MECHANISM OF HYPERTROPHIC SCARRING AFTER THERMAL TRAUMA

许多严重皮肤烧伤的患者会出现夸张的 愈合反应导致增生性瘢痕。 这个多余的伤疤 导致活动受限、关节挛缩和严重毁容。 治疗方式有限。 因此，增生性瘢痕是主要的 限制烧伤完全康复的因素。 先前 调查和初步数据表明， 并且从那里衍生的成纤维细胞表现出更高的胶原比率， 合成和胶原晶格收缩。 从增生性瘢痕生长的成纤维细胞具有较慢的生长速率， 比正常皮肤细胞对血清和EGF的反应更低。 在 此外，初步的实验表明，无序的相互作用 角质形成细胞和成纤维细胞之间以及过量的早期细胞因子释放， 特别是TGF β。 因此，我们的工作假设是， 在早期烧伤愈合诱导细胞外基质增加 产生和异常细胞因子产生。 这些导致稳定的 伤口内的表型改变，表现为过量的 胶原蛋白合成以及异常的自分泌和旁分泌反应 选择细胞因子。 净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，作用 TGF β作为增加基质产生的近因， 记录在案。 第二，增生性瘢痕的表型改变 组织（离体）和细胞（角质形成细胞和成纤维细胞（体外）将 以胶原蛋白和细胞因子（TGF β）基因为特征 利用生物化学、分子生物学和免疫学方法表达 接近。 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、TNF α、TGF β）将被 相比之下，那些来自受伤组织的细胞， 多余的疤痕和正常细胞来自同一个人。 最后 定向调节影响角质形成细胞衍生的细胞因子， 将使用条件培养基在体外检查成纤维细胞， 使用色谱法和免疫学方法鉴定出的负责因子 接近。 待研究的功能终点包括细胞 生长速率、胶原蛋白产生和细胞因子的产生。 在 因此，增生性瘢痕的表型改变将是 并确定了细胞因子在其因果关系中的作用。 的 该项目的长期目标是揭示潜在的关键机制， 增生性疤痕，这可能会导致改善治疗， 预防战略。

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.