SERUM AMYLOID P AND DERMAL WOUND FIBROSIS

描述（由申请人提供）：瘢痕和纤维化伴随着显著的发病率和功能丧失。在皮肤伤口和纤维化病变中，循环单核细胞的子集被募集到伤口并分化成称为纤维细胞的成纤维细胞样细胞。血清淀粉样蛋白P（SAP）可以在体外阻止这种分化。在体内，SAP的全身给药减少博莱霉素诱导的肺纤维化的大鼠和小鼠模型中的纤维化，并在心脏纤维化的小鼠缺血再灌注模型。我们发现，SAP的全身给药或局部注射引起伤口收缩和愈合延迟，并降低小鼠皮肤伤口中的肌成纤维细胞含量。使用雌性红色杜洛克猪（FRDP）模型的肥厚性瘢痕，我们有初步的数据表明，局部注射SAP到深真皮伤口似乎减少瘢痕和胶原含量的这些伤口。基于这些观察，我们建议评估SAP在伤口纤维化中的作用。本研究的关键假设是SAP减少了增生性瘢痕动物模型中的纤维化反应。为了检验这一假设，我们提出了以下具体目标：1：确定是否FRDPs形成过多的疤痕，由于异常低的血清SAP水平或SAP的纤维细胞前体的异常反应。将FRDP血清SAP水平、血清抑制纤维细胞分化的能力和FRDP单核细胞的纤维细胞分化速率与对照约克郡猪进行比较。2.表征SAP对FRDP皮肤愈合反应的影响。将通过伤口的组织学、免疫组织化学和分子分析来评估SAP皮内注射对FRDP深部伤口愈合的影响。3：确定SAP的不同给药途径对伤口愈合反应的影响。将比较全身和局部施用SAP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对复杂伤口愈合过程的影响。如果我们的假设被证明是正确的，其影响将是实质性的和显著的，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，而且在其他纤维化皮肤病和纤维化中。公共卫生相关性：皮肤或内脏器官中的瘢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。治疗或预防疤痕形成的方法将有助于减少这些疾病造成的残疾。该项目将评估一种天然蛋白质在预防过度瘢痕形成中的作用。这项研究的结果将影响我们的治疗和/或预防疤痕，无论是皮肤，肌肉或内脏。

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.