Department of Surgery, School of Medicine, Stanford University, Stanford, California 94305, USA.
Wound Repair Regen. 2011 Jan-Feb;19(1):49-58. doi: 10.1111/j.1524-475X.2010.00643.x. Epub 2010 Dec 6.
Although numerous factors are implicated in skin fibrosis, the exact pathophysiology of hypertrophic scarring remains unknown. We recently demonstrated that mechanical force initiates hypertrophic scar formation in a murine model, potentially enhancing cellular survival through Akt. Here, we specifically examined Akt-mediated mechanotransduction in fibroblasts using both strain culture systems and our murine scar model. In vitro, static strain increased fibroblast motility, an effect blocked by wortmannin (a phosphoinositide-3-kinase/Akt inhibitor). We also demonstrated that high-frequency cyclic strain was more effective at inducing Akt phosphorylation than low frequency or static strain. In vivo, Akt phosphorylation was induced by mechanical loading of dermal fibroblasts in both unwounded and wounded murine skin. Mechanically loaded scars also exhibited strong expression of α-smooth muscle actin, a putative marker of pathologic scar formation. In vivo inhibition of Akt increased apoptosis but did not significantly abrogate hypertrophic scar development. These data suggest that although Akt signaling is activated in fibroblasts during mechanical loading of skin, this is not the critical pathway in hypertrophic scar formation. Future studies are needed to fully elucidate the critical mechanotransduction components and pathways which activate skin fibrosis.
虽然有许多因素与皮肤纤维化有关，但肥厚性瘢痕形成的确切病理生理学仍不清楚。我们最近的研究表明，机械力在小鼠模型中引发了肥厚性瘢痕的形成，可能通过 Akt 增强了细胞的存活。在这里，我们使用应变培养系统和我们的小鼠瘢痕模型，专门研究了 Akt 介导的成纤维细胞的力学转导。在体外，静态应变增加了成纤维细胞的迁移能力，而渥曼青霉素（一种磷酸肌醇-3-激酶/Akt 抑制剂）可以阻断这种作用。我们还证明，高频循环应变比低频或静态应变更有效地诱导 Akt 磷酸化。在体内，未受伤和受伤的小鼠皮肤中的真皮成纤维细胞受到机械加载时，Akt 磷酸化被诱导。机械加载的瘢痕也表现出α-平滑肌肌动蛋白的强烈表达，这是病理性瘢痕形成的一个假定标志物。在体内抑制 Akt 增加了细胞凋亡，但并没有显著阻止肥厚性瘢痕的形成。这些数据表明，尽管在皮肤的机械加载过程中成纤维细胞中 Akt 信号被激活，但这不是肥厚性瘢痕形成的关键途径。需要进一步的研究来阐明激活皮肤纤维化的关键力学转导成分和途径。
