MECHANISM OF HYPERTROPHIC SCARRING AFTER THERMAL TRAUMA

许多严重皮肤烧伤的患者出现了夸张的 愈合反应导致增生性瘢痕。这道多余的伤疤 导致活动受限、关节痉挛和严重毁容。 治疗方式有限。因此，增生性瘢痕是主要的 限制烧伤完全恢复的因素。上一首 调查和初步数据表明，增生性瘢痕组织 从那里获得的成纤维细胞显示出更高的胶原率 相对于无疤痕的皮肤，合成和胶原晶格收缩。 从增生性瘢痕生长的成纤维细胞生长速度较慢， 与正常皮肤细胞相比，它们对血清和EGF的反应较差。在……里面 此外，初步实验已经显示出一种无序相互作用 角质形成细胞和成纤维细胞之间以及过度的早期细胞因子释放， 尤其是TGFbeta。因此，我们的工作假设是，改变 烧伤早期愈合引起细胞外基质增加 产生和异常细胞因子的产生。这些结果是稳定的 伤口内表现为过度的表型改变 胶原合成以及异常的自分泌和旁分泌反应 与选定的细胞因子有关。最终的总体结果是促进旺盛 疤痕形成。 实验策略基于三个主要目标。第一, 烧伤的细胞因子异常将用 生物化学和分子生物学方法。特别是，这个角色 作为基质产量增加的直接原因的TGFbeta将是 有记录在案。第二，增生性瘢痕的表型改变 组织(体外)和细胞(角质形成细胞和成纤维细胞(体外)将 以胶原和细胞因子(TGFbeta)基因为特征 利用生化、分子生物学和免疫学方法进行表达 接近了。瘢痕成纤维细胞和角质形成细胞对 外源性纯细胞因子(EGF、PDGF、IL-8、TNFpha、TGFbeta)将 与从受伤组织中提取的那些在没有愈合的情况下愈合的 过多的疤痕和来自同一个人的正常细胞。最后， 定向调控对角质形成细胞衍生细胞因子的影响 成纤维细胞将在体外使用条件培养液进行检测， 用层析法和免疫学方法确定责任人 接近了。要研究的功能终点包括细胞 生长速度、胶原蛋白的产生和细胞因子的产生。在……里面 这件事在增生性瘢痕中的表型变化将是 描述并确定了细胞因子在其原因中的作用。这个 该项目的长期目标是揭示以下关键机制 肥厚性瘢痕可能会改善治疗效果，也许 预防策略。

Many patients with severe dermal burn injury develop an exaggerated healing response resulting in hypertrophic scarring. This excess scar results in limited mobility, joint contracture and gross disfigurement. Treatment modalities are limited. Hence, hypertrophic scar is the major factor limiting complete recovery from burn injury. Previous investigations and preliminary data suggest that hypertrophic scar tissue and fibroblasts derived there from exhibit higher rates of collagen synthesis and collagen lattice contraction relative to unscarred skin. Fibroblasts grown from hypertrophic scars have slower growth rates and are less responsive than normal skin cells to serum and EGF. In addition, preliminary experiments have shown a disordered interaction between keratinocytes and fibroblasts and excess early cytokine release, in particular TGFbeta. Hence, our working hypothesis is that alterations in early burn healing induce both increased extracellular matrix production and abnormal cytokine production. These result in stable phenotypic alterations within the wound which are manifested by excess collagen synthesis, as well as abnormal autocrine and paracrine responses to selected cytokines. The net overall result is to promote exuberant scar formation. The experimental strategy is based on three primary aims. First, cytokine abnormalities of the burn would will be characterized using biochemical and molecular biologic approaches. In particular, the role of TGFbeta as the proximate cause of increased matrix production will be documented. Second, the phenotypic alterations in hypertrophic scar tissue (ex vivo) and cells (keratinocytes and fibroblasts (in vitro) will be characterized in terms of collagen and cytokine (TGFbeta) gene expression using biochemical, molecular biological and immunological approaches. The response of scar fibroblasts and keratinocytes to exogenous pure cytokines (EGF, PDGF, IL-8, TNFalpha, TGFbeta) will be compared to both those derived from injured tissues which heal without excess scar and normal cells from the same individual. Finally, the directional regulatory influences keratinocyte-derived cytokines on fibroblasts will be examined in vitro using conditioned medium, and the responsible agents identified using chromatographic and immunological approaches. The functional end points to be studied include cellular growth rate, collagen production, and the production of cytokines. In this matter the phenotype alterations in hypertrophic scar will be delineated and the role of cytokines in their causation determined. The long-term goal of this project is to uncover key mechanisms underlying hypertrophic scarring which may lead to improved therapeutic and perhaps preventive strategies.