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/摘要 支气管肺发育不良（BPD）是最常见的慢性婴儿肺部疾病 治疗疗法。此外，BPD增加了早产儿的经济负担和长期病情。 败血症介导的持续性肺部炎症是BPD发病机理的核心，其特征是 肺发育中断，即肺泡简化。但是，调节的分子机制 新生儿肺部炎症知之甚少。调节性T细胞（Tregs）对于维持免疫力至关重要 稳态并防止组织损伤。此外，它们促进了肺部炎症和损伤的分辨率 成年动物；但是，Treg在BPD发病机理中的作用尚不清楚。另外，机制 对新生儿肺的Treg招募的研究很少。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。我们的 新生儿小鼠的初步研究表明：（1）LPS降低Treg及其C-C基序趋化因子 肺中的受体5（CCR5）表达； （2）Treg耗竭会诱发炎症，并增强LPS- 介导的肺损伤。根据我们的新数据，我们将测试中心假设，即Treg是必要的，并且 足以防止新生儿小鼠中LPS诱导的炎症性肺损伤。我们将使用独特的 分子，细胞和功能方法检验该假设的组合。在AIM 1中，我们将使用 转基因小鼠以确定Treg是否需要和足以保护新生小鼠免受LPS- 诱导肺和肺血管损伤和功能障碍。在AIM 2中，我们将使用转基因小鼠检查 肺Treg招募的机制。我们预计这些研究的成功完成将 为靶向Treg提供了为BPD婴儿开发有意义的疗法的机械基本原理。我们的 研究还可能对其他与炎症有关的新生儿研究领域产生积极影响，包括坏死 小肠结肠炎，早产性视网膜病变和脑室白细胞。

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