Organochlorine compound-induced alterations in adipocyte/macrophage crosstalk and effects on wound healing

项目摘要： 肥胖和2型糖尿病的患病率正在以惊人的速度增长， 国家和全世界。与2型糖尿病相关的最普遍的后遗症之一是 使糖尿病患者易患糖尿病足溃疡和其它软组织感染的伤口愈合。 在这些感染中，金黄色葡萄球菌是最常见的分离细菌种类， 以加剧糖尿病引起的伤口愈合缺陷。而高血糖和外周血 循环与糖尿病引起的伤口愈合缺陷有关，环境因素的作用 暴露的情况仍未得到探索。最近的研究表明， 有机污染物（POP），包括遗留的有机氯（OC）农药，可能会促进2型糖尿病 这些化合物可能具有免疫调节作用，例如改变巨噬细胞 极化和脂肪细胞分泌脂肪因子。此外，持久性有机污染物，特别是有机氯农药类持久性有机污染物 在皮下脂肪组织中生物累积，在那里它们可以发挥局部作用以改变脂肪 组织微环境我们目前的初步数据显示， 代谢产物二氯二苯二氯乙烯（DDE）和氧氯噻嗪对巨噬细胞有相反的作用 吞噬活性然而，当接触DDE和氧氯噻嗪时， 在相关混合物中，存在显著的基于混合物的效果，其在低浓度下增强吞噬活性。 浓度，但随着浓度的增加而降低吞噬活性。因此， OC农药增加的持久性有机污染物暴露可能会改变脂肪组织中巨噬细胞/脂肪细胞的相互作用 微环境，可以改变伤口愈合动力学。我们目前的假设是， 流行的持久性有机污染物，DDE，反式-九氯，和氧氯噻嗪将改变脂肪组织微环境 导致改变的巨噬细胞功能/可塑性，这可能对伤口愈合具有有害影响。这 假设将在以下具体目标进行测试：1。确定OC农药持久性有机污染物暴露的影响 对脂肪细胞/巨噬细胞串扰和后续功能的影响，以评估脂肪组织中的变化 微环境2.确定暴露于OC农药持久性有机污染物对S.金黄色 在正常和肥胖/2型糖尿病小鼠中引起局部皮肤和软组织感染。这将是第一 就我们所知，研究OC杀虫剂持久性有机污染物暴露对脂肪细胞/巨噬细胞的影响 脂肪组织微环境中的串扰，重点是伤口愈合的改变。应该 持久性有机污染物显着改变脂肪组织微环境和伤口愈合，这些化合物可能是 用作生物标志物，以识别慢性伤口（如糖尿病足）风险增加的患者 溃疡和其他软组织感染。

Project Summary: The prevalence of obesity and type 2 diabetes are increasing at an alarming rate both within the United States and worldwide. One of the most prevalent sequalae associated with type 2 diabetes is alterations in wound healing which predispose the diabetic patient to diabetic foot ulceration and other soft tissue infections. Within these infections, Staphylococcus aureus is the most commonly isolated bacterial species and is thought to exacerbate diabetes-induced deficits in wound healing. While hyperglycemia and decreased peripheral circulation have been implicated in diabetes-induced deficits in wound healing, the role of environmental exposures remains unexplored. Recent studies have demonstrated environmental exposures to persistent organic pollutants (POPs), including legacy organochlorine (OC) pesticides, may promote type 2 diabetes pathogenesis and that these compounds may have immunomodulatory effects such as altering macrophage polarization and adipocyte secretion of adipokines. Additionally, POPs and especially OC pesticide based POPs bioaccumulate in the subcutaneous adipose tissue where they may exert a localized effect to alter the adipose tissue microenvironment. Our current preliminary data demonstrate exposure to the prevalent OC pesticide metabolites dichlorodiphenyldichloroethylene (DDE) and oxychlordane have opposing effects on macrophage phagocytic activity. However, when DDE and oxychlordane exposure is in the context of an environmentally relevant mixture, there is a significant mixture based effect which potentiates phagocytic activity at low concentrations but decreases phagocytic activity with increasing concentrations. Therefore, the possibility arises that OC pesticide increased POPs exposure may alter macrophage/adipocyte cross-talk in the adipose tissue microenvironment which could alter wound healing kinetics. Our current hypothesis is exposure to the highly prevalent POPs, DDE, trans-nonachlor, and oxychlordane will change the adipose tissue microenvironment leading to altered macrophage function/plasticity which may have a deleterious effect on wound healing. This hypothesis will be tested in the following specific aims: 1. Determine the effects of OC pesticide POPs exposure on adipocyte/macrophage cross-talk and subsequent function to evaluate alterations in adipose tissue microenvironment. 2. Determine the effects of exposure to OC pesticide POPs on the ability of S. aureus to cause localized skin and soft tissue infection in normal and obese/type 2 diabetic mice. This will be the first study to our knowledge to examine the effects of OC pesticide POPs exposure on the adipocyte/macrophage cross-talk in the adipose tissue microenvironment with an emphasis on alterations in wound healing. Should POPs significantly alter the adipose tissue microenvironment and wound healing, these compounds could be used as biomarkers to identify patients which are at increased risk for chronic wounds such as diabetic foot ulcers and other soft tissue infections.