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

Abstract

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.

• Authors: Feng Bian, James Render, Xiao-Dan Ren, Christopher Chio, Kam Chan, Mark Boys, Deepak S Lala, David Pocalyko
• Journal: Plastic and reconstructive surgery (Plast Reconstr Surg) Vol. 128 Issue 5 Pg. 451e-459e (Nov 2011) ISSN: 1529-4242 [Electronic] United States
• PMID: 22030504 (Publication Type: Comparative Study, Journal Article)

Chemical References

• Receptors, Transforming Growth Factor beta
• Transforming Growth Factor beta
• Collagen
• Protein Serine-Threonine Kinases
• Receptor, Transforming Growth Factor-beta Type I
• TGFBR1 protein, human
• Tgfbr1 protein, rat

Topics

• Animals
• Cell Proliferation (drug effects)
• Cicatrix (prevention & control)
• Collagen (drug effects, 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, pharmacology)
• Wound Healing (drug effects, physiology)
• Wounds and Injuries (drug therapy, surgery)