J. Dairy Sci. 86:3430-3439
© American Dairy Science Association, 2003.
Imbalance Between Lipoxin A4 and Leukotriene B4 in Chronic Mastitis-Affected Cows
P. Boutet*,
F. Bureau*,
G. Degand
and
P. Lekeux*
* Department of Physiology and
Department of Analysis of Foodstuffs of Animal Origin, Faculty of Veterinary Medicine, University of Liège, B-4000 Liège, Belgium
Corresponding author: P. Boutet; e-mail: philippe.boutet{at}ulg.ac.be.
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ABSTRACT
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Persistent accumulation of inflammatory cells in the udder, with neutrophils being the predominant cell type, is a characteristic feature of chronic mastitis in dairy cows. Leukotriene (LT) B4 is a potent chemotactic agent, known to induce recruitment and accumulation of neutrophils in the bovine mammary gland. The LTB4-stimulated neutrophil functional responses are closely opposed by lipoxin (LX) A4, which promotes the resolution of inflammation. We thus hypothesized that the chronic inflammation of the udder could be associated with an unfavorable ratio between these two eicosanoids and that the persistence of neutrophil accumulation could be due to an increase in LTB4 synthesis and/or an impaired LXA4 production. In an attempt to verify this hypothesis, we first measured LXA4, LTB4, and their ratio in the milk of healthy and acute and chronic mastitis-affected quarters. Next, we studied the relationships between these variables and the degree of udder inflammation as assessed by somatic cell count measurement. The LTB4 concentration was low in healthy quarters, drastically increased in acute mastitis, and reached intermediate levels in chronic mastitis-affected quarters. However, whereas LXA4 concentration was highly increased in acute mastitis, healthy and chronic quarters had similarly low values. The LXA4:LTB4 ratio was thus significantly lower in chronic mastitis-affected cows. The LTB4 concentrations measured in chronic quarters were highly correlated to somatic cell count and to milk neutrophil and macrophage numbers. A weaker correlation was observed between LXA4 and these variables. For both eicosanoids, the highest correlation was observed with the number of neutrophils. These results show the existence of an LXA4:LTB4 imbalance in chronic mastitis-affected cows because of low LXA4 concentrations. Further studies are needed to determine whether administration of LX or stable analogs could have therapeutic potential in the control of chronic bovine mastitis.
Key Words: chronic mastitis • imbalance • leukotriene B4 • lipoxin A4
Abbreviation key: ATL = aspirin-triggered lipoxin, LO = lipoxygenase, LT = leukotriene, LX = lipoxin, NF-
B = nuclear factor B, PMN = polymorphonuclear leukocytes, QMS = quarter milk sample, TNF = tumor necrosis factor
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INTRODUCTION
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Mastitis is an inflammatory reaction within the udder, usually resulting from bacterial infection (Harmon, 1994). Chronic subclinical mastitis is frequent and causes major economic losses in dairy cattle due to damage to alveolar tissues, reduction in milk yield, and deterioration in milk composition (Gudding et al., 1984). A better understanding of the mechanisms by which inflammation persists in the udder therefore represents a great challenge.
The most common bacteria associated with subclinical infections are contagious mastitis pathogens, such as Staphylococcus aureus and Streptococcus agalactiae, for which the major reservoir is the infected udder (Eberhart et al., 1987). When bacteria enter the mammary gland, a drastic increase in milk SCC occurs, with polymorphonuclear (PMN) neutrophil being the predominant cell type (Paape et al., 1979; Burvenich et al., 1994). Migration of neutrophils to the site of inflammation is one of the most important defense mechanisms. Neutrophils need to be recruited promptly and in sufficient numbers to avoid excessive growth of bacteria and death of the animal (Burvenich et al., 1994). However, neutrophils can also be detrimental to tissues by releasing intracellular products that exacerbate the inflammatory process resulting in chronic inflammation, thus impairing the function of the organ (Harmon, 1994).
Neutrophil recruitment and sequestration to sites of inflammation is initiated by proinflammatory mediators, among which leukotriene (LT) B4 is considered to be important (Ford-Hutchinson et al., 1980; Weissmann et al., 1980; Samuelsson, 1983). Leukotriene B4 is formed by the breakdown of arachidonic acid, via the 5-lipoxygenase (LO) enzyme pathway, giving LTA4 then converted to LTB4. Rose et al. (1989) revealed LTB4 in the milk of Klebsiella pneumoniae-inoculated quarters and suggested that neutrophils initially attracted to a mastitic quarter may be stimulated to release LTB4, which may in turn increase neutrophil migration and prolong neutrophil survival in mammary tissue. This leads to the assumption that persistence of LTB4 production could be of particular importance in the pathogenesis of chronic inflammation in mastitis.
The natural resolution of an inflammatory response is fundamental to health. It depends on multiple processes that include the generation of endogenous "breaking signals" that facilitate a return to the premorbid state (McMahon et al., 2001). Recent results provide evidence for a new appreciation that certain LO-derived eicosanoids possess potent "anti-PMN" actions and anti-inflammatory properties (Serhan et al., 1996; Diamond et al., 1999; Munger et al., 1999). In particular, lipoxins (LX), such as LXA4 and aspirin-triggered LX (ATL), are arachidonic acid-derived bioactive lipids as a result of their exposure to the unique combinations of lipoxygenases that occur during specific heterotypic cell–cell interactions, such those occurring during inflammation (e.g., epithelial–neutrophil interactions). Mobilization of a LX biosynthetic circuit occurs, for example, when infiltrating PMN (which express 5-LO) interact with tissue resident cells (which express 15-LO) in inflamed target organs (Fierro and Serhan, 2001). These molecules appear to play an important role in downregulating neutrophil responses in inflammation (Serhan, 1997). In vitro studies have shown that LXA4, ATL, and stable synthetic LX analogs inhibit PMN chemotaxis in response to LTB4 (Lee et al., 1989; 1991). In experimental models in vivo, LXA4 inhibits LTB4-induced neutrophil margination and diapedesis in the hamster cheek pouch (Hedqvist et al., 1989) and in the mouse ear model of inflammation (Takano et al., 1997). Moreover, injection of a stable synthetic mimetic of ATL into murine dorsal air pouches inhibits leukocyte (neutrophils, eosinophils, basophils, and mononuclear cells) recruitment in response to tumor necrosis factor (TNF)-
(Hachicha et al., 1999), which stimulates the release of IL-8, a potent chemoattractant for neutrophils (Baggiolini et al., 1989; Persson et al., 1993). Furthermore, LX significantly enhances phagocytosis of apoptotic PMN by human monocyte-derived macrophage in vitro, which suggests that LX can promote the clearance of apoptotic leukocytes by macrophages at the inflammatory site (Godson et al., 2000).
Knowing that LXA4 is an anti-inflammatory eicosanoid that is closely opposed to LTB4, a potent chemotactic eicosanoid, we hypothesized that persistent accumulation of neutrophils in chronic mastitis could be due, at least in part, to an increase in LTB4 synthesis and/or impaired LXA4 production in the udder. In an attempt to verify this hypothesis, we first measured LXA4, LTB4, and their ratio in milk of healthy, acute, and chronic mastitis-affected quarters. Next, we studied the relationships between these variables and the degree of udder inflammation as assessed by SCC measurement.
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MATERIALS AND METHODS
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Animals
Twenty-five healthy, 8 acute, and 40 chronic mastitis-affected Holstein-Friesian cows were used in this study. Healthy cows had a low SCC (<105 cells/ml) and were free of any clinical sign of mastitis. Acute mastitis-affected cows had high SCC (>107 cells/ml) and exhibited clinical signs of illness. Neither healthy nor acute mastitis-affected cows had any earlier record of udder disease as measured by clinical symptoms and monthly SCC recordings. Chronic mastitis-affected cows had persistently increased SCC (at least 3 consecutive times >4 x 105 cells/ml), as determined by monthly SCC measurements, but were devoid of any clinical sign of the disease. In order to enter in the study, the chronic quarter SCC had to be >4 x 105 cells/ml at the sampling time. All the cows were between 2 and 8 yr old, had a lactation number ranging from 1 to 6, and were lactating for 3 to 8 mo. Experimental cows did not receive any treatment during the month preceding the experiments.
Sterile Milk Sampling
Quarter milk samples (QMS), taken from one quarter, were collected prior to milking using sampling procedures recommended by the National Mastitis Council (1999). Teat ends were vigorously disinfected with a solution containing 70% alcohol. Approximately 10 ml of milk were collected into sterile vials. Samples were placed in freezer packs and delivered immediately to the mastitis diagnosis laboratory (Centres de Prévention et de Guidance Vétérinaire, Loncin, Belgium). Another 50-ml vial was collected for total and differential cell counts and LXA4 and LTB4 analyses.
Microbiological Analysis
Each QMS was incubated overnight at 37°C. Afterwards, aliquots (10 µl) of each QMS were spread on sheep blood agar, McKonckey agar, M4 agar (selective for Streptococcus spp.), and Ektoen agar (selective for Enterobacteriaceae), and the plates were incubated for another 24 h. Colonies were identified using a classical procedure and appropriate API Sugar sets (BioMérieux, Marcy l’ Etoile, France) and Crystal (Becton Dickinson, Erembodegem-Aalst, Belgium). Isolation of at least one colony of one to three species of bacteria was considered to be an intramammary infection. If three or more bacterial species grew from any sample, that sample was considered contaminated and was excluded from the study. Because one negative QMS does not signify the absence of infection, and because Sta. aureus is shed in a cyclical manner from mammary glands (Sears et al., 1990), 2 or 3 consecutive samples were sometimes necessary for accurate diagnosis of infected quarters. As acute infections were frequently treated after the first sampling, only 1 sample was taken in acute mastitis-affected cows.
Total and Differential Cell Count
Immediately after milk collection, 50 ml of each sample was shipped to the Laboratory of the Milk Committee (Battice, Belgium), where a SCC was performed with a Fossomatic Automatic Cell Counter (Foss Electric, Hjillerød, Denmark).
To determine the somatic cell type, high-SCC milk was diluted in PBS. Low-SCC milk was centrifuged (300 x g) for 20 min at 4°C. Pellets were then suspended in 1 ml of PBS. Cell differentials were performed on 300-µl cytospin samples stained with May-Grundwald Giemsa (VWR, Leuven, Belgium). Neutrophils, lymphocytes, macrophages, and epithelial cells were differentiated according to their morphology. Three hundred cells were counted and the results of cell differentiation were expressed for each cell type as a proportion of the total number of cells counted.
Determination of Milk Eicosanoid Concentrations
Duplicate determinations of LXA4 and LTB4 milk concentrations were performed using specific ELISA (Neogen, Lexington, KY; range was 40 to 4000 pg/ml in the LTB4 kit, 20 to 2000 pg/ml in the LXA4 kit; cross-reactivities were <1 % for LTC4 and LTD4 and <0.1% for arachidonic acid in the LTB4 kit, 1% for LXB4 and <0.01% for LTB4 in the LXA4 kit). Radiolabeled LTB4 ([3H] LTB4, Amersham Pharmacia Biotech, Gent, Belgium) was included to calculate recoveries which were always >90%. Acute QMS were filtered with 70-µm cell strainers (Becton Dickinson) in order to discard cell clusters. One milliliter of QMS was diluted with 1 ml of distilled water, and 1 ml of the mixture was loaded on a 100-mg C18 column (Varian, St-Katelijne-Waver, Belgium) after conditioning with 2 ml of distilled water followed by 2 ml of methanol. The column was subsequently washed with 1 ml of each of the following substances: distilled water, methanol:distilled water (30:70), and hexane. The column was centrifuged at 3200 x g for 3 min to withdraw any trace of hexane. Finally, eicosanoids were eluted from the C18 column with 1 ml of methanol. The collected eluate was evaporated to dryness under a stream of nitrogen. Dried samples were reconstituted in an appropriated volume of assay buffer.
Statistical Analysis
Data are presented as means ± standard errors of the mean. The differences between mean values were estimated using an ANOVA with subsequent Fisher's protected least significant difference test. Linear associations between variables were assessed by the use of standard least squares linear regressions. Correlation coefficients were presented as measures of linear association for regression relationships. Significant differences of the slopes from zero were determined using two-tailed Student's t-test. A P-value < 0.05 was considered significant.
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RESULTS
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Sample Characterization
Cellular characteristics of milk samples recovered from healthy, acute, and chronic mastitis-affected cows are provided in Table 1
. The SCC in milk samples from healthy cows was always <105 cells/ml. Conversely, mastitis was accompanied by a drastic increase in SCC, which was always >107 in the acute form of the disease and ranged from 4.31 x 105 to 107 cells/ml in the chronic form. Differential cell counts showed a significant increase in the percentage of neutrophils associated with a significant decrease in the percentages of lymphocytes and macrophages in milk samples from cows suffering from mastitis compared with healthy cows.
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Table 1. Cellular characteristics of milk recovered from healthy, chronic and acute mastitis-affected quarters (data are presented as mean ± SEM).
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Table 2 shows bacterial species isolated from milk samples of healthy and acute and chronic mastitis-affected quarters. Some quarters were infected by two organisms. Only one healthy quarter was shown to contain an infectious agent, namely Sta. aureus. Streptococcus uberis was the main pathogen isolated in acute infections (37.5%). Interestingly, no bacteria were found in 2 of the 8 acute quarters. Maybe using a single milk sample, rather than three, reduced the sensitivity of diagnosis in this group. Pathogen bacteria were detected in all chronic mastitis-affected quarters, with Str. uberis being the main infectious agent present in those quarters (34%). In this form of the disease, the incidence of Sta. aureus was high, reaching 27.7%.
LXA4 and LTB4 Concentrations in Healthy and Mastitis-Affected Quarters
As expected, LTB4 values were low in milk from healthy quarters and were drastically increased in the acute mastitis-affected quarters (Figure 1A). In chronic infections, LTB4 concentrations reached intermediate levels, which were significantly different from those of healthy and acute mastitis-affected quarters (Figure 1A). The LXA4 concentrations were always lower than the LTB4 concentrations. As observed for LTB4 concentrations, LXA4 values were low in milk from healthy quarters and were highly increased in the acute mastitis-affected quarters (Figure 1B). However, in chronic mastitis-affected quarters, LXA4 concentrations were comparable to those recorded in healthy quarters (P = 0.95), so that the LXA4:LTB4 ratio was significantly lower in chronic quarters compared with those observed in healthy and acute mastitis-affected quarters, which were not significantly different (P = 0.37) (Figure 1C). These results show the existence of an imbalance between LXA4 and LTB4 in the chronic inflammation of the bovine udder, which could be due to a defect of LXA4 synthesis.
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Figure 1. Mean leukotriene (LT) B4 (A) and lipoxin (LX) A4 (B) concentrations and LXA4:LTB4 ratio (C) in milk obtained from healthy (n = 25), chronic (n = 40), and acute (n = 8) mastitis-affected quarters. Data are presented as means ± SD. *Significantly different from the mean obtained with samples of healthy quarters (P < 0.001). Significantly different from the mean obtained with samples of acute quarters (P < 0.001).
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Relationship Between LXA4-LTB4 and SCC in the Chronic Mastitis-Affected Quarters
To better characterize chronic mastitis, in terms of LTB4 and LXA4 production, QMS recovered from chronically affected quarters were categorized into 5 groups according to the SCC measured at sampling time (group 1, 4 x 105 
SCC < 7 x 105; group 2, 7 x 105 SCC < 106; group 3, 106 SCC < 2 x 106; group 4, 2 x 106 SCC < 4 x 106; group 5, SCC 
4 x 106 cells/ml). The values obtained in the 5 groups were compared with those from healthy and acute mastitis-affected quarters. Cellular characteristics of samples recovered from the five groups of quarters are provided in Table 3. As expected, neutrophil percentages gradually increased with the number of somatic cells, whereas macrophage percentages decreased. Lymphocyte percentages remained low in all categories. Bacterial species isolated from samples obtained in the five groups are shown in Table 4. Some quarters were infected by two organisms.
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Table 3. Cellular characteristics of milk recovered from chronic mastitis-affected quarters categorized according to the somatic cell count measured at sampling time.
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Table 4. Bacterial species isolated from milk of chronic mastitis-affected quarters categorized according to the somatic cell count measured at sampling time.
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Eicosanoid concentrations measured in the 5 categories of chronic mastitis-affected quarters were compared with each other and with the concentrations recorded in healthy and acute mastitis-affected quarters (Figure 2). The LTB4 values from groups 1 to 4 were approximately twofold higher than those from healthy quarters (Figure 2A). Mean LTB4 concentrations in group 5 were drastically higher than those of the other groups, but were significantly lower than the acute mastitis-affected quarters mean (Figure 2A). The means of LXA4 concentrations recorded in the 5 chronic groups were all similar to the values obtained in the healthy quarters (Figure 2B). The LXA4:LTB4 ratio in each group of chronic mastitis-affected quarters was thus significantly lower than that of healthy quarters (Figure 2C). Only the LXA4:LTB4 ratio of group 1 was not significantly lower (P = 0.35) than that of the acute mastitis-affected quarters (Figure 2C). These results confirm that whatever the SCC, an imbalance between LXA4 and LTB4 concentrations occurs in the chronic inflammation of the bovine udder because chronic mastitis-affected cows display lower LXA4 concentrations than acute mastitis-affected cows for these potentially protective lipid mediators.
Next, we studied the relationships between each eicosanoid and the degree of udder inflammation as assessed by SCC measurement in chronic mastitis-affected quarters. Accordingly, linear regressions were carried out to assess the relationship between each eicosanoid concentration and SCC, but also between each eicosanoid and the number of neutrophils and macrophages present in milk samples (Figure 3). These regression analyses showed that LTB4 concentration measured in chronic mastitis-affected quarters was highly correlated to SCC, neutrophil, and macrophage numbers. A lower but significant correlation was also observed between LXA4 concentrations and SCC, and neutrophil and macrophage numbers. For each eicosanoid, the highest correlation was observed when comparing LXA4 and LTB4 concentrations with neutrophil number (r = 0.84 for LTB4 and r = 0.53 for LXA4).
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Figure 3. Relationship between leukotriene (LT) B4 and lipoxin (LX) A4 concentrations and SCC (A) and neutrophil (B) and macrophage numbers (C) in milk samples obtained from chronic mastitis-affected quarters.
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No significant correlation was found between eicosanoids concentrations in milk samples and age, stage of lactation, or pathogen.
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DISCUSSION
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Persistent accumulation of inflammatory cells in the udder, with neutrophil being the predominant cell type, is a characteristic feature of chronic mastitis in dairy cows. Leukotriene B4 is a potent chemotactic agent, known to induce recruitment and accumulation of neutrophils in the bovine mammary gland. Leukotriene-stimulated neutrophil functional responses are opposed by LX which represent a unique class of lipid mediators with potent anti-inflammatory actions, like inhibition of neutrophil recruitment by attenuating their chemotaxis, adhesion, and transmigration across vascular and endothelial cells (Serhan, 1997). Moreover, it has been recently demonstrated that LXA4, aspirin-triggered 15-epi-LXA4, and their stable analogs were able to downregulate IL-8 secretion and subsequent recruitment of neutrophils by intestinal epithelia (Gronert et al., 1998). This was due to downregulation of proinflammatory gene expression via inhibition of the nuclear factor B (NF-B) pathway (Gewirtz et al., 2002). This observation is of particular interest because most of the genes encoding inflammatory proteins involved in neutrophil migration and activation have been shown to contain B sites for NF-B within their promoter, and therefore to partly depend on NF-B for their expression (Pahl, 1999). Boulanger et al. (2003) have recently demonstrated that NF-B activity was increased in milk cells from chronic mastitis-affected cows.
All of these considerations led us to hypothesize that the chronic inflammation of the udder could be associated with an unfavorable ratio between these two eicosanoids and that the persistence of neutrophil accumulation could be due to an increase in LTB4 synthesis and/or an impaired LXA4 production. In the present study, we have measured LXA4 and LTB4 concentrations and their ratio in milk of healthy, acute, and chronic mastitis-affected quarters. We showed that LTB4 and LXA4 concentrations were low in healthy quarters but were drastically increased in acute mastitis. In chronic mastitis-affected quarters, although LTB4 concentrations increased with the SCC, LXA4 concentrations remained at levels similar to those found in healthy quarters. Only a slight increase in LXA4 concentrations was observed with the highest SCC. Regression analysis confirmed these observations, showing a high correlation between LTB4 and SCC, and a lower, but significant, correlation between LXA4 and SCC. We therefore found that LXA4:LTB4 ratio was significantly lower in chronic mastitis-affected quarters when compared with healthy and acute mastitis-affected cows. This imbalance could be implicated in the pathogenesis of the chronic bovine mastitis and might explain, at least in part, the persistent accumulation of neutrophils in milk from chronic mastitis-affected cows.
Formation of native LX has been shown in several in vivo studies, such as in nasal lavage fluids from aspirin-sensitive asthmatics (Levy et al., 1993), in experimental nephritis (Papayianni et al., 1995), or in crevicular fluids from localized juvenile periodontitis patients (Pouliot et al., 2000). Moreover, it has been demonstrated that asthmatic patients possess the capacity to generate both LXA4 and 15-epi-LXA4, but aspirin-intolerant asthmatics' whole blood showed reduced LX and 15-epi-LX biosynthetic capacity and lower ratios for LXA4:LTC4 generation when compared with values obtained for aspirin-tolerant asthmatics and healthy patients (Sanak et al., 2000). Here, we document that milk LXA4 concentrations from chronic mastitis-affected cows are approximately sevenfold lower than those from acute mastitis-affected cows, and are similar to those from healthy cows, suggesting that these diminished LXA4 levels may play a role in the mechanisms by which inflammation becomes persistent. Several hypotheses that are not mutually exclusive might account for the low LXA4 concentrations measured in chronic mastitis-affected cows. In humans, LX biosynthesis is an example of LO interaction via transcellular routes (Serhan, 1994). Lipoxins can be generated by 1 of 3 routes that can be operative either independently or in concert, since these biosynthetic pathways are assembled during cell-cell interaction and/or when cells are primed by cytokines (Serhan, 1997). Thus, we may first assume that neutrophils or other cell types are not correctly primed in this model of chronic inflammation. Second, biosynthetic pathways generating LX might be deficient or inhibited. It has been demonstrated, for example, that platelets lose their ability to generate LX during chronic myelogenous leukemia (Stenke et al., 1991). So, the question of whether neutrophils or other cell types lose, partly, their ability to generate LXA4 in chronic mastitis is addressed. Third, another explanation might result from inappropriate distribution within the tissues. It may be hypothesized that LXA4 generated in blood from interaction with endothelial cells may not be able to diffuse within the alveolous lumen in the context of a chronic inflammation. Finally, we may also assume that an increase in the LX catabolism occurs in chronic mastitis, thus leading to local decrease in LXA4 concentrations, but without a diminished biosynthetic capacity.
In view of the present findings, further studies are needed to clearly elucidate the mechanisms that explain why lower LXA4 concentrations were found in the milk of chronic mastitis-affected cows and to determine whether administration of LX or stable analogs could have therapeutic potential in the treatment of chronic bovine mastitis.
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CONCLUSIONS
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The present study shows for the first time the existence of an LXA4:LTB4 imbalance in chronic mastitis-affected cows because of low LXA4 concentrations. Since LXA4 has many anti-inflammatory properties, our study supports the idea that these diminished LXA4 levels, compared with acute mastitis, could be involved in chronic mastitis pathogenesis and that administration of LX or stable analogs could have therapeutic interests in readjustment of the inflammatory imbalance occurring in the chronic inflammation of the bovine mammary gland.
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ACKNOWLEDGEMENTS
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We thank M. Deliège, M. Motkin, D. Mélotte, I. Sbaï, and M. Leblond for excellent technical and secretarial assistance. The Laboratory of the Milk Committee is thanked for the cell count performance. Authors are grateful to J.-M. Godeau, K. Vlaminck, and D. Hoeben for advice; to D. Cassart, K. Phan, and L. Trzpiot for microscopic analysis. This work was partly supported by Janssen Animal Health (Belgium) and the Ministère des Classes Moyennes et de l'Agriculture-Administration Recherche et Développement (Belgium). P. Boutet is a fellow of the Fonds pour la Formation à la Recherche dans l'Industrie et dans l'Agriculture (FRIA, Belgium). F. Bureau is a postdoctoral researcher at the National Fund for Scientific Research (FNRS, Belgium).
Received for publication May 13, 2003.
Accepted for publication July 8, 2003.
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