HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Lewis, G. S. Search for Related Content PubMed PubMed Citation Articles by Lewis, G. S.

Role of ovarian progesterone and potential role of prostaglandin F₂ and prostaglandin E₂ in modulating the uterine response to infectious bacteria in postpartum ewes^1,2

ARS, USDA, U.S. Sheep Experiment Station, Dubois, ID 83423-9602

² Correspondence:
HC 62 Box 2010 (phone: 208-374-5306; fax: 208-374-5582; E-mail:
glewis{at}pw.ars.usda.gov).

	Abstract

Top Abstract Introduction Materials and Methods Results Discussion Implications Literature Cited

 
In sheep and cattle, the postpartum uterus is resistant to bacterial challenge until after corpora lutea develop. A 2 x 2 factorial arrangement of treatments was used to determine whether prostaglandins may mediate the effects of progesterone in transforming the postpartum uterus from resistant to susceptible. On d 14 postpartum, ewes (n = 6/group) were ovariectomized or sham ovariectomized, and the vena cava was catheterized for daily collection of uteroovarian-enriched blood. From d 15 to 20, ewes received twice daily intramuscular injections of progesterone in sesame oil or plain sesame oil. On d 20, each uterus received 75 x 10⁷ cfu of Arcanobacterium pyogenes and 35 x 10⁷ cfu of Escherichia coli. Uteri were collected on d 25 and examined for signs of infection. For each blood sample, unstimulated and mitogen-stimulated lymphocyte proliferation was measured as [³H]thymidine incorporation, smears were prepared for differential white blood cell (WBC) counts, and progesterone, prostaglandin F₂ (PGF₂), and prostaglandin E₂ (PGE₂) were quantified. All 12 progesterone-treated, but only two of the 12 oil-treated, ewes developed uterine infections (P < 0.001). Progesterone treatment increased (P < 0.001; 3.1 vs 1.5 ng/mL) and ovariectomy decreased (P < 0.001; 3.7 vs 0.9 ng/mL) vena caval progesterone. Progesterone treatment reduced (P < 0.01) PGF₂ (303.9 vs 801.3 pg/mL), and PGF₂ was greater (P < 0.05) before than after inoculation (626.4 vs 478.8 pg/mL). The PGE₂ concentration was greater in progesterone-treated, ovary-intact ewes than in ewes in the other groups (ovariectomy x progesterone treatment; P < 0.01). Ovariectomy increased (P < 0.005; 4.4 vs 2.9 pmol) and progesterone treatment decreased (P < 0.05; 3.2 vs 4.1 pmol) concanavalin A-stimulated lymphocyte proliferation. Ovariectomy increased lipopolysaccharides-stimulated proliferation (P < 0.05; 2.4 vs 1.9 pmol). For neutrophils per 100 WBC, the ovariectomy x progesterone and progesterone x period interactions were significant (P < 0.01). The ovariectomy x progesterone interaction was significant (P < 0.01) for lymphocytes per 100 WBC. Ovariectomy decreased monocytes (P < 0.001; 10 vs 13) and increased eosinophils (P < 0.001; 10 vs 5) per 100 WBC. Progesterone makes the postpartum uterus in ewes susceptible to infection, but ovariectomy allows ewes to remain resistant; uterine prostaglandins may mediate this change. This model creates opportunities to determine the mechanisms responsible for the shift from resistance to susceptible.

Key Words: Immunosuppression • Infection • Progesterone • Prostaglandins • Sheep • Uterine Diseases

	Introduction

Top Abstract Introduction Materials and Methods Results Discussion Implications Literature Cited

 
Postpartum uterine infections, which are usually nonspecific, can reduce reproductive efficiency of ruminant livestock. The incidence and consequences of uterine infections are documented far more extensively for dairy cattle than for beef cattle, sheep, or goats (Arthur et al., 1989; Lewis, 1997; Leontides et al., 2000). However, circumstances associated with increased risk of uterine infections in dairy cattle, such as dystocia, assisted births, retained fetal membranes, and unsanitary conditions at parturition, are common in sheep and predispose them to uterine infections (Fthenaki et al., 2000; Leontides et al., 2000).

In most cattle and sheep, the uterus seems to be able to prevent bacteria that typically reside in the postpartum uterus from proliferating and creating infections (Lewis, 1997; Seals et al., 2002a, b). A short exposure to luteal or exogenous progesterone will down-regulate immune functions and, in some animals, transform the uterus from an organ that is resistant to one that is susceptible to infection (Black et al., 1953; Rowson et al., 1953; Seals et al., 2002b). Very little, other than the fact that progesterone induces uterine synthesis of immunosuppressive proteins, is known about the mechanisms responsible for shifting the uterus from resistant to susceptible to infections (Ramadan et al., 1997; Segerson et al., 1997). Thus, this study was conducted to determine whether prostaglandins mediate the effects of progesterone in transforming the postpartum uterus from resistant to susceptible.

	Materials and Methods

Top Abstract Introduction Materials and Methods Results Discussion Implications Literature Cited

 
White-faced ewes were bred in May to lamb in October. Syncro-Mate-B (SMB; Rhone Merieux, Athens, GA) and PG-600 (400 IU of eCG and 200 IU of hCG; Intervet, Millsboro, DE) were used to synchronize estrus and ovulation (Cline et al., 2001). Rams and ewes were joined immediately after removal of SMB implants and injection of PG-600. Rams remained with ewes for approximately 4 wk. Ewes lambed during a 4-wk period. Only ewes with uneventful and unassisted lambings and without signs of spontaneous postpartum uterine infections were used for this study. Before and after parturition, ewes were managed as a group, and their care and feeding was consistent with each stage of the production cycle. Lambs were removed permanently from the ewes within 24 h after birth and reared in a location that was separate from the ewes. As they became available, ewes were incorporated into the experimental phase of the study and managed according to institutional animal care and use guidelines and the experimental protocol.

Just after lambing, 24 ewes (n = 6/treatment group) were assigned to randomized treatments in a 2 x 2 factorial arrangement. Ovariectomy and progesterone treatment were main effects. Ewes were ovariectomized or they received a sham ovariectomy, using standard procedures (Seals et al., 2002b), on d 14 postpartum (d 0 = day of lambing). In addition, progesterone (5 mg/2.5 mL of sesame oil) or sesame oil (2.5 mL) was injected i.m. twice daily, at approximately 12-h intervals, from d 15 to 20 postpartum.

On d 14 postpartum, a catheter was placed in the vena cava via a saphenous vein at a point just cranial to the site of entry of uteroovarian blood (Benoit and Dailey, 1991; Fortín et al., 1994). On d 20 postpartum, all ewes received intrauterine inoculations of 75 x 10⁷ cfu of Arcanobacterium pyogenes and 35 x 10⁷ cfu of Escherichia coli, as described previously (Ramadan et al., 1997; Seals et al., 2002b). On d 25, ewes were anesthetized with sodium pentobarbital (65 mg/mL) and exsanguinated. Catheter placement was confirmed postmortem.

Uteri were collected postmortem, contents were flushed out with 0.9% NaCl solution (wt/vol), samples were cultured for bacteria, flushings were centrifuged, and the appearance of the endometrium was evaluated to determine whether the ewe had developed a uterine infection in response to the bacteria. Clear uterine flushings, small amounts of sediment (<5% by volume), no sign of endometrial inflammation, and the inability to culture A. pyogenes and E. coli from the flushings were signs that the uterus was not infected. By contrast, cloudy uterine flushings, large amounts of sediment (>5%, but usually >20%, by volume), inflamed endometrium, and the ability to culture A. pyogenes and E. coli from the flushings were signs of infection.

Vena caval blood samples were collected daily from d 15 through 25 postpartum. Plasma from a portion of the blood was stored at -20°C until progesterone, PGF₂, and PGE₂ were measured. An [¹²⁵I]progesterone RIA kit (Diagnostic Products, Los Angeles, CA) was used to quantify progesterone, as described recently (Seals et al., 2002b). Enzyme immunoassay kits (Cayman Chemical Co., Ann Arbor, MI) were used to quantify PGF₂ and PGE₂, using procedures similar to those described previously (Del Vecchio et al., 1992b; Fortín et al., 1994).

Another portion of each blood sample was used for lymphocyte isolation and culture to evaluate unstimulated and mitogen-stimulated lymphocyte proliferation (Ramadan et al., 1997; Seals et al., 2002b). Concanavalin A (Con A; stimulates T cells; 1.0 µg/well; Sigma Chemical, St. Louis, MO) and lipopolysaccharides (LPS; stimulates B cells; 0.5 µg/well; Sigma) were the mitogens used (Ramadan et al., 1997; Seals et al., 2002b). The data were expressed as picomoles of [³H]thymidine incorporated during the incubation period. Measurements of radioactive decay were corrected for quench and counting efficiency, and specific activity of the [³H]thymidine was used to calculate picomoles of [³H]thymidine incorporated.

Blood smears were prepared from each sample for differential white blood cell (WBC) counts (Ramadan et al., 1997). Neutrophils, lymphocytes, monocytes, eosinophils, and basophils per 100 WBC were determined for each smear. Typically, smears of sheep blood contain very few basophils, often 0 or 1/100 WBC, and in this experiment, there were too few basophils per smear for meaningful statistical analyses.

The GLM procedures of SAS (SAS Inst., Inc., Cary, NC) were used to analyze the data for all variables measured on a daily basis. The ANOVA model for one analysis included terms for ovariectomy, progesterone, ovariectomy x progesterone, ewe nested within ovariectomy x progesterone, day postpartum, day x ovariectomy, day x progesterone, and day x ovariectomy x progesterone. Ewe nested within ovariectomy x progesterone was the main plot error term, and residual was the subplot error term. For another analysis, period (i.e., before or after intrauterine inoculation with bacteria on d 20) was used instead of day in the model. Day and period were not included in the same model because the two variables were confounded. Unstimulated lymphocyte proliferation was used as a linear covariant in the ANOVA models to analyze the data for mitogen-stimulated proliferation (Ramadan et al., 1997). The Duncan’s and PDIFF options were used as needed to compare means. The CATMOD procedure in SAS was used to determine whether the proportion of ewes developing uterine infections differed with treatment.

	Results

Top Abstract Introduction Materials and Methods Results Discussion Implications Literature Cited

 
A greater (P < 0.001) proportion of the ewes treated with progesterone developed uterine infections in response to intrauterine inoculation with A. pyogenes and E. coli on d 20 postpartum than did ewes treated with sesame oil (Table 1). All 12 progesterone-treated ewes developed uterine infections, but only two of 12 oil-treated ewes developed infections. Those two oil-treated ewes had not been ovariectomized, and their progesterone was consistent with spontaneous development of luteal function (i.e., vena caval progesterone > 2.5 ng/mL for at least three consecutive days; vena caval concentrations are typically greater than jugular concentrations) before the ewes were inoculated.

The progesterone treatment x period interaction was significant (P < 0.001; Table 1). Progesterone was greatest (P < 0.001) in intact ewes after inoculation (3.9 ng/mL) and least in ovariectomized ewes after inoculation (0.7 ng/mL). Likewise, the progesterone treatment x day interaction was significant (P < 0.005; Figure 1). Progesterone concentrations in ovariectomized, oil-treated ewes were less than 1.0 ng/mL throughout the sampling period. In ovariectomized, progesterone-treated ewes, progesterone concentrations increased during progesterone treatment and decreased after treatment ended on d 20. Concentrations in ovary-intact, oil-treated ewes increased somewhat between d 15 and 20, and then increased considerably after d 20. Progesterone concentrations in ovary-intact, progesterone-treated ewes increased during progesterone treatment, decreased after treatment ended on d 20, and increased and decreased again between d 20 and 25.

View larger version (17K): [in this window] [in a new window]   Figure 1. Progesterone concentrations in vena caval blood collected from postpartum ewes that received intrauterine infusions of bacteria. Ewes (n = 6/treatment group) were assigned to treatments in a 2 x 2 factorial arrangement. Ovariectomy and progesterone treatment were main effects. On d 14 postpartum (d 0 = day of lambing), ewes were ovariectomized or received a sham ovariectomy. From d 15 to 20, either progesterone (5 mg/2.5 mL of sesame oil) or sesame oil (2.5 mL) was injected i.m. twice daily. On d 20, all ewes received intrauterine inoculations of 75 x 107 cfu of Arcanobacterium pyogenes and 35 x 107 cfu of Escherichia coli. Uteri were collected and examined on d 25 to determine whether infections developed. Vena caval blood samples were collected daily from d 15 through 25. The progesterone treatment x day interaction was significant (P < 0.005). Data are least squares means. Overall SEM = 0.2. Symbols: = —— ovary intact; - - - = ovariectomized; • = sesame oil; = progesterone.

2

2

View this table: [in this window] [in a new window]   Table 2. Prostaglandin F2 and prostaglandin E2 concentrations in vena caval blood collected from postpartum ewes that received intrauterine infusions of bacteriaa

Unstimulated lymphocyte proliferation was a significant (P < 0.01) covariant for Con A- and LPS-stimulated lymphocyte proliferation. Ovariectomy increased (P < 0.005; ovariectomized, 4.4 vs 2.9 pmol, ovary intact) and progesterone treatment decreased (P < 0.05; progesterone, 3.2 vs 4.1 pmol, oil) Con A-stimulated proliferation (Table 3). Ovariectomy increased LPS-stimulated proliferation (P < 0.05; ovariectomized, 2.4 vs 1.9 pmol, ovary intact; Table 3).

View larger version (19K): [in this window] [in a new window]   Figure 2. Numbers of neutrophils (panel A), lymphocytes (panel B), monocytes (panel C), and eosinophils (panel D) per 100 white blood cells (WBC) in vena caval blood collected from postpartum ewes before and after they received intrauterine infusions of bacteria. Ewes (n = 6/treatment group) were assigned to treatments in a 2 x 2 factorial arrangement. Ovariectomy and progesterone treatment were main effects. On d 14 postpartum (d 0 = day of lambing), ewes were ovariectomized or received a sham ovariectomy. From d 15 to 20, either progesterone (5 mg/2.5 mL of sesame oil) or sesame oil (2.5 mL) was injected i.m. twice daily. On d 20, all ewes received intrauterine inoculations of 75 x 107 cfu of Arcanobacterium pyogenes and 35 x 107 cfu of Escherichia coli. Uteri were collected and examined on d 25 to determine whether infections developed. Vena caval blood samples were collected daily from d 15 through 25. The progesterone treatment x day interaction was significant (P < 0.001) for neutrophils, lymphocytes, and monocytes. Eosinophil numbers changed (P < 0.001) with day. Data are least squares means. Overall SEM: neutrophils = 0.4; lymphocytes = 0.3; monocytes = 0.2; and eosinophils = 0.2. Symbols: —— = ovary intact; - - - = ovariectomized; • = sesame oil; = progesterone.

Ovariectomy decreased (P < 0.001) the number of monocytes (ovariectomy, 10/100 vs 13/100 WBC, ovary intact; Table 4). Progesterone treatment increased (P < 0.001) the number of monocytes (progesterone, 14/100 vs 9/100 WBC, oil), and the number of monocytes before was less (P < 0.001) than the number after inoculation (before, 11/100 vs 13/100 WBC after). The progesterone treatment x day interaction was significant (P < 0.001; Figure 2, Panel C). The number of monocytes per 100 WBC in ovariectomized, oil-treated ewes was less, and the number was greater in ovary-intact, progesterone-treated ewes throughout the study than in ewes in the other two groups. The monocyte profiles for those two groups were intermediate.

Ovariectomy increased (P < 0.001) the number of eosinophils (ovariectomy, 10/100 vs 5/100 WBC, ovary intact), and the number before was less (P < 0.001) than the number after inoculation (before, 7/100 vs 8/100 WBC after; Table 4). Eosinophil numbers changed somewhat with day (P < 0.001), but the profiles did not differ among treatment groups (Figure 2, Panel D).

	Discussion

Top Abstract Introduction Materials and Methods Results Discussion Implications Literature Cited

 
Progesterone, either exogenous or endogenous, transformed the uterus of the postpartum ewes in this study from an organ that was resistant to one that was susceptible to infection. All of the progesterone-treated ewes and two of the six ovary-intact, sesame oil-treated ewes, which had significant increases in endogenous progesterone before intrauterine inoculation with infectious bacteria, developed infections. However, the ovariectomized, oil-treated ewes and four of the six ovary-intact, oil-treated ewes, which did not have significant increases in endogenous progesterone before intrauterine inoculation, did not develop infections. These results are consistent with previous work with cattle (Del Vecchio et al., 1992a) and sheep (Ramadan et al., 1997; Seals et al., 2002b) using the same strains of A. pyogenes and E. coli that were used in this study. The results are also consistent with other studies published during the last 50 yr (Black et al., 1953; Rowson et al., 1953; Seals et al., 2002a). These results indicate that the animal model was appropriate for accomplishing the objectives of this study.

Vena caval PGF₂ concentrations were least and PGE₂ concentrations were greatest in ewes with the greatest concentration of progesterone: the ovary-intact, progesterone-treated ewes. By contrast, PGF₂ was greatest in ewes with the least progesterone: the ovariectomized, oil-treated ewes. Vena caval blood collected at the point where the samples in this study were collected is enriched with uteroovarian blood (Benoit and Dailey, 1991; Wade and Lewis, 1996). Thus, these changes in PGF₂—which are consistent with previous results (Murdoch et al., 1978; Fortín et al., 1994)—and PGE₂ are clear evidence that progesterone affected uterine prostaglandin synthesis.

Even though progesterone stimulates the uterus to produce immunosuppressive proteins (Ramadan et al., 1997; Segerson et al., 1997), the effect of progesterone on uterine eicosanoid (i.e., biologically active compounds, including prostaglandins and leukotrienes, synthesized from arachidonic acid) production and the fact that eicosanoids can modulate immune functions (Tizard, 1996; Roitt et al., 1998) indicate that the immunosuppressive effects of progesterone are mediated through several pathways. Indeed, PGE₂ can down-regulate and PGF₂ can up-regulate immune cell functions.

Increased PGE₂ is consistently associated with decreased neutrophil functions (Robicsek et al., 1991; Roper and Phipps, 1992; Vaillier et al., 1992). Neutrophils are phagocytic leukocytes that are involved in nonspecific (e.g., phagocytosis of new pathogens) and specific (e.g., phagocytosis of antibody-opsonized pathogens) immune functions, and nonspecific phagocytosis seems to be an initial defense against pathogens that invade the uterus (Hussain, 1989).

Intrauterine treatment of postpartum cows with 16,16-dimethyl PGE₂ (a long-acting PGE₂ analog) inhibited lymphocyte proliferation in response to Con A, phytohemagglutinin, and pokeweed mitogen, and it increased the incidence and severity of uterine infections (Slama et al., 1991). Moreover, PGE₂ synthesis was greater in retained bovine fetal placental membranes than was PGF₂ synthesis (Gross et al., 1987). The opposite was true for membranes that were not retained. Cows that retain fetal membranes are almost six times more likely to develop uterine infections than other cows in the herd (Curtis et al., 1985; Erb et al., 1985). Prostaglandin E₂ inhibits T-lymphocyte production of interleukin-2 (IL-2), and PGE₂ can inhibit the formation of IL-2 receptors (Choudhry et al., 1999). Interleukin-2 is a cytokine that is involved with T-cell growth and proper antigen presentation, and it is important for promoting cytotoxic T-cell and B-cell activity (Tizard, 1996; Roitt et al., 1998). Thus, enhanced PGE₂ concentrations would seem to make the uterus more susceptible to infections, although this may depend on whether PGF₂ concentrations are increased or decreased. In the current study, PGE₂ concentrations were increased and PGF₂ concentrations were decreased in ovary-intact, progesterone-treated ewes, all of which developed uterine infections. All ovariectomized, progesterone-treated ewes developed uterine infections; their PGE₂ concentrations were not different from controls, but PGF₂ concentrations were decreased.

In vitro experiments indicated that PGF₂ and another eicosanoid, leukotriene B₄ (LTB₄), were chemoattractant to neutrophils (Hoedemaker et al., 1992), and that PGF₂ increased bactericidal activity of neutrophils from ovariectomized mares (Watson, 1988). Therefore, changes in uterine production of PGF₂ and PGE₂ may mediate the effects of progesterone on the uterine response to infectious bacteria. Shifting the PGE₂:PGF₂ ratio toward PGF₂, and perhaps other immunostimulatory eicosanoids, may enhance uterine immune functions and improve uterine health. Based on results described in Wade and Lewis (1996), exogenous PGF₂ stimulates uterine secretion of PGF₂. Thus, exogenous PGF₂ seems to have the potential to enhance uterine immune functions. Concanavalin A-stimulated lymphocyte proliferation was greatest in ewes with the least progesterone and greatest PGF₂ concentrations (i.e., ovariectomized, oil-treated), and it was least in ewes with the greatest progesterone, least PGF₂, and greatest PGE₂. None of the ewes in the group with the greatest Con A response developed uterine infections, whereas all of the ewes in the group with the least Con A response developed infections. Perhaps, as already suggested, increased PGF₂ in the "protected" group enhanced immune cell functions and played a critical role in preventing the development of uterine infections. Despite this possibility, the presence of the ovaries seemed to modulate the responses. The Con A- and LPS-stimulated responses were greater for ovariectomized than for ovary-intact ewes regardless of progesterone treatment. Luteal progesterone was most likely the ovarian factor responsible for modulating the responses to Con A and LPS in ovary-intact ewes, but this study does not permit one to be absolutely certain of that likelihood and to rule out other ovarian factors.

The number of neutrophils and monocytes per 100 WBC were least and the number of lymphocytes per 100 WBC was greatest in ewes with the least progesterone. However, a shortcoming of the results of differential white blood cell counts is that only 100 randomly selected cells are counted. Thus, changes in the percentages of white blood cells, and not changes in the absolute numbers in circulation, are estimated, and, if the number of one cell type increases, the number of at least one other cell type must decrease proportionally. Despite that limitation, a reduction in the number of neutrophils per 100 WBC in ovariectomized, oil-treated ewes seems to indicate that their neutrophils had the greatest ability to respond to the presence of infectious bacteria in the uterus and perhaps move toward the uterus (Tizard, 1996; Roitt et al., 1998). Indeed, preliminary data (S. Hunter, R. Seals, M. Wulster-Radcliffe, and G. Lewis, unpublished data) indicate that the number of neutrophils decreased from approximately 36/100 WBC to approximately 12/100WBC within 1.5 h after sterile A. pyogenes supernatant was infused into the uterus of ewes. This reduction seemed to be due to the movement of neutrophils to the uterus, because large numbers of activated neutrophils were flushed from the uterine lumen of the ewes treated with A. pyogenes supernatant.

Neutrophils move rapidly to a site of bacterial invasion, but monocytes, which are also phagocytic cells, typically take hours longer to migrate to the site of invasion (Tizard, 1996; Roitt et al., 1998). The reduction in number of monocytes in the ovariectomized, oil-treated ewes in this study probably indicates that the monocytes in those ewes had a greater ability to move to the site of bacterial invasion than did monocytes in ewes in the other groups. The changes in neutrophils and monocytes per 100 WBC may reflect the ability of the ovariectomized, oil-treated ewes to prevent the development of uterine infections. The results for neutrophils and monocytes in the ovary-intact, oil-treated ewes are less clear-cut. Perhaps increases in endogenous progesterone created the ambiguity. Nevertheless, most of the ovary-intact, oil-treated ewes did not develop uterine infections.

The design of this study does not permit one to determine whether the increase in lymphocytes per 100 WBC in the ovariectomized, oil-treated ewes was a mathematical consequence of fewer neutrophils and monocytes or a direct effect of lymphocyte proliferation. Intrauterine inoculation of heifers with A. pyogenes seemed to produce some measure of active immunity (Watson et al., 1990). Perhaps the ewes in this study had been exposed previously to A. pyogenes, which is normally found in the environment and often associated with various types of purulent infections, before they were used for this study. Inoculation with A. pyogenes in this study then might have stimulated a B-lymphocyte response that could have been detected as an increase in lymphocytes per 100 WBC. However, additional research is needed to test this hypothesis.

In conclusion, the uterus in postpartum ewes can prevent the development of infections in response to intrauterine inoculation with infectious bacteria, unless it has been exposed to some threshold amount of progesterone from an endogenous or exogenous source. This is consistent with another study with postpartum ewes (Seals et al., 2002b) and a study with postpartum cows (Seals et al., 2002a), and it seems to indicate that resistance is the "default setting" for the postpartum uterus. In the present study, the relationships among progesterone, PGF₂, PGE₂, lymphocyte proliferation, relative changes in white blood cells, and susceptibility of ewes to intrauterine inoculation with infectious bacteria seem to indicate that PGF₂ and PGE₂ may be involved in mediating the immunosuppressive effects of progesterone and its role in transforming the postpartum uterus from resistant to susceptible. Those relationships were clearly delineated in this study, and they are evident, although somewhat less so, in a previous report (Seals et al., 2002b). Based on the relationships among the variables measured in this study, one may speculate that a method for enhancing uterine PGF₂ production may enhance the ability of the uterus to resist infections.

	Implications

Top Abstract Introduction Materials and Methods Results Discussion Implications Literature Cited

 
Nonspecific uterine infections and their adverse effects on uterine health can reduce reproductive efficiency of ruminant livestock. This is well documented for dairy cattle, but very poorly documented for beef cattle and sheep. Postpartum ewes are exposed to many of the same risk factors that predispose dairy cattle to uterine infections. This research indicates that, under appropriate hormonal conditions, postpartum ewes become susceptible to infectious bacteria and develop purulent uterine infections. The research also seems to indicate that a method for increasing uterine production of prostaglandin F₂ has the potential to enhance immune functions and enhance the ability of the uterus to resist infections. A method for improving uterine health may increase reproductive efficiency.

	Footnotes

 
¹ The use of trade, firm, or corporation names in this publication is for the information and convenience of the reader. Such use does not constitute an official endorsement or approval by the USDA or the ARS of any product or service to the exclusion of others that may be suitable.

Received for publication June 29, 2002. Accepted for publication September 21, 2002.

	Literature Cited

Top Abstract Introduction Materials and Methods Results Discussion Implications Literature Cited

 


Arthur, G. H., D. E. Noakes, and H. Pearson. 1989. Veterinary Reproduction and Obstetrics. 6th ed. Bailliére Tindall, Philadelphia, PA.

Benoit, A. M., and R. A. Dailey. 1991. Catheterization of the caudal vena cava via lateral saphenous vein in the ewe, cow, and gilt: An alternative to uteroovarian and medial coccygeal vein catheters. J. Anim. Sci. 69:2971–2979.[Abstract]

Black, W. G., L. C. Ulberg, H. E. Kidder, J. Simon, S. H. McNutt, and L. E. Casida. 1953. Inflammatory response of the bovine endometrium. Am. J. Vet. Res. 14:179–183.[Medline]

Choudhry, M. A., S. Ahmad, Z. Ahmed, and M. M. Sayeed. 1999. Prostaglandin E₂ down-regulation of T cell IL-2 production is independent of IL-10 during gram-negative sepsis. Immunol. Lett. 67:125–130.[Medline]

Cline, M. A., J. N. Ralston, R. C. Seals, and G. S. Lewis. 2001. Intervals from norgestomet withdrawal and injection of equine chorionic gonadotropin or P. G. 600 to estrus and ovulation in ewes. J. Anim. Sci. 79:589–594.[Abstract/Free Full Text]

Curtis, C. R., H. N. Erb, C. J. Sniffen, R. D. Smith, and D. S. Kronfeld. 1985. Path analysis of dry period nutrition, postpartum metabolic and reproductive disorders, and mastitis in Holstein cows. J. Dairy Sci. 68:2347–2360.

Del Vecchio, R. P., D. J. Matsas, T. J. Inzana, D. P. Sponenberg, and G. S. Lewis. 1992a. Effect of intrauterine bacterial infusions and subsequent endometritis on prostaglandin F₂ metabolite concentrations in postpartum beef cows. J. Anim. Sci. 70:3158–3162.[Abstract]

Del Vecchio, R. P., K. M. Maxey, and G. S. Lewis. 1992b. A quantitative solid-phase enzymeimmunoassay for 13, 14-dihydro-15-keto-prostaglandin F₂ in plasma. Prostaglandins 43:321–330.[Medline]

Erb, H. N., R. D. Smith, P. A. Oltenacu, C. L. Guard, R. B. Hillman, P. A. Powers, M. C. Smith, and M. E. White. 1985. Path model of reproductive disorders and performance, milk fever, mastitis, milk yield, and culling in Holstein cows. J. Dairy Sci. 68:3337–3349.

Fortín, S., B. L. Sayre, and G. S. Lewis. 1994. Does exogenous progestogen alter the relationships among PGF₂, 13,14-dihydro-15-keto-PGF₂, progesterone, and estrogens in ovarian-intact ewes around the time of luteolysis? Prostaglandins 47:171–187.[Medline]

Fthenaki, G. C., L. S. Leontides, G. S. Amiridis, and P. Saratsis. 2000. Incidence risk and clinical features of retention of foetal membranes in ewes in 28 flocks in southern Greece. Prev. Vet. Med. 43:85–90.[Medline]

Gross, T. S., W. F. Williams, J. E. Manspeaker, G. S. Lewis, and E. Russek-Cohen. 1987. Bovine placental prostaglandin synthesis in vitro as it relates to placental separation. Prostaglandins 34:903–917.[Medline]

Hoedemaker, M., L. A. Lund, and W. C. Wagner. 1992. Influence of arachidonic acid metabolites and steroids on function of bovine polymorphonuclear neutrophils. Am. J. Vet. Res. 53:1534–1539.[Medline]

Hussain, A. M. 1989. Bovine uterine defense mechanisms: A review. J. Vet. Med. Ser. B. 36:641–651.

Leontides, L., G. C. Fthenakis, G. S. Amiridis, and P. Saratsis. 2000. A matched case-control study of factors associated with retention of fetal membranes in dairy ewes in Southern Greece. Prev. Vet. Med. 44:113–20.[Medline]

Lewis, G. S. 1997. Uterine health and disorders. J. Dairy Sci. 80:984–994.[Abstract]

Murdoch, W. J., G. S. Lewis, E. K. Inskeep, and S. A. Tillson. 1978. The effect of a progesterone-releasing intrauterine contraceptive device on uterine secretion of prostaglandin F₂ and life span of corpora lutea in the ewe. Am. J. Obstet. Gynecol. 132:81–86.[Medline]

Ramadan, A. A., G. L. Johnson III, and G. S. Lewis. 1997. Regulation of uterine immune function during the estrous cycle and in response to infectious bacteria in sheep. J. Anim. Sci. 75:1621–1632.[Abstract/Free Full Text]

Robicsek, S. A., D. K. Blanchard, J. Y. Djeu, J. J. Krzanowski, A. Szentivanyi, and J. B. Polson. 1991. Multiple high-affinity cAMP-phosphodiesterases in human T-lymphocytes. Biochem. Pharmacol. 42:869–877.[Medline]

Roitt, I., J. Brostoff, and D. Male. 1998. Immunology. 5th ed. Mosby, London.

Roper, R. L., and R. P. Phipps. 1992. Prostaglandin E₂ and cAMP inhibit lymphocyte activation and simultaneously promote IgE and IgG1 synthesis. J. Immunol. 149:2984–2991.[Abstract]

Rowson, L. E. A., G. E. Lamming, and R. M. Fry. 1953. The relationship between ovarian hormones and uterine infection. Vet. Rec. 65:335.

Seals, R. C., I. Matamoros, and G. S. Lewis. 2002a. Relationship between postpartum changes in 13, 14-dihydro-15-keto-PGF₂ concentrations in Holstein cows and their susceptibility to endometritis. J. Anim. Sci. 80:1068–1073.[Abstract/Free Full Text]

Seals, R. C., M. C. Wulster-Radcliffe, and G . S. Lewis. 2002b. Modulation of the uterine response to infectious bacteria in postpartum ewes. Am. J. Reprod. Immunol. 47:57–63.

Segerson, E. C., H. Li, and C. W. Talbott. 1997. Estradiol-17ß and progesterone increase ovine uterine suppressor cell activity. J. Anim. Sci. 75:2778–2787.[Abstract/Free Full Text]

Slama, H., D. Vaillancourt, and A. K. Goff. 1991. Pathophysiology of the puerperal period: Relationship between prostaglandin E₂ (PGE₂) and uterine involution in the cow. Theriogenology 36:1071–1090.

Tizard, I. R. 1996. Veterinary Immunology: An Introduction. 5th ed. W. B. Saunders Co., Philadelphia, PA.

Vaillier, D., R. Daculsi, N. Gualde, and J. H. Bezian. 1992. Effect of LTB4 on the inhibition of natural cytotoxic activity by PGE₂. Cell. Immunol. 139:248–258.[Medline]

Wade, D. E. and G. S. Lewis. 1996. Exogenous prostaglandin F₂ stimulates uteroovarian release of prostaglandin F₂ in sheep: A possible component of the luteolytic mechanism of action of prostaglandin F₂. Domestic Anim. Endocrinol. 13:383–395.[Medline]

Watson, E. D. 1988. Eicosanoids and phagocytic and bactericidal activity of equine neutrophils. Equine Vet. J. 20:373–375.[Medline]

Watson, E. D., N. K. Diehl, and J. F. Evans. 1990. Antibody response in the bovine genital tract to intrauterine infusion of Actinomyces pyogenes. Res. Vet. Sci. 48:70–75.[Medline]

This article has been cited by other articles:

				T. M. Thelen, C. A. Loest, J. B. Taylor, S. Wang, and G. S. Lewis Intrauterine bacterial inoculation and level of dietary methionine alter amino acid metabolism in nulliparous yearling ewes J Anim Sci, December 1, 2007; 85(12): 3371 - 3382. [Abstract] [Full Text] [PDF]

This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Lewis, G. S. Search for Related Content PubMed PubMed Citation Articles by Lewis, G. S.