Wound contraction is attenuated by fasudil inhibition of Rho-associated kinase.
BACKGROUND
Dermal scarring and scar contracture result in restriction of movement. There are no effective drugs to prevent scarring. RhoA and Rho-associated kinase have emerged as regulators of fibrosis and contracture. Fasudil, a Rho-associated kinase inhibitor, has been demonstrated to have antifibrotic effects in models of liver, renal, and cardiac fibrosis. The role of fasudil in preventing dermal scarring and contractures has not been studied. The authors used a rat model of dermal wound healing to assess the effects of fasudil with regard to the prevention of scarring.


METHODS
Human scar tissue and surrounding normal skin were immunostained for RhoA and Rho-associated kinase. Full-thickness wounds were created on Wistar-Han rats, and fasudil (30 mg/kg/day) or saline was continuously delivered subcutaneously. Wound contraction was measured by gravitational planimetry. After 21 days, tissue was harvested for Masson's trichrome, hematoxylin and eosin, Ki-67, and CD31 staining. Fibroblast-populated collagen lattices were used to assess the mechanistic effects of fasudil on contractility. Myofibroblast formation was assessed in the presence of fasudil.


RESULTS
Human scar tissue in the remodeling phase of repair showed increased expression of RhoA and Rho-associated kinase in scar tissue compared with surrounding normal tissue. Fasudil inhibited wound contraction as compared with controls. Hematoxylin and eosin and Masson's trichrome were similar between groups. Fasudil did not alter angiogenesis or proliferation. Fasudil inhibited fibroblast contractility and myofibroblast formation in vitro.


CONCLUSIONS
There is growing evidence that the RhoA/Rho-associated kinase pathway plays an important role in wound healing and scar contracture. The authors present data showing that inhibition of Rho-associated kinase hinders fibroblast contractility and may be beneficial in preventing scar contracture.
Durham, N.C. From the Division of Plastic and Reconstructive Surgery, Department of Surgery, and the Department of Pathology, Duke University Medical Center.
Jennifer E
JE
Bond
George
G
Kokosis
Licheng
L
Ren
M Angelica
MA
Selim
Andrew
A
Bergeron
Howard
H
Levinson
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D000328:Adult; D000818:Animals; D001707:Biopsy, Needle; D015153:Blotting, Western; D002921:Cicatrix / Q000188:drug therapy / Q000517:prevention & control*; D004195:Disease Models, Animal; D005347:Fibroblasts / Q000187:drug effects; D006801:Humans; D007150:Immunohistochemistry; D007279:Injections, Subcutaneous; D008875:Middle Aged; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage*; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D012867:Skin / Q000166:cytology / Q000187:drug effects*; D014945:Wound Healing / Q000187:drug effects* / Q000502:physiology; D014947:Wounds and Injuries / Q000188:drug therapy / Q000473:pathology; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
D047428:Protein Kinase Inhibitors; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D054460:rho-Associated Kinases; C049347:fasudil