Prostaglandin E2 Actions and Enhanced Susceptibility to Skin Infection in Diabetic Mice

前列腺素 E2 的作用和糖尿病小鼠皮肤感染的易感性增强

基本信息

批准号：
10337275
负责人：
C. Henrique Serezani
金额：
$ 50.72万
依托单位：
VANDERBILT UNIVERSITY MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-04-01 至 2024-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10337275
关键词：
Abscess Address Adenosine Monophosphate Antibiotics Antimicrobial Resistance Biological Response Modifiers Cells Chronic Clinical Containment Cyclic AMP Data Diabetes Mellitus Diabetic mouse Dinoprostone Disease Event Extravasation FDA approved Failure Generations Glucose Homeostasis Host Defense Human Hyperglycemia Immune Immune response Immunosuppression Impairment Individual Infection Infectious Skin Diseases Inflammation Inflammation Mediators Inflammatory Inflammatory Response Ingestion Insulin-Dependent Diabetes Mellitus Integration Host Factors Knowledge Lesion Misoprostol Modeling Molecular Mus Necrosis Non-Insulin-Dependent Diabetes Mellitus Ointments Outcome PTPNS1 gene Patients Periodicity Persons Phagocytes Predisposition Prevalence Production Prostaglandins Reporter Resolution Role Scientist Second Messenger Systems Secondary to Site Skin Staphylococcus aureus Structure Systemic infection Techniques Testing Tissues Transgenic Mice Transgenic Organisms Translating Vulnerable Populations analog antimicrobial base improved in vivo in vivo imaging inhibitor intravital microscopy lipid mediator macrophage mass spectrometric imaging methicillin resistant Staphylococcus aureus microbial microscopic imaging migration neutrophil non-diabetic novel therapeutics pathogen phenome prevent receptor repaired response skin damage theories tissue injury tissue repair wound healing

Abscess Address Adenosine Monophosphate Antibiotics Antimicrobial Resistance Biological Response Modifiers Cells Chronic Clinical Containment Cyclic AMP Data Diabetes Mellitus Diabetic mouse Dinoprostone Disease Event Extravasation FDA approved Failure Generations Glucose Homeostasis Host Defense Human Hyperglycemia Immune Immune response Immunosuppression Impairment Individual Infection Infectious Skin Diseases Inflammation Inflammation Mediators Inflammatory Inflammatory Response Ingestion Insulin-Dependent Diabetes Mellitus Integration Host Factors Knowledge Lesion Misoprostol Modeling Molecular Mus Necrosis Non-Insulin-Dependent Diabetes Mellitus Ointments Outcome PTPNS1 gene Patients Periodicity Persons Phagocytes Predisposition Prevalence Production Prostaglandins Reporter Resolution Role Scientist Second Messenger Systems Secondary to Site Skin Staphylococcus aureus Structure Systemic infection Techniques Testing Tissues Transgenic Mice Transgenic Organisms Translating Vulnerable Populations analog antimicrobial base improved in vivo in vivo imaging inhibitor intravital microscopy lipid mediator macrophage mass spectrometric imaging methicillin resistant Staphylococcus aureus microbial microscopic imaging migration neutrophil non-diabetic novel therapeutics pathogen phenome prevent receptor repaired response skin damage theories tissue injury tissue repair wound healing

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项目摘要

Summary Infections caused by Staphylococcus aureus are more frequent and severe in people with both type 1 diabetes (T1D) and T2D than in healthy individuals. For over a century, it has been suggested that phagocytes from people with diabetes show poor antimicrobial functions, which created the paradigm that diabetes leads to immunosuppression. However, hyperglycemia also drives an excessive production of inflammatory mediators by immune cells. Here, we will take our current knowledge in host defense and diabetes in a different direction. We speculated that increased susceptibility to infection is due to an uncontrolled localized inflammatory response that causes skin damage and prevents bacterial elimination. We recently showed that S. aureus skin infection in diabetic mice was accompanied by unrestrained neutrophil migration to the site of infection, increased the production of inflammatory mediators, poor abscess formation (a structure that prevents spread to deeper tissues and systemic infection) and impaired bacterial clearance. We also showed inadequate production of the pleiotropic lipid mediator prostaglandin E2 (PGE2) in the skin of infected diabetic mice and a topical ointment containing misoprostol (an FDA-approved PGE analog) restored bacterial clearance during diabetes. Our preliminary data reveal low PGE2 production could be due to a reduced capacity to phagocytes to ingest and clear dead cells (efferocytosis), leading to secondary necrosis, leakage of endogenous inflammatory mediators, tissue injury and poor host defense. We are hypothesizing that deficient efferocytosis during MRSA skin infection in diabetic mice is responsible for low PGE2 production, which increases inflammation-associated tissue damage and prevents wound healing to ultimately enhance susceptibility to non-healing skin infections. We will utilize transgenic mice producing constitutively PGE2 and fluorescent phagocytes, along with state-of-the-art techniques, including imaging mass spectrometry (IMS), in vivo imaging (IVIS) and intravital microscopy imaging (IVM) to unveil the role of PGE2 levels, the E prostanoid receptors and downstream effectors in tissue repair during skin infection in people and mice with diabetes (Aim 1). Next, we are postulating that misoprostol improves wound healing in the infected skin by increasing the production of actions of the second messenger cyclic adenosine monophosphate (cAMP) downstream effectors involved in misoprostol-improved host defense in diabetic mice (Aim 2). In the Aim 3, we will study whether the failure of a repair mechanism involved in the elimination of dead cells (efferocytosis) leads to deficient PGE2 production and generation of inflammatory mediators, causing tissue injury in the infected skin of diabetic mice. Our project could rapidly translate into clinical use to improve the treatment of skin infection in patients with diabetes. With antimicrobial resistance and increasing prevalence of diabetes worldwide, there is a compelling need for safe, inexpensive, non-antibiotic, and host-centered approaches to prevent and treat infections.

概括两种型糖尿病患者，由金黄色葡萄球菌引起的感染更加频繁和严重（T1D）和T2D比健康个体。一个多世纪以来，有人提出了来自糖尿病患者表现出较差的抗菌功能，这会产生糖尿病导致的范式免疫抑制。但是，高血糖还可以推动炎症介质的过量产生通过免疫细胞。在这里，我们将以不同的方向将目前的宿主防御和糖尿病知识纳入。我们推测，对感染的敏感性增加是由于不受控制的局部炎症反应引起的这会导致皮肤损伤并防止细菌消除。我们最近表明，金黄色葡萄球菌皮肤感染糖尿病小鼠伴随着无情的中性粒细胞迁移到感染部位，增加了炎症介质的产生，脓肿的形成不佳（这种结构可防止扩散到更深的组织和全身感染）和细菌清除受损。我们还表明生产不足受感染的糖尿病小鼠皮肤中的多效脂质介体Prostaglandin E2（PGE2）含有米索前列醇（FDA批准的PGE类似物）在糖尿病期间恢复了细菌清除率。我们的初步数据显示，PGE2的产生较低可能是由于吞噬吞噬的能力降低，并且透明死细胞（胚细胞增多症），导致继发性坏死，内源性炎症介质的泄漏，组织损伤和宿主防御差。我们假设MRSA皮肤感染期间缺乏肿瘤病在糖尿病小鼠中，PGE2的产生负责，这会增加与炎症相关的组织损伤并防止伤口愈合，最终增强对非愈合皮肤感染的敏感性。我们将利用产生组成性PGE2和荧光吞噬细胞的转基因小鼠以及最新的技术，包括成像质谱法（IMS），体内成像（IVI）和内内内显微镜成像（IVM）揭示PGE2水平的作用，E前列腺素受体和下游效应子在组织修复中患有糖尿病的人和小鼠皮肤感染期间（AIM 1）。接下来，我们假设米索前列醇通过增加第二使者的作用产生，改善感染皮肤的伤口愈合循环腺苷单磷酸（CAMP）下游效应子参与米索前列醇改良的宿主防御在糖尿病小鼠中（AIM 2）。在目标3中，我们将研究维修机制的失败是否涉及消除死细胞（肿瘤病）会导致PGE2产生不足和炎症产生介质，导致糖尿病小鼠感染皮肤的组织损伤。我们的项目可以迅速转化为临床用途可改善糖尿病患者皮肤感染的治疗。具有抗菌素的耐药性和全球糖尿病患病率的增加，对安全，廉价，非抗生素的迫切需求，以及以宿主为中心的方法来预防和治疗感染。