Skin wound healing in the SKH-1 female mouse following inducible nitric oxide synthase inhibition.
BACKGROUND
The inducible isoform of the nitric oxide (NO) synthase (NOS) enzyme (iNOS) is upregulated by inflammatory mediators and/or other pathological stresses, generating high, sustained levels of NO. Cumulative data suggest a role for NO in the regulation of skin wound healing, although it is not clear to what extent NO generated by iNOS, and possibly endothelial NOS (eNOS), contribute to that healing process. Because of the current lack of understanding regarding the contribution of iNOS in wound healing, as well as the lack of wound healing data available for SC-842, an iNOS inhibitor, this in vivo study was conducted to investigate the possible role of SC-842 in interfering with wound healing.


OBJECTIVE
This study evaluated whether inhibition of iNOS affects incisional skin wound healing.


METHODS
Using a cutaneous full-thickness, sutured, incisional wound model in hairless SKH-1 mice, the role of iNOS in the wound healing process was evaluated by comparing in vivo effects of the iNOS inhibitor, SC-842, at various doses that result in selective inhibition of iNOS as well as nonselective NOS inhibition (as evidenced by elevated blood pressure resulting in inhibition of eNOS and/or neuronal NOS). Dexamethasone was used as a positive control.


RESULTS
There were no differences in wound healing at day 28 postwounding, as evaluated by tensile strength and histology, between SC-842- and vehicle-treated animals. A decrease in tensile strength was noted at day 14 postwounding in wounds from the mid- and high-dose-treated animals as compared with vehicle-treated animals, but this difference was slight and was not associated with histological differences from vehicle-treated controls.


CONCLUSIONS
These data indicate that iNOS inhibition does not adversely affect the healing of incisional wounds in SKH-1 mice as assessed over 28 days by wound tensile strength and histology.
Drug Safety Research & Development, Pfizer Global Research & Development, Michigan Laboratories, 2800 Plymouth Road, Ann Arbor, MI 48105, U.S.A. rosonald.r.bell@pfizer.com
R R
RR
Bell
R W
RW
Dunstan
N K
NK
Khan
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D051379:Mice; D008815:Mice, Inbred Strains; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors / Q000502:physiology*; D012867:Skin / Q000187:drug effects / Q000293:injuries* / Q000473:pathology; D012879:Skin Physiological Phenomena / Q000187:drug effects*; D013718:Tensile Strength; D014945:Wound Healing / Q000187:drug effects / Q000502:physiology*
D004791:Enzyme Inhibitors; D052247:Nitric Oxide Synthase Type II