Effect of NorLeu³-A(1-7) on scar formation over time after full-thickness incision injury in the rat

Previous studies have shown that the angiotensin peptide NorLeu ³-A(1-7) accelerates dermal healing and reduces scar formation. In this report, the effect of this peptide on scar formation is more fully delineated. The effect of surgical day, time after injury, and observer on the clinical appearance of the incision were determined. Clinical observations of incision site, including inflammation, opening of the injury, and appearance of scar, were conducted by two observers blinded to treatment (two observations per time point) twice weekly. Opening of the incision occurred in 35-40% of incisions early (days 4 and 7) after injury. Administration of NorLeu ³-A(1-7) at the time of injury reduced the incidence of opening at day 7 to approximately 20%. Further, the length of the wound opening was significantly reduced in the peptide-treated incisions at day 7. Starting on day 14 after injury, scar formation was evaluated. Up to 80-90% of control animals had observable scars starting on day 14. Thereafter, the scar remodeled with fewer incisions having visible scar on day 28. With administration of NorLeu³-A(1-7), significantly fewer incisions had observable scars starting on day 14 and throughout the study. As few as 20% of the incisions had observable scars on day 28. The histological appearance of the healing wound was also evaluated at weekly intervals starting on day 7 and continued until day 42. At day 7, the maximal number of fibroblasts at the wound site was observed. Thereafter, the number gradually reduced, reaching a plateau at day 28. The administration of peptide had no effect on fibroblast number at the incision site. A similar pattern was observed in the thickness of the epidermis with the resolution of the hyperplastic phase at day 21. Administration of the peptide significantly increased epidermal height at day 7. Blood vessel formation peaked on day 21 and 28 in control wounds and was further enhanced by peptide administration during the neovascularization phase. After day 28, blood vessel number was comparable between control and treated incisions. Collagen deposition and remodeling were increased by the administration of NorLeu ³-A(1-7) at the time of injury.