Teofoli P, Barduagni S, Ribuffo M, Campanella A, De Pita' O, Puddu P
Department of Immunodermatology, Istituto Dermopatico dell'Immacolata, IDI, IRCCS, Rome, Italy.
J Dermatol Sci. 1999 Dec;22(1):31-7. doi: 10.1016/s0923-1811(99)00040-7.
Keloids and hypertrophic scars represent a model of altered wound healing characterized by overproduction of extracellular matrix and dermal fibroblasts with high mitotic rate. Alteration of apoptosis and cell proliferation has been implicated in the etiology of keloids. The bcl-2 protooncogene encodes a protein that protects cells from programmed cell death while p53 protein functions as negative regulator of cell proliferation. Both protooncogenes have been shown to play a role in tissue homeostasis as apoptotic regulatory genes. The c-jun and c-fos protooncogenes are transactivating factors also involved in fibroblast proliferation. In our study we investigated, by immunohistochemistry, skin specimens from three clinically active hypertrophic scars and keloids, two resting keloids and two early phase morphea to detect both bcl-2 and p53 protein expression, in order to evaluate these apoptotic regulatory genes in different fibrotic conditions. The c-jun and c-fos, at protein and mRNA level, and Ki67 nuclear antigen expression were also investigated. In hypertrophic scars and active keloids we could detect intense Bcl-2 staining in basal keratinocytes and in scattered fibroblast-like and perivascular spindle-shaped cells, while no p53 expression could be demonstrated. The c-jun and c-fos mRNA and protein expression was mainly found in dermal fibroblast-like cells and elongated perivascular cells in all skin biopsies, and similar immunostaining pattern was observed for Ki67 antigen. No protooncogene expression in morphea patients and normal skin, unless Bcl-2 staining in the basal layer of normal epidermis, was documented. Our results suggest that Bcl-2, c-jun and c-fos protein expression and lack of p53 detection in fibroblast-like and perivascular spindle cells are related to increased fibroblast proliferation, confirmed by Ki67 positivity, probably due to alteration of these regulatory apoptotic genes resulting in pathological scarring.
瘢痕疙瘩和增生性瘢痕是伤口愈合改变的一种模型，其特征是细胞外基质过度产生以及有丝分裂率高的真皮成纤维细胞。细胞凋亡和细胞增殖的改变与瘢痕疙瘩的病因有关。bcl-2原癌基因编码一种保护细胞免受程序性细胞死亡的蛋白质，而p53蛋白作为细胞增殖的负调节因子发挥作用。这两种原癌基因均已显示作为凋亡调节基因在组织稳态中发挥作用。c-jun和c-fos原癌基因是也参与成纤维细胞增殖的反式激活因子。在我们的研究中，我们通过免疫组织化学方法研究了来自三个临床活动期增生性瘢痕和瘢痕疙瘩、两个静止期瘢痕疙瘩以及两个早期硬斑病的皮肤标本，以检测bcl-2和p53蛋白表达，从而评估这些凋亡调节基因在不同纤维化状况中的情况。还研究了c-jun和c-fos在蛋白质和mRNA水平以及Ki67核抗原的表达。在增生性瘢痕和活动期瘢痕疙瘩中，我们可以在基底角质形成细胞以及散在的成纤维细胞样和血管周围梭形细胞中检测到强烈的Bcl-2染色，而未显示p53表达。在所有皮肤活检标本中，c-jun和c-fos mRNA及蛋白质表达主要见于真皮成纤维细胞样细胞和伸长的血管周围细胞，并且观察到Ki67抗原具有相似的免疫染色模式。除非在正常表皮基底层有Bcl-2染色，否则在硬斑病患者和正常皮肤中未记录到原癌基因表达。我们的结果表明，在成纤维细胞样和血管周围梭形细胞中Bcl-2、c-jun和c-fos蛋白表达以及未检测到p53与成纤维细胞增殖增加有关，Ki67阳性证实了这一点，这可能是由于这些调节性凋亡基因的改变导致病理性瘢痕形成。
