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

项目总结： 在美国，肥胖症和2型糖尿病的患病率正在以惊人的速度增长。 美国和世界各地。与2型糖尿病相关的最常见的后遗症之一是 伤口愈合使糖尿病患者容易患上糖尿病足溃疡和其他软组织感染。 在这些感染中，金黄色葡萄球菌是最常见的分离细菌种类，并被认为 以加重糖尿病导致的伤口愈合缺陷。而高血糖和外周血细胞减少 循环与糖尿病引起的伤口愈合缺陷有关，环境因素的作用 曝光率仍未被发掘。最近的研究表明，环境中暴露于持久性 有机污染物(POP)，包括遗留的有机氯(OC)杀虫剂，可能会导致2型糖尿病 这些化合物可能具有免疫调节作用，如改变巨噬细胞 脂肪因子的极化与脂肪细胞分泌。此外，持久性有机污染物，特别是基于有机碳农药的持久性有机污染物 在皮下脂肪组织中生物积聚，在那里它们可能会发挥局部作用来改变脂肪 组织微环境。我们目前的初步数据显示，我们接触到了流行的有机碳杀虫剂 代谢产物二氯二苯基二氯乙烯(DDE)和氧氯丹对巨噬细胞有相反的作用 吞噬活性。然而，当滴滴涕和环氧氯丹暴露在环境背景下时 相关混合物，有显著的混合物为基础的作用，增强吞噬活性在低 浓度增加，但吞噬活性随浓度增加而降低。因此，出现了这样的可能性 有机碳农药增加POPs暴露可能改变脂肪组织中巨噬细胞/脂肪细胞的相互作用 可以改变伤口愈合动力学的微环境。我们目前的假设是暴露在高度 流行的POPs、DDE、反式-橙花胺和氧氯丹将改变脂肪组织的微环境 导致巨噬细胞功能/可塑性改变，这可能对伤口愈合产生有害影响。这 假设将在以下具体目标进行检验：1.确定有机化合物农药持久性有机污染物暴露的影响 脂肪细胞/巨噬细胞串扰及其后续功能评价脂肪组织的变化 微环境。2.测定有机氯农药持久性有机污染物对金黄色葡萄球菌能力的影响 引起正常和肥胖/2型糖尿病小鼠的局部皮肤和软组织感染。这将是第一次 有机碳农药POPs暴露对脂肪细胞/巨噬细胞影响的研究 脂肪组织微环境中的串扰，强调伤口愈合中的变化。应该 POPs显著改变脂肪组织微环境和伤口愈合，这些化合物可能是 用作生物标记物，用于识别糖尿病足等慢性伤口风险增加的患者 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.