纳曲酮对OGF-OGFr途径的选择性阻断可加速成纤维细胞增殖和伤口愈合。,Experimental Biology and Medicine

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纳曲酮对OGF-OGFr途径的选择性阻断可加速成纤维细胞增殖和伤口愈合。
Experimental Biology and Medicine ( IF 2.8 ) Pub Date : 2014-07-18 , DOI: 10.1177/1535370214543061
Jessica A Immonen ₁ , Ian S Zagon ₁ , Patricia J McLaughlin ₂

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纳曲酮（NTX）是一种阿片受体拮抗剂，可作用于经典和非经典的阿片受体，包括阿片生长因子受体（OGFr）。1型和2型糖尿病以及正常啮齿动物的动物模型显示，局部NTX可以提高角膜上皮和全层皮肤伤口的愈合率。尚不了解这种普通阿片样物质拮抗剂对生长的机制，特别是所涉及的特异性受体途径。建立了使用NIH 3T3成纤维细胞和原代大鼠耳状成纤维细胞的组织培养研究，以评估阿片受体拮抗剂治疗后的生长。用CTOP，纳曲酮或纳美芬，分别对mu，delta和kappa阿片受体的选择性拮抗剂处理细胞不会加速细胞复制。添加经典阿片受体肽DAMGO，DPDPE或EKC不会改变细胞生长，表明经典阿片受体不参与皮肤伤口愈合。然而，NTX（10（-6）M）在96小时内增加了培养中NIH 3T3成纤维细胞的生长，并且特定的配体OGF降低了细胞的生长，支持OGF-OGFr轴在体内具有声色活性并组成性表达。成纤维细胞，皮肤肉芽组织中的主要细胞类型。OGFr siRNA转染NIH 3T3细胞会降低受体蛋白；随后用NTX进行的治疗并未加速细胞增殖。这些数据表明，在体外以及在耳廓成纤维细胞的原代培养中，OGFr途径的阻断可增强成纤维细胞的增殖，提示NTX对生长的影响是通过OGF-OGFr轴介导的。最后，将经典阿片受体拮抗剂和NTX局部应用于1型糖尿病大鼠的皮肤伤口。只有NTX可以加速伤口闭合。这些研究表明，NTX增强糖尿病和非糖尿病患者皮肤伤口闭合的作用机理是OGF-OGFr调节轴的特异性阻断。

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Selective blockade of the OGF-OGFr pathway by naltrexone accelerates fibroblast proliferation and wound healing.

Naltrexone (NTX) is an opioid receptor antagonist that acts at classical and non-classical opioid receptors including the opioid growth factor receptor (OGFr). Animal models of type 1 and type 2 diabetes, as well as normal rodents, have shown that topical NTX enhances the healing rates of corneal epithelium and full-thickness cutaneous wounds. The mechanism of this general opioid antagonist on growth, and in particular the specific receptor pathway involved, is not understood. Tissue culture studies using NIH 3T3 fibroblasts and primary rat auricular fibroblasts were established to evaluate growth following opioid receptor antagonist treatment. Treatment of cells with CTOP, naltrindole, or nalmefene, selective antagonists for mu, delta, and kappa opioid receptors, respectively, did not accelerate cell replication. Addition of the classical opioid receptor peptides DAMGO, DPDPE, or EKC did not alter cell growth, suggesting that the classical opioid receptors were not involved in cutaneous wound healing. However, NTX (10(-6) M) increased the growth of NIH 3T3 fibroblasts in culture over a 96-h period, and the specific ligand OGF decreased cell growth, supporting that the OGF-OGFr axis is tonically active and constitutively expressed in fibroblasts, the primary cell type in granulation tissue of the skin. Transfection of NIH 3T3 cells with OGFr siRNA reduced receptor protein; subsequent treatment with NTX did not accelerate cell proliferation. These data indicate that blockade of the OGFr pathway enhances proliferation of fibroblasts in vitro, and in a primary culture of auricular fibroblasts, suggesting that the effect of NTX on growth is mediated through the OGF-OGFr axis. Finally, antagonists for classical opioid receptors as well as NTX were topically applied to cutaneous wounds in type 1 diabetic rats; only NTX accelerated wound closure. These studies indicate that the mechanistic pathway underlying the effects of NTX to enhance cutaneous wound closure in diabetic and nondiabetic subjects is specific blockade of the OGF-OGFr regulatory axis.

更新日期：2019-11-01

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