Groton, Conn. From Pfizer Worldwide Research and Development, Pfizer, Inc.
Plast Reconstr Surg. 2011 Nov;128(5):451e-459e. doi: 10.1097/PRS.0b013e31822b65c7.
Excessive dermal scarring is characterized by an overabundant deposition of extracellular matrix caused by fibrosis. The purpose of this study was to modify a rodent model of cutaneous healing for use in the development of compounds to minimize scarring, and to test the model with a small molecule inhibitor of transforming growth factor-β type I receptor, activin receptor-like kinase 5, because this class of inhibitors has been demonstrated to be effective in minimizing fibrosis in other organs.
The rodent model of cutaneous healing consists of uniform full-thickness incisional dermal wounds in rats. Wounds were allowed to heal by secondary intention, generally over a 14-day period. The usefulness of the model was tested by the application of an activin receptor-like kinase 5 inhibitor, CP-639180. Activin receptor-like kinase 5 inhibition antagonizes the transforming growth factor-β pathway, and was used to determine whether there was an effect on collagen deposition in wounds. The compound was applied once per day for 7 days starting at postwounding day 0 or 7 (early or late treatment regimens). Wounds were analyzed histologically for collagen deposition and biochemically for quantification of collagen changes.
Early and late treatment regimens with the activin receptor-like kinase 5 inhibitor significantly reduced collagen deposition without impairing wound healing.
Application of a small molecular inhibitor of activin receptor-like kinase 5 appears to significantly reduce collagen deposition in rat dermal wounds as reported here for the first time. Activin receptor-like kinase 5 inhibition may offer a novel approach to reducing proliferative scars in humans because collagen accumulation is a core event in scarring.
过度的皮肤瘢痕形成的特征是纤维化导致细胞外基质过度沉积。本研究的目的是修改一种用于开发最小化瘢痕形成化合物的皮肤愈合啮齿动物模型，并使用转化生长因子-β 型 I 受体小分子抑制剂激活素受体样激酶 5 来测试该模型，因为这一类抑制剂已被证明在其他器官中最小化纤维化是有效的。
皮肤愈合的啮齿动物模型由大鼠全层切口真皮伤口组成。伤口通过二期愈合，通常在 14 天内愈合。通过应用激活素受体样激酶 5 抑制剂 CP-639180 来测试模型的实用性。激活素受体样激酶 5 抑制作用拮抗转化生长因子-β 途径，用于确定其对伤口胶原沉积是否有影响。该化合物从创伤后第 0 天或第 7 天（早期或晚期治疗方案）开始，每天应用一次，持续 7 天。对伤口进行组织学胶原沉积分析和生物化学胶原变化定量分析。
激活素受体样激酶 5 抑制剂的早期和晚期治疗方案可显著减少胶原沉积，而不影响伤口愈合。
本文首次报道，应用激活素受体样激酶 5 的小分子抑制剂可显著减少大鼠皮肤伤口中的胶原沉积。激活素受体样激酶 5 抑制可能为减少人类增生性瘢痕提供一种新方法，因为胶原积累是瘢痕形成的核心事件。
