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

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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.