An activin receptor-like kinase 5 inhibitor reduces collagen deposition in a rat dermal incision wound healing model

• Published in: Plastic and reconstructive surgery (1963) Vol. 128; no. 5; p. 451e
• Main Authors: Bian, Feng, Render, James, Ren, Xiao-Dan, Chio, Christopher, Chan, Kam, Boys, Mark, Lala, Deepak S, Pocalyko, David
• Format: Journal Article
• Language: English
• Published: United States 01.11.2011
• Subjects: Animals; Cell Proliferation - drug effects; Cicatrix - prevention & control; Collagen - drug effects; Collagen - metabolism; Dermatologic Surgical Procedures; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Immunohistochemistry; Male; Protein-Serine-Threonine Kinases - antagonists & inhibitors; Random Allocation; Rats; Rats, Sprague-Dawley; Real-Time Polymerase Chain Reaction; Receptor, Transforming Growth Factor-beta Type I; Receptors, Transforming Growth Factor beta - antagonists & inhibitors; Reference Values; Skin - drug effects; Transforming Growth Factor beta - antagonists & inhibitors; Transforming Growth Factor beta - pharmacology; Wound Healing - drug effects; Wound Healing - physiology; Wounds and Injuries - drug therapy; Wounds and Injuries - surgery
• ISSN: 1529-4242
• 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.