A novel primate model of delayed wound healing in diabetes: dysregulation of connective tissue growth factor
A novel primate model of delayed wound healing in diabetes: dysregulation of connective tissue growth factor
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DOI：
10.1007/s00125-009-1610-6
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发表时间：
2010-03-01
期刊：
影响因子：
8.2
通讯作者：
Twigg, S. M.
中科院分区：
文献类型：
--
作者：
Thomson, S. E.;McLennan, S. V.;Twigg, S. M.
慢性不愈合伤口是糖尿病的常见并发症。炎症延长和基质积累减少可能是原因之一。结缔组织生长因子（CTGF）在正常伤口愈合过程中被诱导，但其在糖尿病伤口中的调节尚不清楚。我们建立了一个灵长类动物模型，用于研究糖尿病病程较长的狒狒体内伤口愈合。将鼓形植入物皮下植入糖尿病和非糖尿病对照狒狒的大腿。在2周和4周后，去除皮肤切口部位以测量断裂强度和上皮厚度。取出鼓形植入物以分析肉芽组织和炎性细胞、CTGF和基质金属蛋白酶组织抑制剂（TIMP-1）。与对照组相比，糖尿病狒狒愈合的切口部位皮肤更硬（弹性更小），上皮重塑更慢。糖尿病狒狒的肉芽组织在2周和4周时减少，4周时血管腔面积增加。巨噬细胞减少，而中性粒细胞在糖尿病组织中持续存在。在糖尿病伤口组织在4周有较少的CTGF诱导，如免疫组化所示，与对照组相比。与此相反，CTGF的免疫反应性片段显着增加，在糖尿病狒狒的整个组织裂解物，表明CTGF是重新分布在糖尿病肉芽组织进入伤口液。当重组人CTGF与伤口液共孵育时，在对照组和糖尿病组的样本中均观察到CTGF降解产物的增加，这种狒狒伤口愈合模型反映了人类糖尿病伤口中所见的异常微环境，并为糖尿病伤口中CTGF的失调提供了见解。
Chronic non-healing wounds are a common complication of diabetes. Prolonged inflammation and decreased matrix accumulation may contribute. Connective tissue growth factor (CTGF) is induced during normal wound healing, but its regulation in diabetic wounds is unknown. We developed a primate model for the study of in vivo wound healing in baboons with long diabetes duration.Drum implants were placed subcutaneously into thighs of diabetic and non-diabetic control baboons. After 2 and 4 weeks the skin incision sites were removed for measurement of breaking strength and epithelial thickness. Drum implants were removed for analysis of granulation tissue and inflammatory cells, CTGF and tissue inhibitor of matrix metalloproteinase (TIMP-1). Degradation of added CTGF by wound fluid was also examined.Healed incision site skin was stiffer (less elastic) in diabetic baboons and epithelial remodelling was slower compared with controls. Granulation tissue from diabetic baboons was reduced at 2 and 4 weeks, with increased vessel lumen areas at 4 weeks. Macrophages were reduced while neutrophils persisted in diabetic tissue. In diabetic wound tissue at 4 weeks there was less CTGF induced, as shown by immunohistochemistry, compared with controls. In contrast, immunoreactive fragments of CTGF were significantly increased in whole tissue lysate in diabetic baboons, suggesting that CTGF is redistributed in diabetes from granulation tissue into wound fluid. When recombinant human CTGF was co-incubated with wound fluid, increased CTGF degradation products were observed in both control and diabetic samples.This baboon model of wound healing reflects the abnormal microenvironment seen in human diabetic wounds and provides insights into the dysregulation of CTGF in diabetic wounds.