Bell R R, Dunstan R W, Khan N K
Drug Safety Research & Development, Pfizer Global Research & Development, Michigan Laboratories, 2800 Plymouth Road, Ann Arbor, MI 48105, U.S.A.
Br J Dermatol. 2007 Oct;157(4):656-61. doi: 10.1111/j.1365-2133.2007.08096.x. Epub 2007 Aug 2.
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.
This study evaluated whether inhibition of iNOS affects incisional skin wound healing.
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.
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.
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.
一氧化氮（NO）合酶（NOS）的诱导型同工酶（iNOS）可被炎症介质和/或其他病理应激上调，产生高水平、持续的NO。累积数据表明NO在皮肤伤口愈合调节中发挥作用，尽管尚不清楚iNOS以及可能的内皮型NOS（eNOS）产生的NO在多大程度上促进了该愈合过程。由于目前对iNOS在伤口愈合中的作用缺乏了解，以及缺乏iNOS抑制剂SC - 842的伤口愈合数据，因此进行了这项体内研究，以探讨SC - 842在干扰伤口愈合方面的可能作用。
本研究评估抑制iNOS是否会影响切开皮肤伤口的愈合。
在无毛SKH - 1小鼠中使用皮肤全层缝合切开伤口模型，通过比较iNOS抑制剂SC - 842在不同剂量下的体内作用来评估iNOS在伤口愈合过程中的作用，这些剂量可导致对iNOS的选择性抑制以及非选择性NOS抑制（表现为血压升高导致eNOS和/或神经元型NOS抑制）。地塞米松用作阳性对照。
通过拉伸强度和组织学评估，在受伤后第28天，SC - 842处理组和赋形剂处理组动物的伤口愈合情况没有差异。与赋形剂处理组动物相比，中、高剂量处理组动物伤口在受伤后第14天的拉伸强度有所降低，但这种差异很小，且与赋形剂处理对照组的组织学差异无关。
这些数据表明，通过伤口拉伸强度和组织学在28天内评估，抑制iNOS不会对SKH - 1小鼠切开伤口的愈合产生不利影响。
