Department of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, Pennsylvania, United States of America.
PLoS One. 2011 May 6;6(5):e18676. doi: 10.1371/journal.pone.0018676.
Wound healing is a highly dynamic process that requires signaling from the extracellular matrix to the fibroblasts for migration and proliferation, and closure of the wound. This rate of wound closure is impaired in diabetes, which may be due to the increased levels of the precursor for advanced glycation end products, 3-deoxyglucosone (3DG). Previous studies suggest a differential role for p38 mitogen-activated kinase (MAPK) during wound healing; whereby, p38 MAPK acts as a growth kinase during normal wound healing, but acts as a stress kinase during diabetic wound repair. Therefore, we investigated the signaling cross-talk by which p38 MAPK mediates wound healing in fibroblasts cultured on native collagen and 3DG-collagen.
METHODOLOGY/PRINCIPAL FINDINGS: Using human dermal fibroblasts cultured on 3DG-collagen as a model of diabetic wounds, we demonstrated that p38 MAPK can promote either cell growth or cell death, and this was dependent on the activation of AKT and ERK1/2. Wound closure on native collagen was dependent on p38 MAPK phosphorylation of AKT and ERK1/2. Furthermore, proliferation and collagen production in fibroblasts cultured on native collagen was dependent on p38 MAPK regulation of AKT and ERK1/2. In contrast, 3DG-collagen decreased fibroblast migration, proliferation, and collagen expression through ERK1/2 and AKT downregulation via p38 MAPK.
CONCLUSIONS/SIGNIFICANCE: Taken together, the present study shows that p38 MAPK is a key signaling molecule that plays a significantly opposite role during times of cellular growth and cellular stress, which may account for the differing rates of wound closure seen in diabetic populations.
伤口愈合是一个高度动态的过程，需要细胞外基质向成纤维细胞发出信号，以促进其迁移和增殖，并封闭伤口。糖尿病患者的伤口闭合速度受损，这可能是由于晚期糖基化终产物前体 3-脱氧葡萄糖酮（3DG）水平升高所致。先前的研究表明，p38 丝裂原活化蛋白激酶（MAPK）在伤口愈合过程中具有不同的作用；即在正常伤口愈合过程中，p38 MAPK 作为生长激酶发挥作用，但在糖尿病伤口修复过程中，p38 MAPK 作为应激激酶发挥作用。因此，我们研究了 p38 MAPK 通过何种信号转导途径在成纤维细胞培养于天然胶原和 3DG-胶原时介导伤口愈合。
方法/主要发现：我们使用培养于 3DG-胶原的人真皮成纤维细胞作为糖尿病伤口模型，证明 p38 MAPK 可以促进细胞生长或细胞死亡，这取决于 AKT 和 ERK1/2 的激活。天然胶原上的伤口闭合依赖于 p38 MAPK 对 AKT 和 ERK1/2 的磷酸化。此外，培养于天然胶原的成纤维细胞的增殖和胶原产生依赖于 p38 MAPK 对 AKT 和 ERK1/2 的调控。相比之下，3DG-胶原通过 p38 MAPK 下调 ERK1/2 和 AKT，减少成纤维细胞迁移、增殖和胶原表达。
结论/意义：综上所述，本研究表明 p38 MAPK 是一种关键的信号分子，在细胞生长和细胞应激时发挥着截然不同的作用，这可能是糖尿病患者伤口闭合速度不同的原因。
