Philipp Katrin, Riedel Frank, Sauerbier Michael, Hörmann Karl, Germann Günter
Department of Plastic, Reconstructive and Hand Surgery, Burn Center, BG, Trauma Center, Plastic and Hand Surgery, The University of Heidelberg, Ludwig-Gutt-Strasse 13, D-67071 Ludwigshafen, Germany.
Int J Mol Med. 2004 Oct;14(4):589-93.
The pathology of chronic dermal ulcers is characterized by excessive proteolytic activity which degrades extracellular matrix (required for cell migration) and growth factors and their receptors. The transforming growth factor-beta (TGF-beta) has been identified as an important component of wound healing. Recent developments in molecular therapy offer exciting prospects for the modulation of wound healing, specifically those targeting TGF-beta. We investigated expression of angiogenic bFGF and VEGF, and collagenases MMP-2 and MMP-9 in tissue samples from chronic dermal wounds by immunohistochemistry. The effect of TGF-beta targeting using antisense oligonucleotides on the expression of these factors was analysed by ELISA in human keratinocytes. Immunohistochemical investigation demonstrated a decreased expression of bFGF and VEGF protein, and an increased expression of MMP-2 and MMP-9 in tissue samples from chronic dermal wounds compared to normal human skin. Antisense TGF-beta oligonucleotide treatment down-regulated collagenase secretion activity and up-regulated VEGF secretion in vitro. Therefore, TGF-beta antisense oligonucleotide technology may be a potential therapeutic option for the inhibition of proteolytic tissue destruction, and stimulation of angiogenesis in chronic wounds. Improving basic knowledge and pharmaceutical intervention in this area ultimately may help clinicians to identify and proactively intervene in an effort to prevent normal wounds from becoming chronic.
慢性皮肤溃疡的病理学特征是蛋白水解活性过高，这会降解细胞外基质（细胞迁移所需）、生长因子及其受体。转化生长因子-β（TGF-β）已被确定为伤口愈合的重要组成部分。分子治疗的最新进展为调节伤口愈合带来了令人兴奋的前景，特别是那些针对TGF-β的治疗。我们通过免疫组织化学研究了慢性皮肤伤口组织样本中血管生成性碱性成纤维细胞生长因子（bFGF）和血管内皮生长因子（VEGF）以及胶原酶MMP-2和MMP-9的表达。使用反义寡核苷酸靶向TGF-β对这些因子表达的影响通过酶联免疫吸附测定法（ELISA）在人角质形成细胞中进行分析。免疫组织化学研究表明，与正常人类皮肤相比，慢性皮肤伤口组织样本中bFGF和VEGF蛋白表达降低，而MMP-2和MMP-9表达增加。反义TGF-β寡核苷酸处理在体外下调了胶原酶分泌活性并上调了VEGF分泌。因此，TGF-β反义寡核苷酸技术可能是抑制慢性伤口中蛋白水解性组织破坏和刺激血管生成的一种潜在治疗选择。提高该领域的基础知识和药物干预最终可能有助于临床医生识别并积极干预，以防止正常伤口变为慢性伤口。
