Regulatory T cells and Inflammatory Injury of the Developing Murine Lungs

调节性 T 细胞和小鼠肺发育中的炎症损伤

• 批准号: 10368051
• 负责人: Binoy Shivanna
• 金额: $ 8万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-08 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10368051
• 关键词: Address; Adoptive Transfer; Alveolar; Area; Attenuated; Blood Vessels; Bronchopulmonary Dysplasia; CCR5 gene; Chronic; Chronic lung disease; Data; Development; Diphtheria Toxin; Disease; Economic Burden; Escherichia coli; Exposure to; FOXP3 gene; Female; Functional disorder; Goals; Green Fluorescent Proteins; Homeostasis; Hospital Costs; Human; Immune; Infant; Infection; Inflammation; Inflammatory; Injury; Interruption; Intervention; Knowledge; Lead; Life; Lipopolysaccharides; Lung; Lung diseases; Lymphocyte; Mediating; Molecular; Morbidity - disease rate; Mouse Protein; Mus; Necrotizing Enterocolitis; Neonatal; Pathogenesis; Patients; Periventricular Leukomalacia; Phase; Premature Infant; Premature Infant Diseases; Pulmonary Inflammation; RAG1 gene; RANTES; Rag1 Mouse; Regulatory T-Lymphocyte; Research; Resolution; Retinopathy of Prematurity; Role; Secondary to; Sepsis; Severities; Signal Transduction; Structure of parenchyma of lung; Testing; Tissues; Transgenic Mice; Vascular Diseases; Wild Type Mouse; base; chemokine receptor; curative treatments; design; diphtheria toxin receptor; genetic approach; immunomodulatory therapies; infancy; injury and repair; innovation; insight; lung development; lung injury; lung vascular injury; male; mature animal; mouse model; multidisciplinary; mutant; neonatal lung injury; neonatal mice; novel; prevent; recruit; targeted treatment; therapeutic target

Abstract/Summary Bronchopulmonary dysplasia (BPD) is the most common chronic infantile lung disease that lacks curative therapies. Further, BPD increases the economic burden and long-term morbidities in preterm infants. Sepsis-mediated persistent lung inflammation is central to the pathogenesis of BPD, which is characterized by interrupted lung development, i.e., alveolar simplification. However, the molecular mechanisms that modulate neonatal lung inflammation are poorly understood. Regulatory T cells (Tregs) are crucial to maintain immune homeostasis and prevent tissue damage. Further, they promote resolution of lung inflammation and injury in adult animals; however, the role of Tregs in BPD pathogenesis remains unclear. Additionally, the mechanisms of Treg recruitment in neonatal lungs are poorly studied. So, we propose to address these knowledge gaps using a neonatal mouse model of lipopolysaccharide (LPS)-induced chronic inflammatory lung injury. Our preliminary studies in neonatal mice indicate that: (1) LPS decreases Tregs and their C-C motif chemokine receptor 5 (CCR5) expression in lungs; and (2) Treg depletion induces inflammation and potentiates LPS- mediated lung injury. Based on our novel data, we will test the central hypothesis that Tregs are necessary and sufficient to protect against LPS-induced inflammatory lung injury in neonatal mice. We will use a unique combination of molecular, cellular, and functional approaches to test this hypothesis. In Aim 1, we will use transgenic mice to determine if Tregs are necessary and sufficient to protect neonatal mice against LPS- induced lung and pulmonary vascular injury and dysfunction. In Aim 2, we will use transgenic mice to examine the mechanisms of lung Treg recruitment. We expect that successful completion of these studies would provide a mechanistic rationale for targeting Tregs to develop meaningful therapies for BPD infants. Our studies also could positively impact other inflammation-related neonatal research areas, including necrotizing enterocolitis, retinopathy of prematurity, and periventricular leukomalacia.

摘要/概要 支气管肺发育不良（BPD）是最常见的慢性婴儿肺部疾病，缺乏 治愈性疗法此外，BPD增加了早产儿的经济负担和长期发病率。 脓毒症介导的持续性肺部炎症是BPD发病机制的核心，其特征在于： 肺部发育中断，即，肺泡简化然而，调节的分子机制 新生儿肺部炎症知之甚少。调节性T细胞（Treg）是维持免疫功能的关键。 体内平衡和防止组织损伤。此外，它们促进肺部炎症和损伤的消退， 成年动物;然而，TdR在BPD发病机制中的作用仍不清楚。此外，机制 新生儿肺中Treg募集的研究很少。因此，我们建议解决这些知识差距， 使用脂多糖（LPS）诱导的慢性炎性肺损伤的新生小鼠模型。我们 在新生小鼠中的初步研究表明：（1）LPS降低TcR及其C-C基序趋化因子 受体5（CCR 5）在肺中的表达;和（2）Treg耗竭诱导炎症并增强LPS-1的表达。 介导的肺损伤。基于我们的新数据，我们将检验中心假设，即TBI是必要的， 足以保护新生小鼠免受LPS诱导的炎性肺损伤。我们将使用一种独特的 分子，细胞和功能方法的组合来测试这一假设。在目标1中，我们将使用 转基因小鼠，以确定THBE是否是必要的和足够的保护新生小鼠免受LPS- 引起肺和肺血管损伤和功能障碍。在目标2中，我们将使用转基因小鼠来检查 肺Treg募集的机制。我们期望这些研究的成功完成， 提供了一个机制的基本原理，靶向THBE开发有意义的治疗BPD婴儿。我们 研究也可能对其他炎症相关的新生儿研究领域产生积极影响，包括坏死性 小肠结肠炎、早产儿视网膜病和脑室周围白质软化。

项目成果

Ventilation-Induced Lung Injury (VILI) in Neonates: Evidence-Based Concepts and Lung-Protective Strategies.

• DOI: 10.3390/jcm11030557
• 发表时间: 2022-01-22
• 期刊: Journal of clinical medicine
• 影响因子: 3.9
• 作者: Kalikkot Thekkeveedu R;El-Saie A;Prakash V;Katakam L;Shivanna B
• 通讯作者: Shivanna B

Amphiregulin Exerts Proangiogenic Effects in Developing Murine Lungs.

• DOI: 10.3390/antiox13010078
• 发表时间: 2024-01-08
• 期刊: ANTIOXIDANTS
• 影响因子: 7
• 作者: Thapa, Shyam;Shankar, Nithyapriya;Shrestha, Amrit Kumar;Civunigunta, Monish;Gaikwad, Amos S.;Shivanna, Binoy;Liu, Jiankang
• 通讯作者: Liu, Jiankang