Background: 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.
Methods: 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.
Results: Early and late treatment regimens with the activin receptor-like kinase 5 inhibitor significantly reduced collagen deposition without impairing wound healing.
Conclusions: 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.
From Pfizer Worldwide Research and Development, Pfizer, Inc.
Received for publication October 25, 2010; accepted April 7, 2011.
Disclosure: The authors have no financial relationships to disclose. This work was supported by Pfizer, Inc.
Feng Bian, Ph.D.; Pfizer Worldwide Research and Development, Eastern Point Road, Groton, Conn. 06340, firstname.lastname@example.org
Deepak S. Lala, Ph.D.; Vitae Pharmaceuticals, 502 West Office Center Drive, Fort Washington, Penn. 19034, email@example.com