Interleukin-8 Induced Biology in Benign Prostatic Hyperplasia

良性前列腺增生症(BPH)是一种常见的年龄相关性疾病，以上皮和间质为典型 前列腺的增生和进行性增大。前列腺增生症与慢性炎症有关， 然而，具体的机制尚不清楚。我们已经报道了增生性BPH上皮 过度表达白介素8(IL-8)，这与肌成纤维细胞反应性间质显著相关 Tenascin表达改变的表型。IL-8是一种强大的趋化因子，可诱导许多 细胞类型刺激反应性基质/伤口修复机制。我们已经培育出了一只转基因小鼠 表达KC(小鼠IL-8的同源物)，并观察其增殖的上皮和间质表型 Tenascin-C和I型胶原原表达升高。我们的初步数据表明，反应性基质是 从局部组织固定的和循环的骨髓来源的CD34+祖细胞纤维细胞中招募。这是我们的 IL-8升高可激活和/或募集病灶处反应性基质祖细胞的假说 腺性良性前列腺增生症，这种增生性反应性间质进一步推动良性前列腺增生症、腺性和间质增生。 为了解决这一假设，提出了三个具体的目标：1.表征IL-8(KC)/CXCR2的作用 信号转导和Tenascin-C作为下游效应因子在诱导前列腺增生中的作用。2.确定 IL-8/CXCR2受体信号在反应性基质前体细胞募集中的作用3.瞄准目标 药物诱导基因表达解偶联IL-8(KC)/CXCR2信号在反应性基质细胞中的表达 从而减轻良性前列腺增生症中反应性间质和上皮增生的发生。一起， 这些研究将明确IL-8在招募反应性间质和诱导异型增生中的作用。 该项目的目的是提供概念验证和关键数据，以此为基础构建战略 支持临床试验的方法。这项工作的长期目标是开发一种新的治疗策略 靶向IL-8/CXCR2调控通路中用于治疗良性前列腺增生症的成分。

Benign prostatic hyperplasia (BPH) is a common age-associated disorder typified by epithelial and stromal hyperplasia and progressive enlargement of the prostate gland. BPH is associated with chronic inflammation, however specific mechanisms are unknown. We have reported that hyperplastic BPH epithelium overexpresses interleukin-8 (IL-8) and that this correlated significantly with a myofibroblast reactive stroma phenotype with altered expression of tenascin. IL-8 is a potent chemokine that induces chemotaxis of many cell types stimulates reactive stroma / wound repair mechanisms. We have generated a transgenic mouse expressing KC (a murine homolog of IL-8) and observe a hyperplastic epithelial and stromal phenotype with elevated tenascin-C and pro-collagen I expression. Our preliminary data suggests that reactive stroma is recruited from both local tissue-fixed and circulating marrow-derived CD34+ progenitor fibrocyte cells. It is our hypothesis that elevated IL-8 functions to activate and/or recruit reactive stroma progenitor cells at foci of glandular BPH and that this hyperplastic reactive stroma further drives BPH glandular and stromal hyperplasia. To address this hypothesis three Specific Aims are proposed: 1. To characterize the role of IL-8(KC) / CXCR2 signaling and tenascin-C, as a downstream effector, in the induction of prostate hyperplasia. 2. To determine the role of IL-8 / CXCR2 receptor signaling in the recruitment of reactive stroma progenitor cells. 3. To target IL-8(KC) / CXCR2 signaling in reactive stroma cells using drug-inducible gene expression to uncouple signaling and therefore attenuate the genesis of reactive stroma and epithelial hyperplasia in BPH. Together, these studies will pinpoint the role of IL-8 in recruiting reactive stroma and inducing the hyerplastic phenotype. The purpose of this project is to provide proof of concept and key data, from which to build a strategic approach to support clinical trials. The long-range goal of this work is to develop a novel therapeutic strategy that targets components of the IL-8 / CXCR2 regulatory pathway for the treatment of BPH.