Calreticulin enhances porcine wound repair by diverse biological effects
Calreticulin enhances porcine wound repair by diverse biological effects
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DOI：
10.2353/ajpath.2008.071027
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发表时间：
2008-09-01
影响因子：
6
通讯作者：
Gold, Leslie I.
中科院分区：
文献类型：
--
作者：
Nanney, Lillian B.;Woodrell, Christopher D.;Gold, Leslie I.
内质网伴侣蛋白钙网蛋白（CRT）的细胞外功能正在出现。在这里，我们展示了外源性CRT在皮肤伤口加热和与修复相关的各种过程中的新作用。与血小板衍生生长因子-BB处理的对照组相比，局部应用CRT到猪切除伤口提高了伤口再上皮化的速率。在正常和类固醇受损的猪中，CRT增加肉芽组织形成。损伤后5天和10天的伤口的免疫组织化学分析显示转化生长因子-β 3（伤口愈合的关键调节因子）显著上调，巨噬细胞流入增加三倍，以及新表皮的基底角质形成细胞和新真皮细胞的细胞增殖增加。体外研究证实，CRT诱导原代人角质形成细胞、成纤维细胞和微血管内皮细胞的细胞增殖增加两倍以上（分别为100 pg/ml、100 ng/ ml和1.0 pg/ml）。此外，使用划痕板试验，CRT最大限度地诱导角质形成细胞和成纤维细胞的细胞迁移（分别为10 pg/ml和1 ng/ml）。此外，CRT诱导浓度依赖性迁移的角质形成细胞，成纤维细胞巨噬细胞和单核细胞在腔室测定。这些体外生物活性为CRT在体内伤口表皮和真皮上观察到的积极生物学效应提供了机制支持，强调了CRT在皮肤伤口修复中的重要作用。
Extracellular functions of the endoplasmic reticulum chaperone protein calreticulin (CRT) are emerging. Here we show novel roles for exogenous CRT in both cutaneous wound heating and diverse processes associated with repair. Compared with platelet-derived growth factor-BB-treated controls, topical application of CRT to porcine excisional wounds enhanced the rate of wound re-epithelialization. in both normal and steroid-impaired pigs, CRT increased granulation tissue formation. Immunohistochemical analyses of the wounds 5 and 10 days after injury revealed marked up-regulation of transforming growth factor-beta 3 (a key regulator of wound healing), a threefold increase in macrophage influx, and an increase in the cellular proliferation of basal keratinocytes of the new epidermis and of cells of the neodermis. In vitro studies confirmed that CRT induced a greater than twofold increase in the cellular proliferation of primary human keratinocytes, fibroblasts, and microvascular endothelial cells (with 100 pg/ml, 100 ng/ ml, and 1.0 pg/ml, respectively). Moreover, using a scratch plate assay, CRT maximally induced the cellular migration of keratinocytes and fibroblasts (with 10 pg/ml and 1 ng/ml respectively). In addition, CRT induced concentration-dependent migration of keratinocytes, fibroblasts macrophages, and monocytes in chamber assays. These in vitro bioactivities provide mechanistic support for the positive biological effects of CRT observed on both the epidermis and dermis of wounds in vivo, underscoring a significant role for CRT in the repair of cutaneous wounds.