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Up to half of dairy cows are affected by at least one of metritis, purulent vaginal discharge, endometritis or cervicitis in the postpartum period. These conditions result from inadequate immune response to bacterial infection (failure to clear pathogenic bacteria from the uterus) or persistent inflammation that impairs rather than enhances reproductive function. The degree of mobilization of fat and how effectively it is used as a metabolic fuel is well recognized as a risk factor for metabolic and infectious disease. Release of non-esterified fatty acids has direct effects on liver and immune function but also produces pro-inflammatory cytokines (tumor necrosis factor α and interleukin-6), which contribute to systemic inflammation and to insulin resistance. Therefore, reproductive tract inflammatory disease may be a function of both local and systemic inflammatory stimuli and regulation as well as regulation of fat metabolism. Better understanding of variables associated with insulin resistance and inflammatory regulation in the liver and adipose tissue may lead to improvement of reproductive tract health. This paper reviews factors that may contribute to postpartum reproductive tract inflammatory diseases in dairy cows and their inter-relationships, impacts and treatment.

This paper reviews puerperal metritis in the cow, particularly the complex and multi-factorial pathogenesis characterized by an altered cross-talk among infectious agents, endocrine and immune systems. Uterine infections impair fertility and is one of the main causes of economic losses in dairy production. The early postpartum is a period characterized by an increased exposition to infectious agents and the disruption of the metabolic homeostasis, leading to endocrine and immunologic disorders. Dysregulation of uterine defence mechanisms results in the development of metritis. Because there is a complex interaction between infectious, endocrine and immune factors during metritis, there is need to use safer and cheaper drugs which are able to strengthen the anti-infective actions of the routine therapies.

Post-partum uterine disease has a detrimental effect on dairy cow fertility; affected cows require more serves per conception, have reduced conception rates and are more likely to be culled for infertility. Furthermore, the detrimental effects on fertility remain even after clinical resolution of disease. There are many factors that influence a cow's resistance to or development of post-partum disease, and the key drivers determining disease outcome are uterine microbial load, regulation of inflammation and immune responses peripherally and at a local level, production pressure, and metabolic (energy) status. These factors are intricately interlinked, which makes assessment of their individual effects difficult. It is clear, however, that the period surrounding calving is a key transition phase and events during this time point will influence uterine disease outcome and subsequent fertility. Good peripartum management and accurate diagnosis are critical to facilitate the use of the most effective treatment and limit the negative impact of post-partum uterine disease on fertility. If we can improve our understanding of the underlying causes of disease, then we can identify 'at risk' animals and implement management and breeding strategies to prevent uterine disease or reduce its severity. Thus, this article aims to summarize the key factors that drive uterine disease in the post-partum dairy cow., (© 2013 Blackwell Verlag GmbH.)

The incidence and severity of disease in cows is greatest during the transition period, when immune functions are impaired. Intense lipid mobilization is associated with both metabolic and infectious diseases in the transition cow. Significant increases in plasma nonesterified fatty acids contribute to oxidative stress and uncontrolled inflammatory responses. A dysfunctional inflammatory response is the common link between metabolic and infectious diseases around the time of calving. Intervention strategies that can reduce lipid mobilization may improve inflammatory responses and reduce the economic losses associated with health disorders during the transition period., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Whereas neutrophils are the main phagocytic leukocytes, monocytes and macrophages are actively involved in immunomodulation after infection. Recent studies have demonstrated that neutrophil function is impaired by the state of negative energy balance around parturition, and that cows that develop uterine disease have a greater degree of negative energy balance than healthy cows. The objectives of this study were to compare monocyte gene expression and protein secretion of selected cytokines from calving to 42 d after calving in Holstein cows that did or did not develop uterine disease. Real time quantitative RT-PCR (Tumor necrosis factor-α (TNFα), Interleukin (IL)-1β, IL-6, IL-8 and IL-10) and ELISA (TNFα, IL-1β and IL-8) were used to evaluate cytokine response following in vitro stimulation of blood-derived monocytes with irradiated E. coli. Relative to unstimulated cells, E. coli-stimulated monocytes from cows with metritis had lower gene expression of key pro-inflammatory cytokines than healthy cows from calving to 14 d after calving (TNFα at 0, 7, and 14 d after calving, IL-1β and IL-6 at 7 and 14 d after calving; P < 0.05). There were no significant differences between groups for expression of IL-8 or the anti-inflammatory cytokine IL-10. This was due, in part, to higher gene expression in unstimulated monocytes (TNFα, IL-1β, IL-6 and IL-10) in early lactation from cows with metritis. Expression of mRNA in stimulated cells (relative to housekeeping genes) was lower for TNFα (7 and 14 d postpartum) and for IL-10 (7 and 14 d postpartum) in cows with metritis. Concentration of TNFα was lower in the culture medium of E. coli-stimulated monocytes from cows with metritis than healthy cows at calving and 7 and 21 d after calving (P < 0.05). Circulating cytokine concentrations were not different between groups for IL-8 and were below the limits of detection for TNFα and IL-1β. Cytokine gene expression and production were similar between healthy cows and cows that developed endometritis, diagnosed cytologically at 42 d after calving. We concluded that altered levels of expression and production of pro-inflammatory cytokines postpartum could contribute to impaired inflammatory response and predispose cows to development of metritis., (Copyright © 2012 Elsevier Inc. All rights reserved.)

The aim of the present study was to analyse the effect of subclinical endometritis on endometrial and embryonic gene expression. A total of 49 cows at either Day 0 or Day 7 of the oestrous cycle (62-83 days post partum) following superovulation were classified as having subclinical endometritis (SE-0, SE-7) or a healthy endometrium (HE-0, HE-7) on the basis of endometrial cytological evaluation. Endometrial samples and associated embryos were subjected to global transcriptome analysis using the Bovine GeneChip (Affymetrix, Santa Clara, CA, USA) and aberrant transcript profiles were observed in SE-0 and SE-7 cows. At Day 0, 10 transcripts were found to be differentially expressed in endometrial samples. Specifically, the PDZK1, PXDN, DDHD2, GPLD1 and SULT1B1 genes were downregulated, whereas the PKIB, LOC534256, BT29392, LYZ and S100A14 genes were upregulated in SE-0 cows. Similarly, 11 transcripts were found to be differentially regulated on Day 7. Of these, GNPTG, BOLA-DQA5, CHD2, LOC541226, VCAM1 and ARHGEF2 were found to be downregulated, whereas PSTPIP2, BT236441 and MGC166084 were upregulated in SE-7 cows. Accordingly, endometrial health status affected the number of flushed, transferable embryos. In all, 20 genes were differentially regulated in blastocysts derived from HE-7 and SE-7 cows. Of these, GZMK, TCEAL4, MYL7, ADD3 and THEM50B were upregulated, whereas NUDCD2, MYO1E, BZW1, EHD4 and GZMB were downregulated. In conclusion, endometrial polymorphonuclear neutrophil infiltration as an indicator of subclinical endometritis is associated with changes in endometrial gene expression patterns, including genes involved in cell adhesion and immune modulation. Consequently, subclinical endometritis affects gene expression in embryos, including the expression of genes related to membrane stability, the cell cycle and apoptosis.

This paper briefly reviews recent data and concepts on the development and mitigation of infection and inflammation in the reproductive tract of dairy cows during the first 2 mo after calving. The incidence of metritis is typically between 10 and 20%, of clinical endometritis or purulent vaginal discharge (PVD) approximately 15%, and of subclinical or cytological endometritis a further 15%. Worse postpartum negative energy balance is associated with more severe or prolonged uterine inflammation. Changes in feed intake, expression of genes for pro-inflammatory cytokines, notably interleukin (IL) 1, IL6 and IL8, circulating concentrations of beta-hydroxybutyrate (BHBA) or nonesterified fatty acids (NEFA), and innate immune function precede both metritis and endometritis by several weeks. Infections with Escherichia coli and Arcanobacterium pyogenes are associated with both metritis and PVD. There are new data to suggest that specific virulence factors in E. coli associated with adherence may be important in metritis and PVD. Cytological endometritis and PVD are overlapping but largely distinct conditions, and there are emerging data that cervicitis exists both concurrent with and separate from endometritis. Much remains to be learned about what initiates and sustains harmful inflammation of the reproductive tract. Such information is necessary to develop effective treatments for the various forms of disease and, more importantly, to develop means to prevent endometritis and cervicitis. In particular, vaccination against specific uterine pathogens and interventions to modulate innate immune response appear to be important avenues for investigation. Presently, commonly recommended best management practices for cows in the transition period are likely to be helpful to mitigate the risk of reproductive disease., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Bovine uterine disease reduces milk yield, impairs fertility and has implications for animal welfare. During involution, the uterus is usually exposed to multiple potential bacterial pathogens which are cleared by successful orchestration of the local inflammatory response. Unsuccessful resolution leads to the development of disease. The aim of this study was to characterize the local innate immune response in the uterus during physiological involution using histopathological and molecular analyses in 9 cows, 2 weeks after calving (early postpartum, EPP), and 4 cows, 9 weeks after calving (late postpartum, LPP). Uterine biopsies taken from each cow were classified by histopathology, and RNA was extracted for molecular analysis. Two EPP cows were classified with a mild, 5 with a moderate and 2 with a severe inflammatory response. Relative gene expression analysis was then performed using quantitative real-time PCR (qRT-PCR) and specific primers for genes encoding Toll-like receptors (TLRs), chemokines, cytokines, acute phase proteins (APPs) and antimicrobial peptides (AMPs). TLR4, transcription factor NFKB1 and the inflammatory cytokines IFNG, IL1A, IL6, IL8, IL12A were all significantly increased in EPP cows (P<0.05). Increase in HP, SAA3, TAP and DEFB5 genes was particularly marked in cows with severe inflammation. These results reveal evidence of an inflammatory uterine environment in the early postpartum period with significant induction of both AMP and APP genes. Histopathological grades in EPP cows are underpinned by quantitative changes in gene expression. Understanding the molecular mechanisms contributing to uterine immunity in the early postpartum period may identify candidate genes associated with the resolution of inflammation.

Dairy cattle are susceptible to increased incidence and severity of disease during the periparturient period. Increased health disorders have been associated with alterations in bovine immune mechanisms. Many different aspects of the bovine immune system change during the periparturient period, but uncontrolled inflammation is a dominant factor in several economically important disorders such as metritis and mastitis. In human medicine, the metabolic syndrome is known to trigger several key events that can initiate and promote uncontrolled systemic inflammation. Altered lipid metabolism, increased circulating concentrations of non-esterified fatty acids and oxidative stress are significant contributing factors to systemic inflammation and the development of inflammatory-based diseases in humans. Dairy cows undergo similar metabolic adaptations during the onset of lactation, and it was postulated that some of these physiological events may negatively impact the magnitude and duration of inflammation. This review will discuss how certain types of fatty acids may promote uncontrolled inflammation either directly or through metabolism into potent lipid mediators. The relationship of increased lipid metabolism and oxidative stress to inflammatory dysfunction will be reviewed as well. Understanding more about the underlying cause of periparturient health disorders may facilitate the design of nutritional regimens that will meet the energy requirements of cows during early lactation and reduce the susceptibility to disease as a function of compromised inflammatory responses.

The post-partum period in cattle is characterised by an increased risk of infection of the uterus, as the anatomical barriers are broached during parturition and remain open for several days. Infection of the uterus is largely influenced by the balance between bacterial contamination and the local and systemic immune status during pregnancy and around parturition. Infectious diseases are more prevalent during this period, because of an impaired immune status before and immediately after parturition. Neutrophils play a primary role in the defence of the uterus against infection. Influx of neutrophils into the uterus is thought to be mediated by chemoattractants, chemokines and adhesion molecules, such as beta2-integrin (complement receptor 3) and L-selectin (CD62L). Other cellular components activated in the uterus during this period include lymphocytes, eosinophils, mast cells and macrophages. The major classes of immunoglobulins (IgM, IgA and IgG), either by passive diffusion or local production, play an important protective role in the uterus by acting as opsonins to enhance phagocytosis, stimulating the complement pathways or blocking pathogens from adhering to mucosal surfaces. Endometrial cells express toll-like receptor 4 (TLR4), which recognises lipopolysaccharides of Escherichia coli and other Gram negative bacteria, the most common causes of bovine endometritis. Activation of TLR4 triggers the production of tumour necrosis factor alpha and other pro-inflammatory cytokines. The periparturient period is also characterised by an increased secretion of prostaglandin F(2alpha), which enhances uterine immune defences.

The objectives of this study were to investigate the associations between peripheral blood neutrophil (PMN) function, energy status, and uterine health in periparturient dairy cows. Data were collected from 83 multiparous Holstein cows. Blood samples for PMN function determination were collected weekly from 1 week prior to calving (week -1) through 4 weeks after calving and again at 8 weeks after calving. Energy metabolites were measured and dry matter intake (DMI) was determined from weeks -2 to 5 to evaluate energy status of cows during the periparturient period. All cows were examined for uterine health disorders. Blood PMN killing ability was evaluated by determining myeloperoxidase activity and cytochrome c reduction activity in isolated blood PMN's. For cows that were diagnosed with puerperal metritis and subclinical (SC) endometritis and puerperal metritis, blood PMN functions were significantly (P<0.05) impaired during the periparturient period, compared to cows with normal uterine health. Cows with subclinical endometritis and puerperal metritis or SC endometritis also had significantly (P<0.01) higher NEFA and significantly (P<0.001) lower DMI during the periparturient period, and significantly (P<0.05) higher BHBA during early lactation, compared to cows with normal uterine health. Neutrophil function was also significantly (P<0.01) impaired in cows with peripartum negative energy balance, which was characterized by elevated blood levels of NEFA and decreased DMI. Decreased PMN function and energy balance were associated with uterine health disorders and the decreases in PMN function and energy balance occurred prior to parturition and prior to the detection of these uterine disorders.

Mitogenic responses of peripheral blood lymphocytes in naturally occurring clinical puerperal metritis and mastitis were investigated. Glucose consumption index (GCI) values for phytohaemagglutinin (PHA), concanavalin A (Con A) and pokeweed mitogen (PWM) in the puerperal metritic cows and mastitic cows were significantly lower than those in the healthy cows. Suppression of lymphocyte blastogenesis was correlated to an increased concentration of serum ammonia in the puerperal metritic cows, and of alpha 1-acid glycoprotein (alpha 1AG) in the mastitic cows. Lymphocyte blastogenesis in the mastitic cows was also correlated to the serum concentration of vitamin E. These findings indicate that the puerperal metritic and mastitic cows are associated with impaired lymphocyte blastogenesis.