Interactions among local and systemic inflammation and innate immune function in dairy cows

奶牛局部和全身炎症与先天免疫功能之间的相互作用

• 批准号: RGPIN-2020-04483
• 负责人: LeBlanc, Stephen
• 金额: $ 2.91万
• 依托单位: University of Guelph
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2022
• 资助国家: 加拿大
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=763605
• 关键词: Interactions; among; local; systemic; inflammation

Despite advances in nutrition and management, both overt clinical health problems and subtler but pervasive metabolic disturbances remain common in dairy cows. The challenge of supporting a rapid rise to substantial milk production is compounded by the interconnected problems of hypocalcemia, impaired immune function, dysregulated inflammation, and adaptation to negative energy balance. Neutrophils are the primary means of immune response in the uterus after parturition. Aspects of neutrophil function are diminished or dysregulated in dairy cows in the weeks just before and after calving, which appears to be an important contributor to the occurrence of uterine disease. Endometritis is chronic postpartum inflammation of the uterine lining without visible signs but with substantial negative effects on fertility. My lab is a global leader in understanding this condition which affects 20 to 30% of dairy cows and so has a large negative impact in the industry. Many cases of endometritis are negative on bacteriologic culture and preliminary data from my recent Discovery grant indicate a lack of difference in the uterine microbiome before or at diagnosis of endometritis. Therefore, at least a proportion of this disease appears to be a condition of "sterile inflammation", which is the subject of active biomedical research in other species. The work of this Discovery grant will be to understand the interplay of initiation and regulation of inflammation and innate immunity between local inflammation in the uterus and systemic inflammation. The objectives of this program are: 1. To determine whether chronic uterine inflammation can be initiated through systemic inflammation 2. To determine whether uterine inflammation can initiate systemic inflammation 3. To assess the role of metabolic stressors in regulation of neutrophil function in dairy cows We will perform 2 experiments. In the first, we will enroll 2 groups of cows: soon after parturition (disrupted uterine epithelium and high metabolic stress) and at 1.5 months postpartum (intact uterine epithelium and moderate metabolic stress).  Cows will receive intra-uterine infusions or an intravenous challenge with endotoxin, or infusion with saline.  We will measure a comprehensive set of markers of inflammation in the uterus, the liver, and in blood, including immune cell function. We will gain a clear picture of whether uterine inflammation can be initiated from a systemic challenge, whether uterine inflammation persists beyond the initiating insult (local or distant), and which metabolic markers characterize and contribute to both systemic and uterine inflammation.  In the second, we will screen several hundred cows from a commercial dairy farm to identify cows in known risk categories for impaired immune function.  We will then measure aspects of neutrophil function in detail to establish how the interactions of energy and calcium metabolism influence immune function and regulation of inflammation.

尽管在营养和管理方面取得了进展，但公开的临床健康问题和更微妙但普遍的代谢障碍在奶牛中仍然很常见。低钙血症、免疫功能受损、炎症调节失调和适应负能量平衡等相互关联的问题使支持牛奶产量快速增长的挑战变得更加复杂。中性粒细胞是分娩后子宫内免疫反应的主要方式。奶牛在产犊前和产后的几周内，中性粒细胞功能降低或失调，这似乎是子宫疾病发生的一个重要因素。子宫内膜炎是产后子宫内层的慢性炎症，没有明显的迹象，但对生育有实质性的负面影响。我的实验室是了解这种疾病的全球领先者，这种疾病会影响20%到30%的奶牛，因此在行业中有很大的负面影响。许多子宫内膜炎的细菌培养都是阴性的，我最近获得的发现基金的初步数据表明，子宫微生物群在子宫内膜炎诊断之前或诊断时缺乏差异。因此，这种疾病至少有一部分似乎是一种“无菌炎症”，这是其他物种活跃的生物医学研究的主题。这项发现基金的工作将是了解炎症和先天免疫在子宫局部炎症和全身炎症之间的启动和调节的相互作用。这个项目的目标是：1.确定是否可以通过全身炎症引发慢性子宫炎症2.确定子宫炎症是否可以引发全身炎症3.为了评估代谢应激源在奶牛中性粒细胞功能调节中的作用，我们将进行2个实验。在第一组中，我们将招募两组奶牛：分娩后不久(子宫上皮受损和高代谢应激)和产后1.5个月(子宫上皮完整和中等代谢应激)。这两组奶牛将接受宫内输液或静脉注射内毒素，或输注生理盐水。我们将测量子宫、肝脏和血液中的一套全面的炎症标志物，包括免疫细胞功能。我们将清楚地了解是否可以从系统性挑战引发子宫炎症，子宫炎症是否会持续到最初的侮辱(局部或远处)之后，以及哪些代谢标志物表征并促成了全身和子宫炎症。在第二部分中，我们将从一个商业奶牛场筛选数百头奶牛，以识别免疫功能受损的已知风险类别的奶牛。然后我们将详细测量中性粒细胞功能的各个方面，以确定能量和钙代谢的相互作用如何影响免疫功能和炎症调节。