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: 2020
• 资助国家: 加拿大
• 起止时间: 2020-01-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=716109
• 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，但明显的临床健康问题和微妙但普遍的代谢紊乱在奶牛中仍然很常见。低钙血症、免疫功能受损、炎症失调和适应负能量平衡等相互关联的问题加剧了支持快速增加大量牛奶产量的挑战。中性粒细胞是分娩后子宫内免疫反应的主要手段。产犊前后数周内，奶牛中性粒细胞功能减少或失调，这似乎是子宫疾病发生的重要因素。子宫内膜炎是产后子宫内膜的慢性炎症，没有明显的迹象，但对生育能力有实质性的负面影响。我的实验室是了解这种情况的全球领导者，这种情况影响了20%到30%的奶牛，因此对行业产生了很大的负面影响。多例 子宫内膜炎在细菌培养上是阴性的，我最近的发现基金的初步数据表明，在子宫内膜炎诊断之前或诊断时，子宫微生物组缺乏差异。因此，至少有一部分这种疾病似乎是一种“无菌炎症”的条件，这是其他物种积极的生物医学研究的主题。这项发现资助的工作将是了解子宫局部炎症和全身炎症之间炎症和先天免疫的启动和调节的相互作用。 该方案的目标是： 1.确定慢性子宫炎症是否可以通过全身炎症启动 2.确定子宫炎症是否可引发全身炎症 3.研究代谢应激因素对奶牛中性粒细胞功能的调节作用 我们将做两个实验。首先，我们将入组2组奶牛：分娩后不久（子宫上皮破裂和高代谢应激）和产后1.5个月（子宫上皮完整和中度代谢应激）。 奶牛将接受子宫内输注或内毒素静脉内激发，或盐水输注。 我们将测量子宫，肝脏和血液中炎症的一系列标志物，包括免疫细胞功能。我们将清楚地了解子宫炎症是否可以从全身性挑战开始，子宫炎症是否持续超过初始损伤（局部或远处），以及哪些代谢标志物表征并有助于全身性和子宫炎症。 在第二阶段，我们将筛选来自商业奶牛场的数百头奶牛，以确定已知免疫功能受损风险类别的奶牛。 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。