Mechanical load initiates hypertrophic scar formation through decreased cellular apoptosis
Mechanical load initiates hypertrophic scar formation through decreased cellular apoptosis
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DOI：
10.1096/fj.07-8218com
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发表时间：
2007-10-01
期刊：
影响因子：
4.8
通讯作者：
Gurtner, Geoffrey C.
中科院分区：
文献类型：
--
作者：
Aarabi, Shahram;Bhatt, Kirit A.;Gurtner, Geoffrey C.
皮肤损伤后会出现增生性瘢痕，并导致严重的功能和审美缺陷。这一过程的病理生理学仍不清楚。在这里，我们第一次证明了对愈合的伤口施加机械应力足以在小鼠身上产生增生性瘢痕。由此产生的疤痕在组织病理学上与人类增生性瘢痕相同，并在伤口愈合的增殖期经过短暂(一周)机械应力增加后持续六个月以上。由此产生的疤痕在结构上与人类增生性瘢痕相同，并显示出体积(20倍)和细胞密度(20倍)的急剧增加。随着细胞密度的增加，细胞凋亡率减少了四倍，生存标记物Akt的激活增加。为了阐明细胞凋亡在增生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p53基因缺失的小鼠中，随着细胞凋亡的下调，我们观察到显著更大的瘢痕肥大和细胞密度。相反，在促凋亡的bclII缺失小鼠中，瘢痕肥大和细胞密度显著减少。我们得出结论，创伤愈合早期的机械负荷通过Akt依赖的机制抑制细胞凋亡，从而产生增生性瘢痕。
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.