Sandulache Vlad C, Parekh Aron, Li-Korotky Ha-Sheng, Dohar Joseph E, Hebda Patricia A
Department of Pediatric Otolaryngology, Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA.
Wound Repair Regen. 2006 Sep-Oct;14(5):633-43. doi: 10.1111/j.1743-6109.2006.00156.x.
Cyclooxygenase-2 is up-regulated shortly after dermal injury and it has been shown to have important activity during the repair process. Its main product in the skin, prostaglandin E2 (PGE2), modulates both inflammatory and fibrotic processes during wound healing and partially dictates the overall outcome of wound healing. PGE2 signaling has been shown to be altered during fetal wound healing. This study was designed to examine the mechanism(s) by which PGE2 regulates fibroblast migration and contraction and to determine whether these mechanisms are conserved in fetal-derived dermal fibroblasts. Fetal and adult dermal fibroblasts express all four PGE2 receptors. PGE2 inhibits fetal and adult fibroblast migration in a dose-dependent manner through the EP2/EP4-cAMP-protein kinase A pathway. However, fetal fibroblasts appear to be refractory to this effect, requiring a 10-fold higher concentration of PGE2 to achieve a similar degree of inhibition as adult fibroblasts. Inhibition of adult fibroblast migration correlated with disruption of the actin cytoskeleton. In contrast, PGE2 or a cAMP analog did not disrupt the actin cytoskeleton of fetal dermal fibroblasts. These findings were extended using a modified free-floating, fibroblast-populated collagen lattice (FPCL) contraction assay designed to measure fibroblast contraction. PGE2-inhibited FPCL contraction by adult fibroblasts, but fetal fibroblasts exhibited higher rates of FPCL contraction and a blunted response to exogenous modulation by PGE2 or a cyclase activator (forskolin). These findings indicate that fetal dermal fibroblasts are partially refractory to the effects of PGE2, a major inflammatory mediator associated with dermal wound healing. This effect may have significant and specific relevance to the scarless fetal wound-healing phenotype.
环氧化酶-2在皮肤损伤后不久即上调，并且已证实在修复过程中具有重要活性。其在皮肤中的主要产物前列腺素E2（PGE2）在伤口愈合过程中调节炎症和纤维化过程，并部分决定伤口愈合的总体结果。已证实在胎儿伤口愈合过程中PGE2信号传导会发生改变。本研究旨在探讨PGE2调节成纤维细胞迁移和收缩的机制，并确定这些机制在胎儿来源的真皮成纤维细胞中是否保守。胎儿和成人真皮成纤维细胞表达所有四种PGE2受体。PGE2通过EP2/EP4-环磷酸腺苷-蛋白激酶A途径以剂量依赖的方式抑制胎儿和成人成纤维细胞的迁移。然而，胎儿成纤维细胞似乎对这种作用具有抗性，需要比成人成纤维细胞高10倍的PGE2浓度才能达到相似程度的抑制。抑制成人成纤维细胞迁移与肌动蛋白细胞骨架的破坏相关。相比之下，PGE2或环磷酸腺苷类似物不会破坏胎儿真皮成纤维细胞的肌动蛋白细胞骨架。使用改良的自由漂浮、成纤维细胞填充的胶原格子（FPCL）收缩试验（旨在测量成纤维细胞收缩）扩展了这些发现。PGE2抑制成人成纤维细胞的FPCL收缩，但胎儿成纤维细胞表现出更高的FPCL收缩率，并且对外源性PGE2或环化酶激活剂（福斯高林）的调节反应迟钝。这些发现表明，胎儿真皮成纤维细胞对与皮肤伤口愈合相关的主要炎症介质PGE2的作用具有部分抗性。这种作用可能与无瘢痕胎儿伤口愈合表型具有显著且特定的相关性。
