Pierce G F, Mustoe T A, Lingelbach J, Masakowski V R, Griffin G L, Senior R M, Deuel T F
Department of Pathology, Jewish Hospital, Washington University Medical Center, St. Louis, Missouri 63110.
J Cell Biol. 1989 Jul;109(1):429-40. doi: 10.1083/jcb.109.1.429.
Platelet-derived growth factor (PDGF) and transforming growth factor-beta (TGF-beta) markedly potentiate tissue repair in vivo. In the present experiments, both in vitro and in vivo responses to PDGF and TGF-beta were tested to identify mechanisms whereby these growth factors might each enhance the wound-healing response. Recombinant human PDGF B-chain homodimers (PDGF-BB) and TGF-beta 1 had identical dose-response curves in chemotactic assays with monocytes and fibroblasts as the natural proteins from platelets. Single applications of PDGF-BB (2 micrograms, 80 pmol) and TGF-beta 1 (20 micrograms, 600 pmol) were next applied to linear incisions in rats and each enhanced the strength required to disrupt the wounds at 5 d up to 212% of paired control wounds. Histological analysis of treated wounds demonstrated an in vivo chemotactic response of macrophages and fibroblasts to both PDGF-BB and to TGF-beta 1 but the response to TGF-beta 1 was significantly less than that observed with PDGF-BB. Marked increases of procollagen type I were observed by immunohistochemical staining in fibroblasts in treated wounds during the first week. The augmented breaking strength of TGF-beta 1 was not observed 2 and 3 wk after wounding. However, the positive influence of PDGF-BB on wound breaking strength persisted through the 7 wk of testing. Furthermore, PDGF-BB-treated wounds had persistently increased numbers of fibroblasts and granulation tissue through day 21, whereas the enhanced cellular influx in TGF-beta 1-treated wounds was not detectable beyond day 7. Wound macrophages and fibroblasts from PDGF-BB-treated wounds contained sharply increased levels of immunohistochemically detectable intracellular TGF-beta. Furthermore, PDGF-BB in vitro induced a marked, time-dependent stimulation of TGF-beta mRNA levels in cultured normal rat kidney fibroblasts. The results suggest that TGF-beta transiently attracts fibroblasts into the wound and may stimulate collagen synthesis directly. In contrast, PDGF is a more potent chemoattractant for wound macrophages and fibroblasts and may stimulate these cells to express endogenous growth factors, including TGF-beta, which, in turn, directly stimulate new collagen synthesis and sustained enhancement of wound healing over a more prolonged period of time.
血小板衍生生长因子（PDGF）和转化生长因子-β（TGF-β）在体内能显著增强组织修复。在本实验中，对PDGF和TGF-β的体外和体内反应进行了测试，以确定这些生长因子各自增强伤口愈合反应的机制。重组人PDGF B链同二聚体（PDGF-BB）和TGF-β1在以单核细胞和成纤维细胞作为来自血小板的天然蛋白质的趋化性测定中具有相同的剂量反应曲线。接下来，将PDGF-BB（2微克，80皮摩尔）和TGF-β1（20微克，600皮摩尔）单次应用于大鼠的线性切口，两者均使在第5天时破坏伤口所需的强度增强至配对对照伤口的212%。对处理过的伤口进行组织学分析表明，巨噬细胞和成纤维细胞在体内对PDGF-BB和TGF-β1均有趋化反应，但对TGF-β1的反应明显小于对PDGF-BB观察到的反应。在第一周，通过免疫组织化学染色观察到处理过的伤口中的成纤维细胞中I型前胶原显著增加。在受伤后2周和3周未观察到TGF-β1增强的抗张强度。然而，PDGF-BB对伤口抗张强度的积极影响在长达7周的测试中持续存在。此外，经PDGF-BB处理的伤口在第21天时成纤维细胞和肉芽组织数量持续增加，而经TGF-β1处理的伤口中增强的细胞流入在第7天后无法检测到。来自经PDGF-BB处理的伤口的巨噬细胞和成纤维细胞中免疫组织化学可检测到的细胞内TGF-β水平急剧增加。此外，PDGF-BB在体外诱导培养的正常大鼠肾成纤维细胞中TGF-β mRNA水平出现明显的、时间依赖性的刺激。结果表明，TGF-β可短暂地将成纤维细胞吸引到伤口中，并可能直接刺激胶原蛋白合成。相比之下，PDGF对伤口巨噬细胞和成纤维细胞是一种更强效的趋化剂，可能刺激这些细胞表达内源性生长因子，包括TGF-β，而TGF-β反过来又直接刺激新的胶原蛋白合成，并在更长的时间内持续增强伤口愈合。
