Development of apotosis-inducing therapy for keloids and hypertrophic scars

瘢痕疙瘩是皮肤异常，其特征在于真皮中胶原束的过度沉积。瘢痕疙瘩患者不仅抱怨其外观美观，而且还抱怨与慢性炎症相关的持续瘙痒和/或压痛。细胞外基质（ECM）的降解可能上调，与瘢痕疙瘩向周围皮肤的扩展相关，并且瘢痕疙瘩组织的高代谢活性可能是由于基质金属蛋白酶（MMP）活性增加。基于这些假设，我们研究了瘢痕疙瘩和正常皮肤成纤维细胞中MMP-1、MMP-8和MMP-13表达的差异。由于类维生素A在光老化皮肤和癌症的治疗中是MMPs的有效抑制剂，我们还研究了维甲酸是否影响瘢痕疙瘩来源的成纤维细胞的MMP表达。实时荧光定量PCR和ELISA结果显示，MMP-13表达显著上调，MMP-13表达显著下调 ...更多信息 瘢痕疙瘩成纤维细胞中MMP-1和MMP-8的表达。对照组MMP-1 mRNA表达在添加维甲酸后显著上调，而瘢痕疙瘩组中未观察到显著变化。对照组MMP-8 mRNA表达明显上调，12 h达高峰，而瘢痕疙瘩成纤维细胞MMP-8 mRNA表达无明显变化。与此相反，瘢痕疙瘩组MMP-13 mRNA的表达明显受到抑制，在加入维甲酸后12 h达到峰值，而对照组MMP-13 mRNA的表达无明显变化。MMP-1和MMP-8的减少可能有助于瘢痕疙瘩组织中I型和III型胶原的积累，并且这种机制可能通过与MMP-13的分子相互作用来调节。维甲酸似乎逆转了瘢痕疙瘩来源的成纤维细胞中MMP-13的异常表达，如MMP-13的表达显著升高，部分原因是AP-1通路的失活。目前的研究结果表明，维甲酸可能是临床上有用的，以改善慢性炎症瘢痕疙瘩，并防止瘢痕疙瘩组织扩展到周围正常皮肤。少

Keloids are skin abnormalities that are characterized by excessive deposition of collagen bundles in the dermis. Patients with keloids complain not only about their cosmetic appearance, but also about continuous itching and/or tenderness associated with chronic inflammation. Degradation of extracellular matrix (ECM) may be upregulated, associated with the expansion of keloids into circumferential skin, and high metabolic activity of keloid tissues may be due to increased matrix metalloproteinase (MMP) activity. Based on these hypotheses, we examined differences in expression of MMP-1, MMP-8, and MMP-13 between keloid-derived and normal dermal fibroblasts. Since retinoids are potent inhibitors of MMPs in the treatment of photoaged skin and cancers, we also examined whether or not tretinoin affects MMP expression of keloid-derived fibroblasts. The results of real-time polymerase chain reaction and ELISA demonstrated significant upregulation of MMP-13 and significant downregulation of MMP … More -1 and MMP-8 in keloid-derived fibroblasts, at both mRNA and protein levels. MMP-1 mRNA expression in the control group was significantly upregulated after the addition of tretinoin, whereas no significant change was observed in the keloid group. MMP-8 mRNA expression in the control group was significantly upregulated by tretinoin, with the peak at 12 h, while no significant change was observed in the keloid-derived fibroblasts. In contrast, the remarkably elevated MMP-13 mRNA expression in the keloid group was significantly suppressed, with the peak suppression at 12 h after addition of tretinoin, while MMP-13 mRNA expression in the control group was not significantly changed. The decrease in MMP-1 and MMP-8 may contribute to accumulation of type I and type III collagen in keloid tissues, and this mechanism may be modulated by molecular interaction with MMP-13. Tretinoin appeared to reverse the abnormal expression profile of MMPs in keloid-derived fibroblasts, such as markedly elevated expression of MMP-13, partly through inactivation of AP-1 pathway. The present results suggest that tretinoin may be clinically useful to improve the chronic inflammation seen in keloids and prevent expansion of keloid tissues into circumferential normal skin. Less