The role of Poldip2 in macrophages during sepsis-induced lung injury

Poldip2 在脓毒症引起的肺损伤期间巨噬细胞中的作用

• 批准号: 9911114
• 负责人: Elena Dolmatova
• 金额: $ 7.59万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9911114
• 关键词: Acute Lung Injury; Affect; Alveolar; Alveolar Macrophages; Amino Acids; Anti-Inflammatory Agents; Binding; CCL2 gene; CXCL1 gene; CXCL11 gene; CXCL2 gene; Cause of Death; Cell physiology; Cells; DNA Polymerase III; Data; Endothelium; Epithelial; Epithelium; Functional disorder; IFNGR1 gene; IRF1 gene; IRF4 gene; Immune; Immune response; Immunohistochemistry; In Vitro; Infiltration; Inflammation; Inflammatory; Inflammatory Response; Injections; Interferon Type II; Interferon-beta; Interleukin-12; Interleukin-13; Interleukin-4; Intervention; JAK1 gene; JAK2 gene; Leukocytes; Life; Lipopolysaccharides; Liquid substance; Lung; Lung Inflammation; MAP Kinase Gene; Macrophage Activation; Molecular; Morbidity - disease rate; Mus; NF-kappa B; Organ; PTGS1 gene; Pathway interactions; Patients; Permeability; Phenotype; Polymerase; Process; Production; Proliferating Cell Nuclear Antigen; Protein Secretion; Proteins; Reactive Oxygen Species; Respiratory Failure; Role; SIRT1 gene; STAT1 gene; STAT6 gene; Sepsis; Severities; Signal Transduction; System; TLR4 gene; TNF gene; Testing; Transcription Factor AP-1; Tumor-infiltrating immune cells; Western Blotting; Work; cell motility; chemokine; immune function; improved; insight; lung injury; macrophage; migration; mortality; neutrophil; new therapeutic target; recruit; response; therapeutic target

Sepsis constitutes a major cause of morbidity and mortality worldwide by causing life-threatening organ dysfunction, with almost 50% of patients developing acute lung injury and respiratory failure being a major cause of death. Current evidence suggests multiple processes involved in sepsis-induced acute lung injury, including endothelial barrier disruption with subsequent infiltration by immune cells. Recent studies also suggest a special role for alveolar macrophages in the progression of lung inflammation through their influence on other immune cells in the lung. However, the exact molecular mechanisms of sepsis-induced acute lung injury remain unknown and only a handful of potential interventions have been investigated. Polymerase-δ-interacting protein 2 (Poldip2) is a multifunctional protein originally described over a decade ago as a 368 amino acid binding partner of DNA polymerase delta and proliferating cell nuclear antigen. Work by our lab showed that Poldip2 depletion in mice inhibited lipopolysaccharide (LPS)-induced infiltration of leukocytes into the alveolar space and strongly reduced endothelial permeability, resulting in improved mortality. Here we hypothesize that lower Poldip2 levels also affect the function of the immune cells and macrophages in particular, thus decreasing sepsis-induced lung injury. We will test our hypothesis in two specific aims. In the first aim, we will investigate the role of Poldip2 in immune cell recruitment during sepsis-induced lung injury. We will evaluate the total number of alveolar macrophages at baseline as well as the total count and percentage of pro-inflammatory and anti-inflammatory macrophages after LPS injection in Poldip2+/+ and Poldip2+/- mice. We will also assess the levels of chemokine secretion by Poldip2+/+ and Poldip2+/- macrophages and their effect on neutrophil migration. In the second aim, we will investigate the molecular mechanisms underlying the differences in macrophage activation in Poldip2 deficient mice during sepsis. We will explore classic pro-inflammatory and anti-inflammatory activation pathways in Poldip2+/+ and Poldip2+/- macrophages as well as alternative pathways previously implicated in sepsis-induced lung injury. Completion of these aims will result in a better understanding of the role of Poldip2 in sepsis-induced acute lung injury and will provide insight into new potential therapeutic targets.

败血症是造成威胁生命的全球发病率和死亡率的主要原因 器官功能障碍，近50％的患者发生急性肺损伤和呼吸衰竭 是主要的死亡原因。当前的证据表明涉及的多个过程 败血症引起的急性肺损伤，包括内皮屏障破坏，随后 免疫细胞浸润。最近的研究还表明了肺泡巨噬细胞的特殊作用 在肺部感染通过对肺中其他免疫细胞的影响进展。 但是，败血症诱导的急性肺损伤的确切分子机制仍然未知，仅 已经研究了一些潜在的干预措施。聚合酶 - δ相互作用蛋白2 （Poldip2）是一种多功能蛋白，最初十年前描述为368氨基酸 DNA聚合酶三角洲和增殖细胞核抗原的结合伴侣。我们的实验室工作 表明POLDIP2在小鼠中的部署抑制了脂多糖（LPS）诱导的浸润 白细胞进入肺泡空间，并大大降低内皮渗透性，导致 在改善死亡率中。在这里，我们假设较低的poldip2水平也会影响 特别是免疫细胞和巨噬细胞，从而减少了败血症诱导的肺损伤。我们将 在两个具体目标中检验我们的假设。在第一个目标中，我们将研究Poldip2的作用 在败血症引起的肺损伤期间的免疫细胞募集中。我们将评估总数 基线时肺泡巨噬细胞以及促炎和促疾病的总数和百分比 LPS注射后Poldip2+/+和Poldip2 +/-小鼠的抗炎巨噬细胞。我们也会 评估Poldip2+/+和Poldip2 +/-巨噬细胞的趋化因子分泌水平及其作用 关于中性粒细胞迁移。在第二个目标中，我们将研究基础的分子机制 败血症期间，POLDIP2缺乏小鼠巨噬细胞激活的差异。我们将探索 POLDIP2+/+和POLDIP2 +/-中经典的促炎和抗炎激活途径 巨噬细胞以及先前在败血症诱导的肺损伤中实施的替代途径。 这些目标的完成将使人们更好地了解Poldip2在 败血症引起的急性肺损伤，并将洞悉新的潜在治疗靶标。

项目成果

On the Selectivity of Heparan Sulfate Recognition by SARS-CoV-2 Spike Glycoprotein.

• DOI: 10.1021/acsmedchemlett.1c00343
• 发表时间: 2021-11-11
• 期刊: ACS medicinal chemistry letters
• 影响因子: 4.2
• 作者: Chittum JE;Sankaranarayanan NV;O'Hara CP;Desai UR
• 通讯作者: Desai UR

Myeloid Poldip2 Contributes to the Development of Pulmonary Inflammation by Regulating Neutrophil Adhesion in a Murine Model of Acute Respiratory Distress Syndrome.

• DOI: 10.1161/jaha.121.025181
• 发表时间: 2022-05-17
• 期刊: JOURNAL OF THE AMERICAN HEART ASSOCIATION
• 影响因子: 5.4
• 作者: Ou, Ziwei;Dolmatova, Elena;Mandavilli, Rohan;Qu, Hongyan;Gafford, Georgette;White, Taylor;Valdivia, Alejandra;Lassegue, Bernard;Hernandes, Marina S.;Griendling, Kathy K.
• 通讯作者: Griendling, Kathy K.