Cytokine induced abnormal wound healing

描述(由申请人提供)伤口愈合紊乱是一个重要的 导致烧伤后过度愈合的临床问题 增生性疤痕和愈合不充分导致慢性伤口。我们 而其他人则记录了相对浓度的显著变化 在这些临床情况下有三种特殊的细胞因子。这些都在转变 生长因子-β、转化生长因子-β、肿瘤坏死因子-α、肿瘤坏死因子-α和 白介素8、白介素8。这些调解人的出席人数增加了。 异常愈合的伤口，并导致填充细胞的变化 伤口和细胞所在的基质环境。例如，我们 显示烧伤疤痕自分泌和旁分泌转化生长因子-β增加 诱导真皮纤维持续合成过量的I型和III型胶原 和合同矩阵以更高的速度。肿瘤坏死因子-α上调基质金属蛋白酶-2和-9， 两种与伤口慢性化有关的蛋白酶。IL-8水平下降 角质形成细胞的复制和成纤维细胞收缩基质的能力。这个 这项提案的目标是确定这些调解人通过哪些机制 调节皮肤细胞和基质之间的相互作用。 实验策略基于两个主要目标。第一，细胞因子诱导 细胞骨架的含量、合成、磷酸化和组织的变化 蛋白质；α-平滑肌肌动蛋白、Talin、vinculin和Alpha2Beta1整合素的反应 对细胞因子的治疗将用生化和分子表征 生物学方法。将特别注意以下方面的作用 Rho/GTP酶作为成纤维细胞重组的关键信号系统 矩阵。第二，这些细胞因子对细胞的诱导、合成和释放的影响 将测定基质金属蛋白水解酶的活性。我们将分析 基质金属蛋白酶-2和基质金属蛋白酶-9的启动子区对细胞因子和 单个基质蛋白作为其调节的特定机制。 最后，细胞因子介导的MMPs对胶原的调节作用 收缩将被记录在案。这些研究将增加我们对 关于细胞因子诱导的伤口愈合异常的机制。这个 该项目的长期目标是揭示以下关键机制 肥厚性瘢痕可能会改善治疗效果，也许， 预防策略。

DESCRIPTION (provided by applicant) Disordered wound healing is a significant clinical problem resulting in both the exaggerated healing of post-bum hypertrophic scar and the inadequate healing that results in chronic wounds. We and others have documented significant changes in the relative concentration of three particular cytokines in these clinical situations. These are transforming growth factor-beta, TGF-beta, tumor necrosis factor-alpha, TNF-alpha and interleukin-8, IL-8. These mediators are present in increased amounts in abnormally healing wounds and induce changes in the cells that populate the wounds and the matrix environment in which the cells reside. For example, we have shown increased burn scar production of autocrine and paracrine TGF-beta induces dermal fibrob lasts to synthesize excessive Types I and III collagen and contract matrix at an increased rate. TNF-alpha up-regulates both MMP-2 and -9, two proteases which have been linked to wound chronicity. IL-8 decreases keratinocyte replication and the ability of fibroblasts to contract matrix. The Goal of this proposal is to determine the mechanisms whereby these mediators regulate the interactions between skin cells and matrix. The experimental strategy is based on two primary aims. First, cytokine induced changes in content, synthesis, phosphorylation and organization of cytoskeletal proteins; alpha-smooth muscle actin, talin, vinculin, and alpha2Beta1 integrin in response to cytokine treatment will be characterized using biochemical and molecular biologic approaches. Particular attention will be directed to the role of Rho/GTPases as a critical signaling system in fibroblast reorganization of matrix. Second, the effects of these cytokines on the induction, synthesis and activation of matrix metalloproteases will be determined. We will analyze the promoter regions of MMP-2 and -9 for response elements to cytokines and individual matrix proteins as a specific mechanism for their regulation. Finally, the effects of cytokine-mediated modulation of MMPs on collagen contraction will be documented. These studies will increase our understanding for the mechanism of cytokine-induced abnormalities of wound healing. The long-term goal of this project is to uncover key mechanisms underlying hypertrophic scarring that may lead to improved therapeutic and, perhaps, preventive strategies.