SERUM AMYLOID P AND DERMAL WOUND FIBROSIS

描述(由申请人提供)：疤痕和纤维化伴随着严重的发病率和功能丧失。在皮肤创伤和纤维化损伤中，循环单核细胞亚群被招募到伤口并分化为成纤维细胞样细胞，称为成纤维细胞。一种血清蛋白，血清淀粉样蛋白P(SAP)，可以在体外阻止这种分化。在体内，在博莱霉素诱导的大鼠和小鼠肺纤维化模型以及小鼠心肌纤维化的缺血-再灌注模型中，系统地给药SAP减少了纤维化。我们发现全身注射或局部注射SAP可延迟小鼠皮肤创面的收缩和愈合，并减少小鼠皮肤创面中肌成纤维细胞的含量。采用雌性红色杜洛克猪(FRDP)增生性瘢痕模型，初步数据表明，真皮深层创面局部注射SAP可减少创面瘢痕形成，减少创面胶原含量。基于这些观察，我们建议评估SAP在伤口纤维化中的作用。这项研究的关键假设是SAP降低了增生性瘢痕动物模型的纤维化反应。为了验证这一假设，我们提出了以下具体目标：1：确定FRDP是否由于血清SAP水平异常低或纤维细胞前体对SAP的异常反应而形成过度瘢痕。FRDP血清SAP水平、血清抑制纤维细胞分化的能力以及FRDP单核细胞向纤维细胞分化的比率将与对照约克夏猪进行比较。2.研究SAP对FRDP皮肤愈合反应的影响。皮内注射SAP对FRDP深部创面愈合的影响将通过创面的组织学、免疫组织化学和分子分析来评估。3：确定SAP不同给药途径对创面愈合反应的影响。比较全身给药和局部给药对伤口愈合的影响。这项高度集中的研究将评估这种血清蛋白在复杂的伤口愈合过程中的作用。如果我们的假设被证明是正确的，影响将是巨大的和显著的，因为我们可能能够使用SAP来防止过度瘢痕形成，不仅在增生性瘢痕和瘢痕疙瘩中，而且在其他纤维性皮肤状况和一般情况下也是如此。与公共卫生相关：皮肤或内脏的疤痕形成可导致功能丧失或严重毁容，给个人和整个社会带来巨大的情感和经济代价。治疗或防止疤痕形成的方法将有助于减少这些疾病造成的残疾。这个项目将评估一种自然产生的蛋白质在防止过度疤痕方面的效果。这项研究的结果将影响我们对皮肤、肌肉或内脏疤痕的治疗和/或预防。

DESCRIPTION (provided by applicant): Scarring and fibrosis is accompanied by significant morbidity and loss of function. In dermal wounds and fibrotic lesions, a subset of circulating monocytes are recruited to the wound and differentiate into fibroblast-like cells called fibrocytes. A serum protein, serum amyloid P (SAP), can prevent this differentiation in vitro. In vivo, systemic administration of SAP reduced fibrosis in rat and mouse models of bleomycin-induced pulmonary fibrosis and in a murine ischemia-reperfusion model of cardiac fibrosis. We found that systemic administration or local injections of SAP caused delayed wound contraction and healing, and decreased myofibroblast content in murine dermal wounds. Using the female red Duroc pig (FRDP) model of hypertrophic scarring, we have preliminary data indicating that local injection of SAP into deep dermal wounds appears to reduce scarring and the collagen content of these wounds. Based on these observations, we propose to evaluate the role of SAP in wound fibrosis. The key hypothesis of this study is that SAP reduces the fibrotic response in an animal model of hypertrophic scar. To test this hypothesis, we propose the following specific aims: 1: Determine if FRDPs form excessive scars due to either abnormally low serum SAP levels or an abnormal response of fibrocyte precursors to SAP. FRDP serum SAP levels, the sera's ability to inhibit fibrocyte differentiation, and the rate of fibrocyte differentiation by FRDP monocytes will be compared with control Yorkshire pigs. 2. Characterize the effect of SAP on the dermal healing response of FRDP. The effect of intradermal injection of SAP on the healing of deep wounds on FRDP will be assessed by histological, immunohistochemical and molecular analysis of the wounds. 3: Determine the effects of different routes of administration of SAP on the wound healing response. The effect of systemic and local administration of SAP on wound healing will be compared. This highly focused study will evaluate the effect of this serum protein on the complex wound healing process. If our hypothesis proves to be correct, the impact would be substantial and significant, as we might be able to use SAP to prevent excessive scarring not only in hypertrophic scars and keloids but other fibrotic skin conditions and fibrosis in general. PUBLIC HEALTH RELEVANCE: Scar formation in the skin or internal organs can result in loss of function or severe disfigurement with a substantial emotional and financial cost to the individual and society at large. Modalities to treat or prevent scar formation would help reduce the disability resulting from these conditions. This project will evaluate the effect of a naturally occurring protein in the prevention of excessive scarring. Findings of this study would impact our treatment and/or prevention of scarring, be it of the skin, muscle or internal organs.