Aarabi Shahram, Bhatt Kirit A, Shi Yubin, Paterno Josemaria, Chang Edward I, Loh Shang A, Holmes Jeffrey W, Longaker Michael T, Yee Herman, Gurtner Geoffrey C
Department of Surgery, Stanford University School of Medicine, Stanford, California, USA.
FASEB J. 2007 Oct;21(12):3250-61. doi: 10.1096/fj.07-8218com. Epub 2007 May 15.
Hypertrophic scars occur following cutaneous wounding and result in severe functional and esthetic defects. The pathophysiology of this process remains unknown. Here, we demonstrate for the first time that mechanical stress applied to a healing wound is sufficient to produce hypertrophic scars in mice. The resulting scars are histopathologically identical to human hypertrophic scars and persist for more than six months following a brief (one-week) period of augmented mechanical stress during the proliferative phase of wound healing. Resulting scars are structurally identical to human hypertrophic scars and showed dramatic increases in volume (20-fold) and cellular density (20-fold). The increased cellularity is accompanied by a four-fold decrease in cellular apoptosis and increased activation of the prosurvival marker Akt. To clarify the importance of apoptosis in hypertrophic scar formation, we examine the effects of mechanical loading on cutaneous wounds of animals with altered pathways of cellular apoptosis. In p53-null mice, with down-regulated cellular apoptosis, we observe significantly greater scar hypertrophy and cellular density. Conversely, scar hypertrophy and cellular density are significantly reduced in proapoptotic BclII-null mice. We conclude that mechanical loading early in the proliferative phase of wound healing produces hypertrophic scars by inhibiting cellular apoptosis through an Akt-dependent mechanism.
肥厚性瘢痕在皮肤创伤后出现，会导致严重的功能和美观缺陷。这一过程的病理生理学尚不清楚。在此，我们首次证明，对愈合伤口施加机械应力足以在小鼠身上产生肥厚性瘢痕。所形成的瘢痕在组织病理学上与人类肥厚性瘢痕相同，并且在伤口愈合增殖期短暂（一周）的增强机械应力作用后持续超过六个月。所形成的瘢痕在结构上与人类肥厚性瘢痕相同，体积（增加20倍）和细胞密度（增加20倍）显著增加。细胞增多伴随着细胞凋亡减少四倍以及促生存标志物Akt的激活增加。为了阐明细胞凋亡在肥厚性瘢痕形成中的重要性，我们研究了机械负荷对细胞凋亡途径改变的动物皮肤伤口的影响。在细胞凋亡下调的p53基因敲除小鼠中，我们观察到瘢痕肥大和细胞密度显著增加。相反，在促凋亡的BclII基因敲除小鼠中，瘢痕肥大和细胞密度显著降低。我们得出结论，伤口愈合增殖期早期的机械负荷通过Akt依赖机制抑制细胞凋亡而产生肥厚性瘢痕。
