Pathobiology of MRSA-induced Endothelial Permeability and Acute Lung Injury

MRSA 诱导的内皮通透性和急性肺损伤的病理学

• 批准号: 10608606
• 负责人: STEVEN M DUDEK
• 金额: $ 65.27万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-12-20 至 2026-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10608606
• 关键词: Acute Lung Injury; Acute Respiratory Distress Syndrome; Address; Agonist; Antibiotic Resistance; Attenuated; Bacteria; Blood flow; CYP1A1 gene; ChIP-seq; Critical Illness; Data; Development; Disease; Endothelial Cells; Endothelium; Enzymes; Epigenetic Process; Functional disorder; Gene Expression; Genes; Gram-Positive Bacteria; Health; Histone Acetylation; Histone Deacetylase; Human; Immune response; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Injury; Intervention; Knowledge; Life; Lung; Medical; Modeling; Molecular; Morbidity - disease rate; Mus; Organism; Pathogenicity; Patients; Permeability; Pharmacologic Substance; Phospholipids; Play; Pneumonia; Pre-Clinical Model; Process; Property; Reporting; Resistance; Role; Sepsis; Signal Transduction; Source; Staphylococcus aureus; Staphylococcus aureus infection; Targeted Research; Testing; Therapeutic; Ubiquitination; Vascular Endothelial Cell; Virulent; Work; analog; clinically relevant; efficacy evaluation; improved; in vivo; inflammatory lung disease; insight; lung injury; methicillin resistant Staphylococcus aureus; mortality; new therapeutic target; novel; novel therapeutics; organ injury; pharmacologic; phosphonate; protective pathway; receptor; resistant strain; response; screening; sepsis induced ARDS; sphingosine 1-phosphate; targeted treatment; therapeutic candidate; therapeutic effectiveness; therapy development; tool; trafficking

SUMMARY: Despite decades of targeted research, no effective pharmacologic interventions have been identified for the Acute Respiratory Distress Syndrome (ARDS), which is a life-threatening disease process characterized by dysregulated immune responses. Sepsis is a major cause of ARDS, and the pathophysiology of both processes is characterized by alterations in microcirculatory blood flow, with vascular endothelial cell (EC) dysfunction playing a major role in organ injury. Novel mechanistic insights are needed to assist the development of therapies to address the EC barrier dysfunction that underlies ARDS and sepsis. Staphylococcus (S.) aureus is a frequently identified organism in gram-positive sepsis, and the highly virulent, antibiotic-resistant methicillin-resistant S. aureus (MRSA) strain is particularly challenging to treat and a major cause of ARDS. Important knowledge gaps exist both in MRSA-induced pathophysiology relevant to ARDS and in the mechanistic understanding of EC-specific processes that can be targeted therapeutically. Endogenous sphingosine-1-phosphate (S1P) and the structurally similar pharmaceutical compound, FTY720 (FTY), have EC barrier-enhancing effects in preclinical models of ARDS. However, both S1P and FTY also induce a myriad of other effects that are potentially harmful in critically ill patients and make them poor therapeutic candidates. We therefore have explored the barrier-regulatory properties of novel FTY720 analogs to better understand how these compounds regulate permeability. Our work has revealed that FTY720 (S)- phosphonate (Tys) has superior efficacy in several preclinical models and maintains expression levels of the essential S1PR1 receptor, unlike other agonists which induce its degradation. In addition, epigenetic processes are increasingly being recognized as important pathogenic steps during inflammatory acute lung injury (ALI)/ARDS and sepsis, and epigenetic responses (such as histone acetylation) can be altered by S1P-related signaling. Our central hypothesis is that MRSA causes EC dysfunction relevant to ARDS by epigenetic and other pathophysiologic mechanisms that can be targeted by Tys/S1PR1-related signaling. Using ChIP-seq analysis and other epigenetic tools, we have generated new insights that MRSA triggers histone acetylation in lung EC to regulate genes involved in lung EC dysfunction. Exciting new data suggest Tys-S1PR1 signaling may ameliorate key aspects of these epigenetic effects. Aim #1 will determine the mechanisms by which Tys/S1PR1 signaling protects against MRSA-induced lung EC barrier disruption in vitro. Aim #2 will use state- of-the-art ChIP-seq and other approaches to characterize novel MRSA- and Tys/S1PR1-induced epigenetic changes that have functional consequences in lung EC, including the novel MRSA target identified by our epigenetic screening, CYP1A1. Aim #3 will extend these studies in vivo by characterizing epigenetic and other mechanisms of MRSA-induced lung injury in mice and determine the efficacy of Tys. Overall, these studies will advance our mechanistic understanding of MRSA-induced ARDS to identify novel therapeutic targets.

总结： 尽管进行了数十年的靶向研究，但尚未确定有效的药物干预措施。 急性呼吸窘迫综合征（ARDS），是一种危及生命的疾病过程，其特征在于： 免疫反应失调脓毒症是ARDS的主要原因， 过程的特征在于微循环血流的改变，血管内皮细胞（EC） 在器官损伤中起主要作用的功能障碍。需要新的机械见解来帮助 开发治疗以解决作为ARDS和脓毒症基础的EC屏障功能障碍。 葡萄球菌（S.）金黄色葡萄球菌是革兰氏阳性脓毒症中经常鉴定的生物体，并且高毒性， 耐甲氧西林S.金黄色葡萄球菌（MRSA）菌株的治疗特别具有挑战性， 因为ARDS。在MRSA诱导的与ARDS相关的病理生理学方面， 以及对EC特异性过程的机制理解，这些过程可以在治疗上靶向。 内源性鞘氨醇-1-磷酸（S1 P）和结构相似的药物化合物FTY 720 (FTY)，在ARDS的临床前模型中具有EC屏障增强作用。然而，S1 P和FTY也 会引起无数其他对危重病人有潜在危害的影响，使他们变得贫穷 治疗候选人。因此，我们探索了新型FTY 720类似物的屏障调节特性 以更好地了解这些化合物如何调节渗透性。我们的工作表明，FTY 720（S）- 膦酸盐（Tys）在几种临床前模型中具有上级功效，并维持 必需的S1 PR 1受体，不像其他激动剂诱导其降解。此外，表观遗传过程 越来越多地被认为是炎症性急性肺损伤的重要致病步骤 (ALI)/ARDS和脓毒症，以及表观遗传反应（如组蛋白乙酰化）可以被S1 P相关的 发信号。我们的中心假设是MRSA通过表观遗传学和免疫学途径引起与ARDS相关的EC功能障碍， Tys/S1 PR 1相关信号传导可靶向的其他病理生理机制。使用ChIP-seq 分析和其他表观遗传工具，我们已经产生了新的见解，MRSA触发组蛋白乙酰化， 肺EC调节参与肺EC功能障碍的基因。令人兴奋的新数据表明Tys-S1 PR 1信号传导 可能会改善这些表观遗传效应的关键方面。目标#1将确定 Tys/S1 PR 1信号通路在体外保护免于MRSA诱导的肺EC屏障破坏。目标#2将使用状态- 最先进的ChIP-seq和其他方法来表征新型MRSA和Tys/S1 PR 1诱导的表观遗传 在肺EC中具有功能性后果的变化，包括我们发现的新型MRSA靶点。 表观遗传学筛查，CYP 1A 1。目标#3将通过表征表观遗传和其他遗传学特征来扩展这些体内研究。 在小鼠中研究MRSA诱导的肺损伤的机制，并确定Tys.总的来说，这些研究将 推进我们对MRSA诱导的ARDS机制的理解，以确定新的治疗靶点。