target in profibrogenic diseases.
Highlights
Wound healing normally progresses through coagulation, inflammation, proliferation, and remodeling phases
Persistent tissue fibrosis due to abnormal dermal fibroblast activity and excessive synthesis of extracellular matrix (ECM) components is a common manifestation in cutaneous scarring [1,2]
When we compared the expression of hypoxia-inducible factor-1α (HIF-1α) between Keloid fibroblasts (KFs) and human dermal fibroblasts (HDFs) after 12 h of hypoxia (1% O2), we found that KFs showed more nuclear translocation of Hypoxia-inducible factor (HIF)-1α compared with HDFs (Figure 1c)
Summary
Wound healing normally progresses through coagulation, inflammation, proliferation, and remodeling phases. Persistent tissue fibrosis due to abnormal dermal fibroblast activity and excessive synthesis of extracellular matrix (ECM) components is a common manifestation in cutaneous scarring [1,2]. Keloids and hypertrophic scars are types of excessive scarring that result from defects in the normal wound healing process. Previous reports demonstrate that KFs originate from the EMT of epithelial and endothelial cell components during wound healing [6,9], and keloid tissue shows increased expression of EMT markers [10]. Hypoxia-induced cutaneous fibrosis and the associated EMT process are known to be involved in keloid formation, the underlying molecular mechanisms are not well understood. The link between hypoxia-induced ERK activation and ECM accumulation in cutaneous wound healing has not been investigated. We elucidated the molecular mechanisms of ERK activation in cultured fibroblasts under hypoxia
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