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

尽管在营养和管理方面取得了进步，但在奶牛中，明显的临床健康问题和微妙但普遍的代谢紊乱仍然很常见。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，使支持大量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免疫反应的主要手段。在奶牛产犊前后的几周内，中性粒细胞功能的各个方面减少或失调，这似乎是子宫疾病发生的重要因素。子宫内膜炎是一种慢性产后子宫内膜炎症，无明显体征，但对生育能力有明显的负面影响。我的实验室在了解这种影响20%到30%奶牛的情况方面处于全球领先地位，因此对该行业产生了很大的负面影响。许多子宫内膜炎的病例细菌学培养呈阴性，我最近的发现基金的初步数据表明，子宫内膜炎诊断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”，这是其他物种生物医学研究的积极课题。这项发现基金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。

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.