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Relationship of peripartum inflammation with reproductive health in dairy cows*

Open AccessPublished:January 12, 2023DOI:https://doi.org/10.3168/jdsc.2022-0328

      Highlights

      • The incidence and consequences of postpartum reproductive disease are tied to effective immune response and well-regulated inflammation.
      • Systemic inflammation is an intriguing concept in dairy cows in the transition period, but it is not well defined.
      • Metritis and purulent vaginal discharge are associated with changes in the reproductive microbiome and consequent inflammation, whereas endometritis appears to reflect persistent, dysregulated inflammation that does not seem to be caused by infection.

      Abstract

      Failure of a robust but well-regulated immune response may result in reproductive tract inflammatory disease, such as metritis, purulent vaginal discharge, or endometritis. Metritis is consistently associated with reduced diversity of the uterine microbiome. Similarly, purulent vaginal discharge at 4 to 6 wk postpartum is strongly associated with bacterial infection of the uterus. Conversely, the microbiome of healthy cows and those with subclinical endometritis is generally similar, so endometritis is thought to be a consequence of dysregulation of inflammation rather than changes in uterine microbiota. There is an emerging concept that inflammation is not only a reaction to injury or disease but that it can be a consequence of or precursor to metabolic disturbances. The degree of systemic inflammation is associated with the level of trauma and bacterial contamination of the uterus or mammary gland, the degree of fat mobilization and release of nonesterified fatty acids, and perhaps leaky gut, all of which result in the release of proinflammatory cytokines. Therefore, uterine inflammation may be exacerbated by systemic inflammation, but may also contribute to heightened systemic inflammation in transition cows. However, clarity and progress are limited by a lack of validated criteria to quantify systemic inflammation and to identify its sources.

      Graphical Abstract

      Figure thumbnail fx1
      Graphical AbstractSummary: Inflammation is part of the normal process of uterine involution after calving. Inadequate immune response, trauma to the reproductive tract, and changes in the uterine microbiome soon after calving combine to cause metritis or, later, purulent vaginal discharge. In contrast, endometritis is associated with excessive or persistent uterine inflammation but generally not with bacterial infection. Uterine inflammatory disease may contribute to postpartum systemic inflammation. It is not clear what causes the chronic inflammation that characterizes endometritis but it may relate to systemic inflammation, with roots before calving.
      Uterine inflammation is suppressed from the time of signaling of pregnancy until parturition. The immediate postpartum period requires an immune response to inevitable uterine contamination with bacteria. Uterine disease is common in dairy cows and results from the balance between the uterine microbiome and the innate immune response and the regulation of inflammation (
      • de Lima F.S.
      Recent advances and future directions for uterine diseases diagnosis, pathogenesis, and management in dairy cows.
      ;
      • Sheldon I.M.
      • Molinari P.C.C.
      • Ormsby T.J.R.
      • Bromfield J.J.
      Preventing postpartum uterine disease in dairy cattle depends on avoiding, tolerating and resisting pathogenic bacteria.
      ). That balance is influenced by the metabolic status of cows adapting more or less successfully to the demands of lactation (
      • Mezzetti M.
      • Bionaz M.
      • Trevisi E.
      Interaction between inflammation and metabolism in periparturient dairy cows.
      ). This paper provides a brief narrative review of current concepts of the role of inflammation in the transition period in reproductive health in dairy cows.
      Systemic inflammation is a concept in biomedical science (
      • Furman D.
      • Campisi J.
      • Verdin E.
      • Carrera-Bastos P.
      • Targ S.
      • Franceschi C.
      • Ferrucci L.
      • Gilroy D.W.
      • Fasano A.
      • Miller G.W.
      • Miller A.H.
      • Mantovani A.
      • Weyand C.M.
      • Barzilai N.
      • Goronzy J.J.
      • Rando T.A.
      • Effros R.B.
      • Lucia A.
      • Kleinstreuer N.
      • Slavich G.M.
      Chronic inflammation in the etiology of disease across the life span.
      ) that appears to have elements relevant to dairy cows in the transition period. Classically, inflammation is a response to tissue trauma or infection, producing heat, pain, swelling, or redness at the affected site. If inflammation is severe enough to produce systemic signs, there will also be fever, decreased feed intake (
      • Brown W.E.
      • Bradford B.J.
      Invited review: Mechanisms of hypophagia during disease.
      ), and changes in social behavior (
      • Proudfoot K.L.
      • Jensen M.B.
      • Weary D.M.
      • von Keyserlingk M.A.
      Dairy cows seek isolation at calving and when ill.
      ). However, new insights in human medicine in the past ~15 yr shifted this paradigm substantially. Systemic inflammation (also called sterile or metabolic inflammation) refers to chronic, low-grade inflammation that precedes and contributes to clinical disease risk (
      • Kotas M.E.
      • Medzhitov R.
      Homeostasis, inflammation, and disease susceptibility.
      ). This is primarily associated with obesity in people and rodent models, in which adipose macrophages release proinflammatory cytokines [e.g., tumor necrosis factor α (TNFα)] that lead to chronic systemic inflammation and insulin resistance (
      • Gregor M.F.
      • Hotamisligil G.S.
      Inflammatory mechanisms in obesity.
      ). One severe form of this syndrome is nonalcoholic fatty liver disease, which bears similarities to fatty liver disease seen in dairy cows (
      • Bobe G.
      • Young J.W.
      • Beitz D.C.
      Invited review: Pathology, etiology, prevention, and treatment of fatty liver in dairy cows.
      ). Systemic inflammation contributes to a heightened risk of type 2 diabetes and cardiovascular disease (
      • Hotamisligil G.S.
      Inflammation, metaflammation and immunometabolic disorders.
      ), which do not have direct parallels in dairy cows.
      There are intriguing parallels to some aspects of metabolism in transition cows that have inspired investigation of systemic inflammation in dairy cows. For example, dairy cows are in homeorrhetic (adaptive) peripheral insulin resistance, but this can be excessive or maladaptive. Most fresh cows are not obese and are in a catabolic state with substantial lipid mobilization. However, this level of oxidative stress and adipose activity might produce a state similar to metabolic inflammation in people (
      • Mavangira V.
      • Sordillo L.M.
      Role of lipid mediators in the regulation of oxidative stress and inflammatory responses in dairy cattle.
      ;
      • Bradford B.J.
      • Swartz T.H.
      Review: Following the smoke signals: Inflammatory signaling in metabolic homeostasis and homeorhesis in dairy cattle.
      ;
      • Zachut M.
      • Contreras G.A.
      Symposium review: Mechanistic insights into adipose tissue inflammation and oxidative stress in periparturient dairy cows.
      ). Short-term treatment of clinically healthy cows with nonsteroidal antiinflammatory drugs in the days after calving increased milk yield throughout lactation (
      • Farney J.K.
      • Mamedova L.K.
      • Coetzee J.F.
      • Minton J.E.
      • Hollis L.C.
      • Bradford B.J.
      Sodium salicylate treatment in early lactation increases whole-lactation milk and milk fat yield in mature dairy cows.
      ;
      • Carpenter A.J.
      • Ylioja C.M.
      • Mamedova L.K.
      • Olagaray K.E.
      • Bradford B.J.
      Effects of early postpartum sodium salicylate treatment on long-term milk, intake, and blood parameters of dairy cows.
      ;
      • Barragan A.A.
      • Hovingh E.
      • Bas S.
      • Lakritz J.
      • Byler L.
      • Ludwikowski A.
      • Takitch S.
      • Zug J.
      • Hann S.
      Effects of postpartum acetylsalicylic acid on metabolic status, health, and production in lactating dairy cattle.
      ). This suggests that modulation of postpartum inflammation in the absence of visible disease is beneficial and that systemic inflammation is at play in dairy cows.
      The direction of the association between inflammation and feed intake in transition dairy cows is not yet clear. A small but intriguing study (
      • Bertoni G.
      • Trevisi E.
      • Lombardelli R.
      Some new aspects of nutrition, health conditions and fertility of intensively reared dairy cows.
      ) of DMI in the transition period found that cows with an early and large decrease in DMI (~10% at −10 d with a further ~17% decrease at −5 d) had a substantial increase in circulating haptoglobin (Hp) concurrent with the onset of reduced intake. If activation of adipocytes by lipolysis and release of TNFα and IL-1β from adipose macrophages occurs because of decreased DMI, decreased intake could cause systemic inflammation (reflected in increased plasma Hp concentration). Feed restriction is used experimentally to induce “leaky gut,” which could initiate inflammation (
      • Kvidera S.K.
      • Horst E.A.
      • Sanz Fernandez M.V.
      • Abuajamieh M.
      • Ganesan S.
      • Gorden P.J.
      • Green H.B.
      • Schoenberg K.M.
      • Trout W.E.
      • Keating A.F.
      • Baumgard L.H.
      Characterizing effects of feed restriction and glucagon-like peptide 2 administration on biomarkers of inflammation and intestinal morphology.
      ), perhaps due to greater systemic exposure to LPS, but the required magnitude of restriction (≥60% reduction from ad libitum) is greater than that seen in
      • Bertoni G.
      • Trevisi E.
      • Lombardelli R.
      Some new aspects of nutrition, health conditions and fertility of intensively reared dairy cows.
      or is typical before calving (
      • Hayirli A.
      • Grummer R.R.
      • Nordheim E.V.
      • Crump P.M.
      Animal and dietary factors affecting feed intake during the prefresh transition period in Holsteins.
      ), even preceding clinical disease (
      • Huzzey J.M.
      • Veira D.M.
      • Weary D.M.
      • Von Keyserlingk M.A.G.
      Prepartum behavior and dry matter intake identify dairy cows at risk for metritis.
      ;
      • Pérez-Báez J.
      • Risco C.A.
      • Chebel R.C.
      • Gomes G.C.
      • Greco L.F.
      • Tao S.
      • Thompson I.M.
      • do Amaral B.C.
      • Zenobi M.G.
      • Martinez N.
      • Staples C.R.
      • Dahl G.E.
      • Hernández J.A.
      • Santos J.E.P.
      • Galvão K.N.
      Association of dry matter intake and energy balance prepartum and postpartum with health disorders postpartum: Part I. Calving disorders and metritis.
      ). Feed restriction of 50% in late-lactation cows did not induce changes in circulating LPS binding protein, endotoxin, serum amyloid A (SAA), or IL-1β (
      • Piantoni P.
      • Abeyta M.A.
      • Schroeder G.F.
      • Ramírez-Ramírez H.A.
      • Tucker H.A.
      • Baumgard L.H.
      Induction of leaky gut through feed restriction or abomasal infusion of resistant starch in healthy post-peak lactating cows.
      ). We applied a 40% feed restriction for 4 d to cows 2 wk before calving (
      • Pascottini O.B.
      • Carvalho M.R.
      • Van Schyndel S.J.
      • Ticiani E.
      • Spricigo J.W.
      • Mamedova L.K.
      • Ribeiro E.S.
      • LeBlanc S.J.
      Feed restriction to induce and meloxicam to mitigate potential systemic inflammation in dairy cows before calving.
      ). As expected, this induced substantial lipid mobilization, as evidenced by serum nonesterified fatty acid concentrations that tripled to levels similar to d −1 and 7 around calving. However, based on very similar serum concentrations of Hp and LPS binding protein during or after the feed restriction, we were not able to replicate the observations of
      • Bertoni G.
      • Trevisi E.
      • Lombardelli R.
      Some new aspects of nutrition, health conditions and fertility of intensively reared dairy cows.
      and did not detect evidence that even a substantial reduction in feed intake could cause systemic inflammation.
      Conversely, metabolic inflammation theory (
      • Kotas M.E.
      • Medzhitov R.
      Homeostasis, inflammation, and disease susceptibility.
      ;
      • Hotamisligil G.S.
      Foundations of immunometabolism and implications for metabolic health and disease.
      ) and knowledge of feed intake changes in illness (
      • Brown W.E.
      • Bradford B.J.
      Invited review: Mechanisms of hypophagia during disease.
      ) could support the hypothesis that systemic inflammation could reduce DMI. After calving, there are numerous strong candidate causes for this scenario, reviewed by
      • Bradford B.J.
      • Yuan K.
      • Farney J.K.
      • Mamedova L.K.
      • Carpenter A.J.
      Invited review: Inflammation during the transition to lactation: New adventures with an old flame.
      : calving trauma, metritis, mastitis, oxidative stress, or LPS from the rumen (
      • Plaizier J.C.
      • Mulligan F.J.
      • Neville E.W.
      • Guan L.L.
      • Steele M.A.
      • Penner G.B.
      Invited review: Effect of subacute ruminal acidosis on gut health of dairy cows.
      ) or the intestinal tract (
      • Kvidera S.K.
      • Horst E.A.
      • Sanz Fernandez M.V.
      • Abuajamieh M.
      • Ganesan S.
      • Gorden P.J.
      • Green H.B.
      • Schoenberg K.M.
      • Trout W.E.
      • Keating A.F.
      • Baumgard L.H.
      Characterizing effects of feed restriction and glucagon-like peptide 2 administration on biomarkers of inflammation and intestinal morphology.
      ). Before or after calving, social stress (e.g., due to pen changes or competition for feed access or lying space) or heat stress are additional possible triggers of systemic inflammation. Each of these is plausible, but none has compelling primary evidence in the cow as a cause of systemic inflammation in the transition period.
      On average, feed intake decreases starting 4 to 7 d before calving, but healthy, high-yielding cows have little decrease, followed by a greater DMI acceleration, and absolute DMI after calving (
      • Huzzey J.M.
      • Veira D.M.
      • Weary D.M.
      • Von Keyserlingk M.A.G.
      Prepartum behavior and dry matter intake identify dairy cows at risk for metritis.
      ;
      • Pérez-Báez J.
      • Risco C.A.
      • Chebel R.C.
      • Gomes G.C.
      • Greco L.F.
      • Tao S.
      • Thompson I.M.
      • do Amaral B.C.
      • Zenobi M.G.
      • Martinez N.
      • Staples C.R.
      • Dahl G.E.
      • Hernández J.A.
      • Santos J.E.P.
      • Galvão K.N.
      Association of dry matter intake and energy balance prepartum and postpartum with health disorders postpartum: Part I. Calving disorders and metritis.
      ). Under field conditions, between-cow variation or decreases in average prepartum intake can be magnified due to restricted feeding space and competition, social antagonism, periods of empty feed bunks or poor feed quality, heat stress, or lameness. However, despite the controlled environment of individually housed cows in research herds, there are still cows that have >20% reductions in DMI in the 7 to 10 d before calving (
      • Hammon D.S.
      • Evjen I.M.
      • Dhiman T.R.
      • Goff J.P.
      • Walters J.L.
      Neutrophil function and energy status in Holstein cows with uterine health disorders.
      ). It is an important challenge to decipher the reasons for this. If systemic inflammation is a possible cause, what could trigger inflammation in the last or second-last week before calving in cows that are neither obese nor visibly ill?
      Evidence of inflammation preceding disease in dairy cows exists. Calving inherently involves inflammation, both for the process of parturition and in response to inevitable trauma to and contamination of the reproductive tract. Accordingly, healthy cows have a transient increase in circulating Hp that peaks at about 3 DIM. Cows that have metritis have 2 to 3 times greater peak serum Hp at 3 to 6 DIM, preceding diagnosis of metritis by 1 to 4 d (
      • Huzzey J.M.
      • Duffield T.F.
      • LeBlanc S.J.
      • Veira D.M.
      • Weary D.M.
      • von Keyserlingk M.A.
      Short communication: Haptoglobin as an early indicator of metritis.
      ;
      • Dubuc J.
      • Duffield T.F.
      • Leslie K.E.
      • Walton J.S.
      • LeBlanc S.J.
      Risk factors for postpartum uterine diseases in dairy cows.
      ). Similarly elevated Hp in the first week postpartum (>0.8 g/L) was also associated with 2 times greater odds of purulent vaginal discharge (PVD) and 1.6 times greater odds of endometritis at 35 DIM (
      • Dubuc J.
      • Duffield T.F.
      • Leslie K.E.
      • Walton J.S.
      • LeBlanc S.J.
      Risk factors for postpartum uterine diseases in dairy cows.
      ). Others have shown similar increases in markers of inflammation before metritis (
      • Dervishi E.
      • Zhang G.
      • Hailemariam D.
      • Goldansaz S.
      • Deng Q.
      • Dunn S.M.
      • Ametaj B.N.
      Alterations in innate immunity reactants and carbohydrate and lipid metabolism precede occurrence of metritis in transition dairy cows.
      ) or ketosis (
      • Abuajamieh M.
      • Kvidera S.K.
      • Fernandez M.V.S.
      • Nayeri A.
      • Upah N.C.
      • Nolan E.A.
      • Lei S.M.
      • DeFrain J.M.
      • Green H.B.
      • Schoenberg K.M.
      • Trout W.E.
      • Baumgard L.H.
      Inflammatory biomarkers are associated with ketosis in periparturient Holstein cows.
      ;
      • Zhang G.
      • Hailemariam D.
      • Dervishi E.
      • Goldansaz S.A.
      • Deng Q.
      • Dunn S.M.
      • Ametaj B.M.
      Dairy cows affected by ketosis show alterations in innate immunity and lipid and carbohydrate metabolism during the dry off period and postpartum.
      ), among other diseases. These data point to inflammation preceding disease, which is consistent with several elements of systemic inflammation (
      • Furman D.
      • Campisi J.
      • Verdin E.
      • Carrera-Bastos P.
      • Targ S.
      • Franceschi C.
      • Ferrucci L.
      • Gilroy D.W.
      • Fasano A.
      • Miller G.W.
      • Miller A.H.
      • Mantovani A.
      • Weyand C.M.
      • Barzilai N.
      • Goronzy J.J.
      • Rando T.A.
      • Effros R.B.
      • Lucia A.
      • Kleinstreuer N.
      • Slavich G.M.
      Chronic inflammation in the etiology of disease across the life span.
      ).
      The best-described mediators of acute, and perhaps systemic, inflammation are TNFα, IL-1β, and IL-6 (
      • Holdsworth S.R.
      • Gan P.-Y.
      Cytokines: Names and numbers you should care about.
      ). These proteins can be measured in circulation in dairy cows, but the concentrations are low, ELISA assays are not consistently validated in the bovine (
      • Farney J.K.
      • Mamedova L.K.
      • Godsey B.H.
      • Bradford B.J.
      Technical note: Validation of an ELISA for measurement of tumor necrosis factor alpha in bovine plasma.
      ;
      • Sipka A.
      • Mann S.
      • Babasyan S.
      • Freer H.
      • Wagner B.
      Development of a bead-based multiplex assay to quantify bovine interleukin-10, tumor necrosis factor-α, and interferon-γ concentrations in plasma and cell culture supernatant.
      ), and results may be inconsistent (
      • Pascottini O.B.
      • Carvalho M.R.
      • Van Schyndel S.J.
      • Ticiani E.
      • Spricigo J.W.
      • Mamedova L.K.
      • Ribeiro E.S.
      • LeBlanc S.J.
      Feed restriction to induce and meloxicam to mitigate potential systemic inflammation in dairy cows before calving.
      ). Among their many effects, these proinflammatory cytokines change the synthesis and release of several acute phase proteins from the liver (
      • Ceciliani F.
      • Ceron J.J.
      • Eckersall P.D.
      • Sauerwein H.
      Acute phase proteins in ruminants.
      ). In the dairy cow, SAA, Hp, and albumin were useful markers of disease and inflammatory response in numerous studies (e.g., Huzzey al., 2009;
      • Dubuc J.
      • Duffield T.F.
      • Leslie K.E.
      • Walton J.S.
      • LeBlanc S.J.
      Risk factors for postpartum uterine diseases in dairy cows.
      ;
      • Chandler T.L.
      • Westhoff T.A.
      • Sipka A.S.
      • Overton T.R.
      • Mann S.
      Lipopolysaccharide challenge following intravenous amino acid infusion in postpartum dairy cows: II. Clinical and inflammatory responses.
      ;
      • Spaans O.K.
      • Kuhn-Sherlock B.
      • Hickey A.
      • Crookenden M.A.
      • Heiser A.
      • Burke C.R.
      • Phyn C.V.C.
      • Roche J.R.
      Temporal profiles describing markers of inflammation and metabolism during the transition period of pasture-based, seasonal-calving dairy cows.
      ; Table 1).
      Table 1Putative markers of systemic inflammation
      The list is not comprehensive but represents the better-described markers used in dairy cows in studies of peripartum inflammation, reproductive disease, or experimentally induced inflammation.
      In humansIn dairy cows
      Acute phase protein
       C-reactive proteinHaptoglobin
       Serum amyloid ASerum amyloid A
       AlbuminAlbumin
      LPS binding protein
      α-1 acid glycoprotein
      Cytokine
       Tumor necrosis factor α (TNFα)TNFα
       IL-1βIL-1β
       IL-6IL-6
      1 The list is not comprehensive but represents the better-described markers used in dairy cows in studies of peripartum inflammation, reproductive disease, or experimentally induced inflammation.
      Models of the acute inflammatory response can inform measurement of systemic inflammation. In experimentally induced acute inflammation in nonlactating dairy cows (i.v. LPS challenge), SAA concentrations increased in 6 to 12 h and remained elevated for 36 to 96 h (increasing with the dose of LPS from 0.01 to 1 μg/kg of BW), whereas Hp concentration increased at 36 h and was elevated until 48 to 144 h (
      • Jacobsen S.
      • Andersen P.H.
      • Toelboell T.
      • Heegaard P.M.
      Dose dependency and individual variability of the lipopolysaccharide-induced bovine acute phase protein response.
      ). In dairy cows at 8 DIM, i.v. infusion of 0.625 μg/kg of BW LPS over 1 h increased SAA 3- to 4-fold at 24 h and Hp 4- to 6-fold, with the peak at 48 h; concentrations of both proteins were decreasing but still elevated at 72 h (
      • Chandler T.L.
      • Westhoff T.A.
      • Sipka A.S.
      • Overton T.R.
      • Mann S.
      Lipopolysaccharide challenge following intravenous amino acid infusion in postpartum dairy cows: II. Clinical and inflammatory responses.
      ). Among cows with metritis, those with lower Hp concentrations (<0.5 to 0.8 g/L) at diagnosis were more likely to cure (
      • Machado V.S.
      • Celestino M.L.
      • Oliveira E.B.
      • Lima F.S.
      • Ballou M.A.
      • Galvão K.N.
      The association of cow-related factors assessed at metritis diagnosis with metritis cure risk, reproductive performance, milk yield, and culling for untreated and ceftiofur-treated dairy cows.
      ). The 30% of cows with metritis that had Hp <0.5 g/L at diagnosis and were untreated in a randomized controlled trial had similar milk yield and pregnancy outcomes to cows that did not have metritis (
      • Machado V.S.
      • Celestino M.L.
      • Oliveira E.B.
      • Lima F.S.
      • Ballou M.A.
      • Galvão K.N.
      The association of cow-related factors assessed at metritis diagnosis with metritis cure risk, reproductive performance, milk yield, and culling for untreated and ceftiofur-treated dairy cows.
      ). Albeit among cows with clinical disease, this hints at the possibility of classifying inflammatory status into levels to which the cow can respond successfully or which exceed the cow's resilience, contribute to undesirable outcomes, and might benefit from intervention.
      Although the concept fits with some of the metabolic circumstances of transition dairy cows, there are no validated criteria to diagnose systemic inflammation in cows. Some studies have attempted to classify cows or herds to an inflammatory “load” or “state” based on analysis of panels of circulating acute phase proteins in the transition period (
      • Bossaert P.
      • Trevisi E.
      • Opsomer G.
      • Bertoni G.
      • De Vliegher S.
      • Leroy J.L.
      The association between indicators of inflammation and liver variables during the transition period in high-yielding dairy cows: An observational study.
      ;
      • Schmitt R.
      • Pieper L.
      • Gonzalez-Grajales L.A.
      • Swinkels J.
      • Gelfert C.-C.
      • Staufenbiel R.
      Evaluation of different acute-phase proteins for herd health diagnostics in early postpartum Holstein Friesian dairy cows.
      ), but were of limited scope. A series of studies (summarized in
      • Bertoni G.
      • Trevisi E.
      Use of the liver activity index and other metabolic variables in the assessment of metabolic health in dairy herds.
      ) identified sets of markers in plasma (e.g., acute phase proteins, bilirubin, and metabolic markers such as cholesterol and vitamin A) used to classify liver “activity” or “functionality.” Although the primary studies (e.g.,
      • Trevisi E.
      • Amadori M.
      • Cogrossi S.
      • Razzuoli E.
      • Bertoni G.
      Metabolic stress and inflammatory response in high-yielding, periparturient dairy cows.
      ) had small numbers of animals selected based on extremes of the indexes, the patterns of numerous markers are similar to those seen in cows that go on to have displaced abomasum (
      • LeBlanc S.J.
      • Leslie K.E.
      • Duffield T.F.
      Metabolic predictors of displaced abomasum in dairy cattle.
      ), metritis (
      • Huzzey J.M.
      • Duffield T.F.
      • LeBlanc S.J.
      • Veira D.M.
      • Weary D.M.
      • von Keyserlingk M.A.
      Short communication: Haptoglobin as an early indicator of metritis.
      ), or endometritis (
      • Ishikawa Y.
      • Nakada K.
      • Hagiwara K.
      • Kirisawa R.
      • Iwai H.
      • Moriyoshi M.
      • Sawamukai Y.
      Changes in interleukin-6 concentration in peripheral blood of pre- and post-partum dairy cattle and its relationship to postpartum reproductive diseases.
      ;
      • Burke C.R.
      • Meier S.
      • McDougall S.
      • Compton C.
      • Mitchell M.
      • Roche J.R.
      Relationships between endometritis and metabolic state during the transition period in pasture-grazed dairy cows.
      ). Therefore, these markers may be useful candidate indicators of systemic inflammation. However, that will require a reference test. One approach would be to seek indicators of inflammation that are risk factors for subsequent disease, such as demonstrated for Hp before metritis (
      • Huzzey J.M.
      • Duffield T.F.
      • LeBlanc S.J.
      • Veira D.M.
      • Weary D.M.
      • von Keyserlingk M.A.
      Short communication: Haptoglobin as an early indicator of metritis.
      ;
      • Dubuc J.
      • Duffield T.F.
      • Leslie K.E.
      • Walton J.S.
      • LeBlanc S.J.
      Risk factors for postpartum uterine diseases in dairy cows.
      ). Another approach would be to seek markers of inflammation that identify clinically healthy cows that benefit (e.g., greater milk yield or better fertility) from receiving antiinflammatory treatment (
      • Farney J.K.
      • Mamedova L.K.
      • Coetzee J.F.
      • Minton J.E.
      • Hollis L.C.
      • Bradford B.J.
      Sodium salicylate treatment in early lactation increases whole-lactation milk and milk fat yield in mature dairy cows.
      ;
      • Bradford B.J.
      • Yuan K.
      • Farney J.K.
      • Mamedova L.K.
      • Carpenter A.J.
      Invited review: Inflammation during the transition to lactation: New adventures with an old flame.
      ). It remains to be seen whether systemic inflammation will be a quantifiable and actionable concept for transition dairy cows.
      Systemic inflammation seems to fit as a contributor to the balance between adaptive/homeorhetic changes in support of high milk yield and maladaptation and risk of disease or reduced performance. As discussed, there are numerous plausible causes of systemic inflammation in the early postpartum period. However, to potentially explain decreased feed intake before calving that may be caused by inflammation (
      • Bertoni G.
      • Trevisi E.
      • Lombardelli R.
      Some new aspects of nutrition, health conditions and fertility of intensively reared dairy cows.
      ;
      • Trevisi E.
      • Amadori M.
      • Cogrossi S.
      • Razzuoli E.
      • Bertoni G.
      Metabolic stress and inflammatory response in high-yielding, periparturient dairy cows.
      ) for at least some cows, one or more causes of systemic inflammation in the weeks before calving need to be identified.
      • Horst E.A.
      • Kvidera S.K.
      • Baumgard L.H.
      Invited review: The influence of immune activation on transition cow health and performance—A critical evaluation of traditional dogmas.
      posited that inflammation from immune activation leads to decreased DMI and, consequently, to hypocalcemia, elevated nonesterified fatty acid concentrations, and ketosis. They suggested that this flips the direction of association dogma that these risk factors contribute to the risk of disease, reduced milk yield, or fertility; rather, if excessive, they reflect direct or indirect consequences of inflammation. This is a useful challenge to paradigms of the physiology and epidemiology of health and performance in the transition period. They assert that compromised epithelial barriers in the gut, udder, or uterus are likely sources of immune activation. They suggest that mastitis, metritis, or leaky gut lead to LPS exposure and inflammation, which is consistent with several studies (
      • Huzzey J.M.
      • Duffield T.F.
      • LeBlanc S.J.
      • Veira D.M.
      • Weary D.M.
      • von Keyserlingk M.A.
      Short communication: Haptoglobin as an early indicator of metritis.
      ;
      • Dervishi E.
      • Zhang G.
      • Hailemariam D.
      • Goldansaz S.
      • Deng Q.
      • Dunn S.M.
      • Ametaj B.N.
      Alterations in innate immunity reactants and carbohydrate and lipid metabolism precede occurrence of metritis in transition dairy cows.
      ;
      • Zhang G.
      • Hailemariam D.
      • Dervishi E.
      • Goldansaz S.A.
      • Deng Q.
      • Dunn S.M.
      • Ametaj B.M.
      Dairy cows affected by ketosis show alterations in innate immunity and lipid and carbohydrate metabolism during the dry off period and postpartum.
      ). However, the main gap is an explanation of what might activate the immune system and inflammation in apparently healthy cows 1 to 2 wk before calving. Some candidate causes of prepartum inflammation include obesity (which fits with systemic/metabolic inflammation in humans but accounts for a minority of cows), excessive energy intake (
      • Khan M.J.
      • Jacometo C.B.
      • Riboni M.V.
      • Trevisi E.
      • Graugnard D.E.
      • Corrêa M.N.
      • Loor J.J.
      Stress and inflammatory gene networks in bovine liver are altered by plane of dietary energy during late pregnancy.
      ;
      • Janovick N.A.
      • Dann H.M.
      • Loor J.J.
      • Drackley J.K.
      Prepartum dietary energy intake alters hepatic expression of genes related to peroxisome proliferator-activated receptor and inflammation in peripartal dairy cows.
      ), or differences in the substantial inherent endocrine changes in late pregnancy (
      • Goff J.P.
      • Horst R.L.
      Physiological changes at parturition and their relationship to metabolic disorders.
      ).
      A line of study is emerging that may help to guide investigation of the relationship between inflammation and reproductive disease. Briefly, the idea is that the balance of signals representing pathogens [pathogen-associated molecular patterns (PAMP)] and tissue damage [damage-associated molecular patterns (DAMP)] modulates immune responses. Acute inflammation may be triggered by PAMP (infection) and DAMP (trauma), but systemic inflammation is suggested to be triggered by DAMP associated with metabolic dysfunction and more chronic tissue damage (
      • Furman D.
      • Campisi J.
      • Verdin E.
      • Carrera-Bastos P.
      • Targ S.
      • Franceschi C.
      • Ferrucci L.
      • Gilroy D.W.
      • Fasano A.
      • Miller G.W.
      • Miller A.H.
      • Mantovani A.
      • Weyand C.M.
      • Barzilai N.
      • Goronzy J.J.
      • Rando T.A.
      • Effros R.B.
      • Lucia A.
      • Kleinstreuer N.
      • Slavich G.M.
      Chronic inflammation in the etiology of disease across the life span.
      ). For postpartum reproductive disease in dairy cows, the best-described PAMP is LPS (
      • Sheldon I.M.
      • Cronin J.G.
      • Bromfield J.J.
      Tolerance and innate immunity shape the development of postpartum uterine disease and the impact of endometritis in dairy cattle.
      ). Phospholipids are found in all plasma membranes, and oxidized phospholipids act as DAMP to signal cell damage (
      • Zhivaki D.
      • Kagan J.C.
      Innate immune detection of lipid oxidation as a threat assessment strategy.
      ). These authors propose that oxidized phosphocholines in particular, which are not inherently pro- or antiinflammatory, combine with PAMP to modulate innate immune threat assessment and response. Detection of PAMP without oxidized phospholipids would indicate a lesser threat and presumably a milder response, whereas detection of PAMP and oxidized phospholipids signals a greater threat and heightened response (
      • Zhivaki D.
      • Kagan J.C.
      Innate immune detection of lipid oxidation as a threat assessment strategy.
      ). Broadly, this aligns with elements of the pathophysiology of reproductive disease in dairy cows (Table 2). There is a shift in the microbiome of cows that develop metritis or PVD to a lower diversity and greater abundance of gram-negative anaerobic bacteria, which expose the cow locally and systemically to LPS. Additionally, Trueperella pyogenes is an important gram-positive pathogen in uterine disease, especially PVD. A substantial part of the damage it causes appears to be attributable to its secreted toxin, pyolysin, but this has little effect on intact endometrial epithelial cells. However, if uterine stromal cells are exposed to pyolysin, as happens when the endometrial epithelium is damaged or sloughed after calving, substantial cellular damage occurs (
      • Amos M.R.
      • Healey G.D.
      • Goldstone R.J.
      • Mahan S.M.
      • Düvel A.
      • Schuberth H.J.
      • Sandra O.
      • Zieger P.
      • Dieuzy-Labaye I.
      • Smith D.G.
      • Sheldon I.M.
      Differential endometrial cell sensitivity to a cholesterol-dependent cytolysin links Trueperella pyogenes to uterine disease in cattle.
      ). Similarly, after many years without the means to reproduce PVD experimentally, a successful model uses scarification and infusion of Trueperella and Escherichia coli, as well as elevation of plasma progesterone (
      • Piersanti R.L.
      • Zimpel R.
      • Molinari P.C.C.
      • Dickson M.J.
      • Ma Z.
      • Jeong K.C.
      • Santos J.E.P.
      • Sheldon I.M.
      • Bromfield J.J.
      A model of clinical endometritis in Holstein heifers using pathogenic Escherichia coli and Trueperella pyogenes.
      ). Tissue trauma is a risk factor for uterine disease [e.g., indicated by vulvovaginal laceration for metritis (
      • Machado V.S.
      • Celestino M.L.
      • Oliveira E.B.
      • Lima F.S.
      • Ballou M.A.
      • Galvão K.N.
      The association of cow-related factors assessed at metritis diagnosis with metritis cure risk, reproductive performance, milk yield, and culling for untreated and ceftiofur-treated dairy cows.
      ) or dystocia, or retained placenta for metritis or PVD (
      • Dubuc J.
      • Duffield T.F.
      • Leslie K.E.
      • Walton J.S.
      • LeBlanc S.J.
      Risk factors for postpartum uterine diseases in dairy cows.
      )]. Additionally, local and systemic immune responses are attenuated to support pregnancy, and investigation is needed into whether and why some cows fail to upregulate inflammation successfully after calving (
      • Hansen P.J.
      Physiology and Endocrinology Symposium: Maternal immunological adjustments to pregnancy and parturition in ruminants and possible implications for postpartum uterine health: Is there a prepartum-postpartum nexus?.
      ). Finally, although endometritis seems in many cases to reflect persistent, dysregulated inflammation without differences in the uterine microbiome (
      • Pascottini O.B.
      • Van Schyndel S.J.
      • Spricigo J.F.W.
      • Rousseau J.
      • Weese J.S.
      • LeBlanc S.J.
      Dynamics of uterine microbiota in postpartum dairy cows with clinical or subclinical endometritis.
      ), other studies show benefits to fertility with intrauterine antimicrobial treatment of endometritis (
      • Denis-Robichaud J.
      • Dubuc J.
      Randomized clinical trial of intrauterine cephapirin infusion in dairy cows for the treatment of purulent vaginal discharge and cytological endometritis.
      ).
      Table 2Key features of postpartum reproductive tract disease in dairy cows
      Metritis refers to cows with fetid vulvar discharge with or without fever <14 d after calving. Purulent vaginal discharge (PVD) is muco-purulent or purulent discharge in the vagina at 4 to 6 wk postpartum. Endometritis is diagnosed based on >5% neutrophils in endometrial cytology at 4 to 6 wk postpartum.
      VariableDisease status
      HealthyMetritis and PVDEndometritis
      Uterine microbiomeDiverse microbiome. Potential pathogens (e.g., Bacteroides, Fusobacterium, and Porphorymonas spp.) are present but in low abundanceAltered microbiome from >2 DIM. Predominance of gram-negative anaerobes and (especially for PVD) Trueperella pyogenesNot associated with bacterial infection at diagnosis or with the uterine microbiome between calving and diagnosis
      Physical injuryMinimal trauma at calvingDystocia or visible physical trauma Probably greater loss or slower recovery of endometrial epitheliumNot associated with trauma
      Immune response and inflammationFast, robust, effective, well-regulated inflammatory response in the reproductive tract Returns to baseline by ~3 wk postpartumImpaired neutrophil function (primarily oxidative burst) precedes disease Uterine or cervical inflammation associated with pathological changes in the microbiomeGreater endometrial expression of proinflammatory genes ~2 wk postpartum (2–3 wk before diagnosis) Chronic uterine inflammation that is not associated with differences in the uterine microbiome before or at diagnosis at 4–5 wk postpartum
      Response to treatmentWell-documented benefits from antibiotic therapy (systemic ceftiofur or ampicillin for metritis; local cephapirin for PVD) Little evidence of benefit from antiinflammatory therapyMixed evidence of benefit of antimicrobial therapy Some evidence of benefit from nonsteroidal antiinflammatory therapy
      1 Metritis refers to cows with fetid vulvar discharge with or without fever <14 d after calving. Purulent vaginal discharge (PVD) is muco-purulent or purulent discharge in the vagina at 4 to 6 wk postpartum. Endometritis is diagnosed based on >5% neutrophils in endometrial cytology at 4 to 6 wk postpartum.
      Progress in understanding and applying the concept of systemic inflammation in transition dairy cows depends on defining and validating criteria to classify inflammation that is associated with impaired health or performance. A better understanding of the initiation and modulation of systemic and uterine inflammation will allow for improved prevention and treatment of postpartum reproductive disease.

      Notes

      This study received no external funding.
      No animals were used in this study, and ethical approval for the use of animals was thus deemed unnecessary.
      The author has not stated any conflicts of interest.

      References

        • Abuajamieh M.
        • Kvidera S.K.
        • Fernandez M.V.S.
        • Nayeri A.
        • Upah N.C.
        • Nolan E.A.
        • Lei S.M.
        • DeFrain J.M.
        • Green H.B.
        • Schoenberg K.M.
        • Trout W.E.
        • Baumgard L.H.
        Inflammatory biomarkers are associated with ketosis in periparturient Holstein cows.
        Res. Vet. Sci. 2016; 109 (27892878): 81-85
        • Amos M.R.
        • Healey G.D.
        • Goldstone R.J.
        • Mahan S.M.
        • Düvel A.
        • Schuberth H.J.
        • Sandra O.
        • Zieger P.
        • Dieuzy-Labaye I.
        • Smith D.G.
        • Sheldon I.M.
        Differential endometrial cell sensitivity to a cholesterol-dependent cytolysin links Trueperella pyogenes to uterine disease in cattle.
        Biol. Reprod. 2014; 90 (24478394): 54
        • Barragan A.A.
        • Hovingh E.
        • Bas S.
        • Lakritz J.
        • Byler L.
        • Ludwikowski A.
        • Takitch S.
        • Zug J.
        • Hann S.
        Effects of postpartum acetylsalicylic acid on metabolic status, health, and production in lactating dairy cattle.
        J. Dairy Sci. 2020; 103: 8443-8452
        • Bertoni G.
        • Trevisi E.
        Use of the liver activity index and other metabolic variables in the assessment of metabolic health in dairy herds.
        Vet. Clin. North Am. Food Anim. Pract. 2013; 29 (23809898): 413-431
        • Bertoni G.
        • Trevisi E.
        • Lombardelli R.
        Some new aspects of nutrition, health conditions and fertility of intensively reared dairy cows.
        Ital. J. Anim. Sci. 2009; 8: 491-518
        • Bobe G.
        • Young J.W.
        • Beitz D.C.
        Invited review: Pathology, etiology, prevention, and treatment of fatty liver in dairy cows.
        J. Dairy Sci. 2004; 87 (15377589): 3105-3124
        • Bossaert P.
        • Trevisi E.
        • Opsomer G.
        • Bertoni G.
        • De Vliegher S.
        • Leroy J.L.
        The association between indicators of inflammation and liver variables during the transition period in high-yielding dairy cows: An observational study.
        Vet. J. 2012; 192 (21742524): 222-225
        • Bradford B.J.
        • Swartz T.H.
        Review: Following the smoke signals: Inflammatory signaling in metabolic homeostasis and homeorhesis in dairy cattle.
        Animal. 2020; 14 (32024563): s144-s154
        • Bradford B.J.
        • Yuan K.
        • Farney J.K.
        • Mamedova L.K.
        • Carpenter A.J.
        Invited review: Inflammation during the transition to lactation: New adventures with an old flame.
        J. Dairy Sci. 2015; 98 (26210279): 6631-6650
        • Brown W.E.
        • Bradford B.J.
        Invited review: Mechanisms of hypophagia during disease.
        J. Dairy Sci. 2021; 104 (34099296): 9418-9436
        • Burke C.R.
        • Meier S.
        • McDougall S.
        • Compton C.
        • Mitchell M.
        • Roche J.R.
        Relationships between endometritis and metabolic state during the transition period in pasture-grazed dairy cows.
        J. Dairy Sci. 2010; 93 (20965352): 5363-5373
        • Carpenter A.J.
        • Ylioja C.M.
        • Mamedova L.K.
        • Olagaray K.E.
        • Bradford B.J.
        Effects of early postpartum sodium salicylate treatment on long-term milk, intake, and blood parameters of dairy cows.
        J. Dairy Sci. 2018; 101 (29224877): 1437-1447
        • Ceciliani F.
        • Ceron J.J.
        • Eckersall P.D.
        • Sauerwein H.
        Acute phase proteins in ruminants.
        J. Proteomics. 2012; 75 (22521269): 4207-4231
        • Chandler T.L.
        • Westhoff T.A.
        • Sipka A.S.
        • Overton T.R.
        • Mann S.
        Lipopolysaccharide challenge following intravenous amino acid infusion in postpartum dairy cows: II. Clinical and inflammatory responses.
        J. Dairy Sci. 2022; 105 (35282917): 4611-4623
        • de Lima F.S.
        Recent advances and future directions for uterine diseases diagnosis, pathogenesis, and management in dairy cows.
        Anim. Reprod. 2020; 17 (33029222)e20200063
        • Denis-Robichaud J.
        • Dubuc J.
        Randomized clinical trial of intrauterine cephapirin infusion in dairy cows for the treatment of purulent vaginal discharge and cytological endometritis.
        J. Dairy Sci. 2015; 98 (26210270): 6856-6864
        • Dervishi E.
        • Zhang G.
        • Hailemariam D.
        • Goldansaz S.
        • Deng Q.
        • Dunn S.M.
        • Ametaj B.N.
        Alterations in innate immunity reactants and carbohydrate and lipid metabolism precede occurrence of metritis in transition dairy cows.
        Res. Vet. Sci. 2016; 104 (26850534): 30-39
        • Dubuc J.
        • Duffield T.F.
        • Leslie K.E.
        • Walton J.S.
        • LeBlanc S.J.
        Risk factors for postpartum uterine diseases in dairy cows.
        J. Dairy Sci. 2010; 93 (21094748): 5764-5771
        • Farney J.K.
        • Mamedova L.K.
        • Coetzee J.F.
        • Minton J.E.
        • Hollis L.C.
        • Bradford B.J.
        Sodium salicylate treatment in early lactation increases whole-lactation milk and milk fat yield in mature dairy cows.
        J. Dairy Sci. 2013; 96 (24140330): 7709-7718
        • Farney J.K.
        • Mamedova L.K.
        • Godsey B.H.
        • Bradford B.J.
        Technical note: Validation of an ELISA for measurement of tumor necrosis factor alpha in bovine plasma.
        J. Dairy Sci. 2011; 94 (21700038): 3504-3509
        • Furman D.
        • Campisi J.
        • Verdin E.
        • Carrera-Bastos P.
        • Targ S.
        • Franceschi C.
        • Ferrucci L.
        • Gilroy D.W.
        • Fasano A.
        • Miller G.W.
        • Miller A.H.
        • Mantovani A.
        • Weyand C.M.
        • Barzilai N.
        • Goronzy J.J.
        • Rando T.A.
        • Effros R.B.
        • Lucia A.
        • Kleinstreuer N.
        • Slavich G.M.
        Chronic inflammation in the etiology of disease across the life span.
        Nat. Med. 2019; 25 (31806905): 1822-1832
        • Goff J.P.
        • Horst R.L.
        Physiological changes at parturition and their relationship to metabolic disorders.
        J. Dairy Sci. 1997; 80 (9241588): 1260-1268
        • Gregor M.F.
        • Hotamisligil G.S.
        Inflammatory mechanisms in obesity.
        Annu. Rev. Immunol. 2011; 29 (21219177): 415-445
        • Hammon D.S.
        • Evjen I.M.
        • Dhiman T.R.
        • Goff J.P.
        • Walters J.L.
        Neutrophil function and energy status in Holstein cows with uterine health disorders.
        Vet. Immunol. Immunopathol. 2006; 113 (16740320): 21-29
        • Hansen P.J.
        Physiology and Endocrinology Symposium: Maternal immunological adjustments to pregnancy and parturition in ruminants and possible implications for postpartum uterine health: Is there a prepartum-postpartum nexus?.
        J. Anim. Sci. 2013; 91: 1639-1649
        • Hayirli A.
        • Grummer R.R.
        • Nordheim E.V.
        • Crump P.M.
        Animal and dietary factors affecting feed intake during the prefresh transition period in Holsteins.
        J. Dairy Sci. 2002; 85 (12512616): 3430-3443
        • Holdsworth S.R.
        • Gan P.-Y.
        Cytokines: Names and numbers you should care about.
        Clin. J. Am. Soc. Nephrol. 2015; 10 (25941193): 2243-2254
        • Horst E.A.
        • Kvidera S.K.
        • Baumgard L.H.
        Invited review: The influence of immune activation on transition cow health and performance—A critical evaluation of traditional dogmas.
        J. Dairy Sci. 2021; 104 (34053763): 8380-8410
        • Hotamisligil G.S.
        Inflammation, metaflammation and immunometabolic disorders.
        Nature. 2017; 542 (28179656): 177-185
        • Hotamisligil G.S.
        Foundations of immunometabolism and implications for metabolic health and disease.
        Immunity. 2017; 47 (28930657): 406-420
        • Huzzey J.M.
        • Veira D.M.
        • Weary D.M.
        • Von Keyserlingk M.A.G.
        Prepartum behavior and dry matter intake identify dairy cows at risk for metritis.
        J. Dairy Sci. 2007; 90 (17582105): 3220-3233
        • Huzzey J.M.
        • Duffield T.F.
        • LeBlanc S.J.
        • Veira D.M.
        • Weary D.M.
        • von Keyserlingk M.A.
        Short communication: Haptoglobin as an early indicator of metritis.
        J. Dairy Sci. 2009; 92 (19164673): 621-625
        • Ishikawa Y.
        • Nakada K.
        • Hagiwara K.
        • Kirisawa R.
        • Iwai H.
        • Moriyoshi M.
        • Sawamukai Y.
        Changes in interleukin-6 concentration in peripheral blood of pre- and post-partum dairy cattle and its relationship to postpartum reproductive diseases.
        J. Vet. Med. Sci. 2004; 66 (15585955): 1403-1408
        • Jacobsen S.
        • Andersen P.H.
        • Toelboell T.
        • Heegaard P.M.
        Dose dependency and individual variability of the lipopolysaccharide-induced bovine acute phase protein response.
        J. Dairy Sci. 2004; 87 (15377612): 3330-3339
        • Janovick N.A.
        • Dann H.M.
        • Loor J.J.
        • Drackley J.K.
        Prepartum dietary energy intake alters hepatic expression of genes related to peroxisome proliferator-activated receptor and inflammation in peripartal dairy cows.
        J. Dairy Sci. 2022; 105: 8069-8086
        • Khan M.J.
        • Jacometo C.B.
        • Riboni M.V.
        • Trevisi E.
        • Graugnard D.E.
        • Corrêa M.N.
        • Loor J.J.
        Stress and inflammatory gene networks in bovine liver are altered by plane of dietary energy during late pregnancy.
        Funct. Integr. Genomics. 2015; 15: 563-576
        • Kotas M.E.
        • Medzhitov R.
        Homeostasis, inflammation, and disease susceptibility.
        Cell. 2015; 160 (25723161): 816-827
        • Kvidera S.K.
        • Horst E.A.
        • Sanz Fernandez M.V.
        • Abuajamieh M.
        • Ganesan S.
        • Gorden P.J.
        • Green H.B.
        • Schoenberg K.M.
        • Trout W.E.
        • Keating A.F.
        • Baumgard L.H.
        Characterizing effects of feed restriction and glucagon-like peptide 2 administration on biomarkers of inflammation and intestinal morphology.
        J. Dairy Sci. 2017; 100 (28918138): 9402-9417
        • LeBlanc S.J.
        • Leslie K.E.
        • Duffield T.F.
        Metabolic predictors of displaced abomasum in dairy cattle.
        J. Dairy Sci. 2005; 88 (15591379): 159-170
        • Machado V.S.
        • Celestino M.L.
        • Oliveira E.B.
        • Lima F.S.
        • Ballou M.A.
        • Galvão K.N.
        The association of cow-related factors assessed at metritis diagnosis with metritis cure risk, reproductive performance, milk yield, and culling for untreated and ceftiofur-treated dairy cows.
        J. Dairy Sci. 2020; 103 (32828506): 9261-9276
        • Mavangira V.
        • Sordillo L.M.
        Role of lipid mediators in the regulation of oxidative stress and inflammatory responses in dairy cattle.
        Res. Vet. Sci. 2018; 116: 4-14
        • Mezzetti M.
        • Bionaz M.
        • Trevisi E.
        Interaction between inflammation and metabolism in periparturient dairy cows.
        J. Anim. Sci. 2020; 98 (32810244): S155-S174
        • Pascottini O.B.
        • Carvalho M.R.
        • Van Schyndel S.J.
        • Ticiani E.
        • Spricigo J.W.
        • Mamedova L.K.
        • Ribeiro E.S.
        • LeBlanc S.J.
        Feed restriction to induce and meloxicam to mitigate potential systemic inflammation in dairy cows before calving.
        J. Dairy Sci. 2019; 102 (31400891): 9285-9297
        • Pascottini O.B.
        • Van Schyndel S.J.
        • Spricigo J.F.W.
        • Rousseau J.
        • Weese J.S.
        • LeBlanc S.J.
        Dynamics of uterine microbiota in postpartum dairy cows with clinical or subclinical endometritis.
        Sci. Rep. 2020; 10 (32704012)12353
        • Pérez-Báez J.
        • Risco C.A.
        • Chebel R.C.
        • Gomes G.C.
        • Greco L.F.
        • Tao S.
        • Thompson I.M.
        • do Amaral B.C.
        • Zenobi M.G.
        • Martinez N.
        • Staples C.R.
        • Dahl G.E.
        • Hernández J.A.
        • Santos J.E.P.
        • Galvão K.N.
        Association of dry matter intake and energy balance prepartum and postpartum with health disorders postpartum: Part I. Calving disorders and metritis.
        J. Dairy Sci. 2019; 102 (31326177): 9138-9150
        • Piantoni P.
        • Abeyta M.A.
        • Schroeder G.F.
        • Ramírez-Ramírez H.A.
        • Tucker H.A.
        • Baumgard L.H.
        Induction of leaky gut through feed restriction or abomasal infusion of resistant starch in healthy post-peak lactating cows.
        J. Dairy Sci. 2018; 101 (Abstr.): 228
        • Piersanti R.L.
        • Zimpel R.
        • Molinari P.C.C.
        • Dickson M.J.
        • Ma Z.
        • Jeong K.C.
        • Santos J.E.P.
        • Sheldon I.M.
        • Bromfield J.J.
        A model of clinical endometritis in Holstein heifers using pathogenic Escherichia coli and Trueperella pyogenes.
        J. Dairy Sci. 2019; 102 (30692014): 2686-2697
        • Plaizier J.C.
        • Mulligan F.J.
        • Neville E.W.
        • Guan L.L.
        • Steele M.A.
        • Penner G.B.
        Invited review: Effect of subacute ruminal acidosis on gut health of dairy cows.
        J. Dairy Sci. 2022; 105 (35879171): 7141-7160
        • Proudfoot K.L.
        • Jensen M.B.
        • Weary D.M.
        • von Keyserlingk M.A.
        Dairy cows seek isolation at calving and when ill.
        J. Dairy Sci. 2014; 97 (24630650): 2731-2739
        • Schmitt R.
        • Pieper L.
        • Gonzalez-Grajales L.A.
        • Swinkels J.
        • Gelfert C.-C.
        • Staufenbiel R.
        Evaluation of different acute-phase proteins for herd health diagnostics in early postpartum Holstein Friesian dairy cows.
        J. Dairy Res. 2021; 88 (33594968): 33-37
        • Sheldon I.M.
        • Cronin J.G.
        • Bromfield J.J.
        Tolerance and innate immunity shape the development of postpartum uterine disease and the impact of endometritis in dairy cattle.
        Annu. Rev. Anim. Biosci. 2019; 7 (30359085): 361-384
        • Sheldon I.M.
        • Molinari P.C.C.
        • Ormsby T.J.R.
        • Bromfield J.J.
        Preventing postpartum uterine disease in dairy cattle depends on avoiding, tolerating and resisting pathogenic bacteria.
        Theriogenology. 2020; 150 (31973964): 158-165
        • Sipka A.
        • Mann S.
        • Babasyan S.
        • Freer H.
        • Wagner B.
        Development of a bead-based multiplex assay to quantify bovine interleukin-10, tumor necrosis factor-α, and interferon-γ concentrations in plasma and cell culture supernatant.
        JDS Commun. 2022; 3: 207-211
        • Spaans O.K.
        • Kuhn-Sherlock B.
        • Hickey A.
        • Crookenden M.A.
        • Heiser A.
        • Burke C.R.
        • Phyn C.V.C.
        • Roche J.R.
        Temporal profiles describing markers of inflammation and metabolism during the transition period of pasture-based, seasonal-calving dairy cows.
        J. Dairy Sci. 2022; 105 (34998544): 2669-2698
        • Trevisi E.
        • Amadori M.
        • Cogrossi S.
        • Razzuoli E.
        • Bertoni G.
        Metabolic stress and inflammatory response in high-yielding, periparturient dairy cows.
        Res. Vet. Sci. 2012; 93 (22197526): 695-704
        • Zachut M.
        • Contreras G.A.
        Symposium review: Mechanistic insights into adipose tissue inflammation and oxidative stress in periparturient dairy cows.
        J. Dairy Sci. 2022; 105 (35151484): 3670-3686
        • Zhang G.
        • Hailemariam D.
        • Dervishi E.
        • Goldansaz S.A.
        • Deng Q.
        • Dunn S.M.
        • Ametaj B.M.
        Dairy cows affected by ketosis show alterations in innate immunity and lipid and carbohydrate metabolism during the dry off period and postpartum.
        Res. Vet. Sci. 2016; 107 (27474003): 246-256
        • Zhivaki D.
        • Kagan J.C.
        Innate immune detection of lipid oxidation as a threat assessment strategy.
        Nat. Rev. Immunol. 2022; 22 (34548649): 322-330