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Many factors can adversely affect the equine industry, but none more so than the loss of production due to preterm delivery of foals. Placental dysfunction is regarded as the leading cause of premature delivery in the horse and results in severe financial loss and emotional stress to horse owners and breeders alike.

Annual losses run between 0.5 and 1 billion USD in the US, but are difficult to assess due to the high individual value of animals. Thus, a reduction in the incidence of preterm delivery due to placental dysfunction would markedly enhance the profitability and sustainability of the equine industry.

The single most common cause of abortion, stillbirth and prematurity is placentitis (Giles et al., 1993; Hong et al., 1993; Whitwell, 1988; Swerczek, 1986). Moreover, based on the pathology records of horses, Giles and colleagues reported that 60% of fetal abortions, stillbirths and foals that died within 24 h of birth were associated with placental insufficiency, of which a third of the abortions and fetal deaths were associated with placental infections.

There are three modes of infection that potentially lead to placentitis. The first is ascending placentitis, where the opportunistic organism accesses the uterine environment via the cervix. The most frequently found organism contributing to this mode of infection is the opportunistic pathogen Streptococcus equi zooepidemicus (S. equi) with Escherichia coli (E. coli) being the next most common.

The second is diffuse or multifocal placentitis, where the organism is hematogenously borne, and thirdly, focally extensive placentitis, where the organism tends to locate at the base of the placental horns and placental body (i.e., nocardioform infections). Furthermore, several reports indicate that in women, uterine infection is highly correlated with idiopathic preterm labor (Hillier et al., 1993; Dudley, 1997; Romero et al., 1998).

Unlike in women, premature birth usually results in the delivery of a non-viable foal because complete fetal maturation in the horse for successful extra-uterine life does not occur until the final 5-7 days of development in utero (Silver and Fowden, 1994; 1995).

The etiology of preterm labor with infection involves the release of inflammatory cytokines such as tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), interleukin 6 (IL-6) and interleukin-8 (IL-8) that results in prostaglandin production and subsequent increased uterine myometrial activity (Dudley and Trautman, 1994; Pollard and Mitchell, 1996).

Inflammatory cytokines have been measured in increased concentrations in blood, amniotic fluid and cervical secretions of women with preterm labor associated with uterine infections (Torbe and Czajak, 2004; Jacobsson et al., 2003; Hasegawa et al., 2003). McGlothlin et al. (2004), using a novel equine ascending placentitis model, demonstrated that mares with induced placentitis had altered uterine contractility (myoelectrical activity) suggestive of a myometrial response to local inflammation.

Moreover, premature delivery in ascending placentitis was associated with greater mRNA expression of pro-inflammatory cytokines in placental tissue and elevated allantoic fluid concentrations of both pro-inflammatory cytokines and prostaglandin E2 and F2α in the 48 h period prior to delivery than found in control mares (LeBlanc et al., 2002; LeBlanc, personnal communication).

What is more alarming are the findings from human studies that report a disquieting association between maternal infection and a fetal inflammatory response characterized by increased levels of inflammatory cytokines in fetal brain and peripheral blood, which predisposes infants to development of periventricular leukomalacia (white matter brain lesions) and cerebral palsy (Yoon et al., 1997; 2003; Minagawa et al., 2002; Nelson et al., 1998; Grether et al., 1999).

Similarly, premature foals that do survive are frequently neurologically compromised and never reach their full potential as adults. The maladjusted foal symdrome has been well documented (Palmer and Rossdale, 1976; Rossdale, 2004), but growth retardation and birth trauma are not the only factors that contribute to cranial hypoxia.

Uterine infections may also contribute to neural vascular ischemia leading to cortical and/or brain stem damage. While such trauma in itself may not be fatal, it may prevent the neonate from attaining its full potential as an adult (i.e., performing athlete). A clearer understanding of the relationship between premature foals born to dams with placentitis and fetal foal brain lesions is needed.

Our inability to effectively prevent placental dysfunction, the onset of preterm labor and the difficulty in saving premature foals with current therapeutic strategies results in serious economic loss to the equine industry. To reduce the incidence of preterm delivery and fetal and perinatal mortality of foals, it is critical that we develop more effective therapeutic strategies to combat infection and stabilize the equine pregnancy.

Moreover, pathogen progression during the course of uterine infection leading to invasion of the fetal tissues is poorly understood. With the development of animal models for investigating the role of pathogens in preterm labor and the development of real-time bioluminescence imaging technology, it is now possible to ask two important questions regarding pathogeninduced preterm labor in women and domestic animal species:

1) Is combinatorial drug therapy that includes antibiotics and immunomodulators (i.e., the anti-inflammatory cytokine IL-10, dexamethasone, progestin) more effective in preventing pro-inflammatory cytokine-mediated preterm birth in dams with uterine infection than with antibiotics alone?

2) Is it possible to track pathogen progression from the infected uterus into fetal tissues using transgenically modified infectious organisms (i.e., E. coli or S. equi) with the lux gene and real-time bioluminescence imaging technologies?


Animal models of uterine infection-induced preterm labor

In 2000, Bennett et al. first described a novel rat model of infection-mediated preterm delivery. This model involved the implantation of an indwelling uterine catheter system on day 15 of gestation followed by intra-uterine infusion of lipopolysaccharide (LPS).

Using this model Bennett and colleagues found that intra-uterine infusion of 25 or 50 g of LPS induced preterm delivery of low birthweight pups and increased fetal wastage. In a subsequent study using this model, the same investigators found that intra-uterine infusion of IL-10, administered concurrently with LPS or 24 h thereafter, increased the interval to delivery, improved birth weights, and increased litter size (Terrone et al., 2001).

In an attempt to more accurately mimic what occurs in women with chorioamnionitis, the Bennett group at the University of Mississippi Medical School subsequently applied live E. coli as the infectious agent, initially administering both the bacteria and IL-10 via the intra-uterine catheter system (Barrilleaux et al., 2002).

In more recent studies, Bennett and colleagues have sought to examine the effects of intravenous IL-10 alone or in combination with antibiotics on pregnancy outcome and subsequent inflammatory cytokine responses of the neonatal brain (Rodts-Palenik et al., 2003). Moreover, this group has demonstrated the efficacy of IL-10 therapy in reducing maternal infection-induced white brain injury in rat pups (Rodts-Palenik et al., 2004).

In these studies, the E. coli was directly inoculated at the bifurcation of the uterine horns and IL-10 administered via an indwelling femoral vein catheter. IL-10 treatment was found to reduce (P<0.05) the percent of periventricular swelling observed (saline, 0.1%; E. coli, 3.10%; E. coli+IL-10, 0.97%).

Although the monkey and rat species possess a hemochorial placentation, in a preliminary study investigating the pharmacokinetics of IL-10 in pregnant sheep we observed that I125-labeled IL-10 can cross the maternal/fetal placental unit and localize in the fetal brain (Klauser et al., 2004), thereby demonstrating that IL-10 therapy has promise as a strategy to prevent development of periventricular white matter fetal brain lesions and thus reduce the incidence of neurological abnormalities in foals born to dams with placentitis.

Additionally, we observed lesions in the periventricular white matter brain tissue in preterm lambs born to ewes following intra-uterine inoculation with E. coli (1 x 106 and 10 x 106 colony forming units (CFU) at ~105 days gestation; Moulton et al., 2006), and brain lesions in a dysmature neurologically compromised foal delivered prematurely to a mare with symptoms of fescue toxicity (Ryan, unpublished observations spring 2005).

In the same sheep study, serum cortisol and progesterone were elevated (P<0.05) above controls in ewes following intra-uterine inoculation with E. coli (Moulton et al., 2005), consistent with observations in mares with uterine placental infections (Ousey et al., 2005; Rossdale et al., 1991).

Interestingly, in some cases of placentitis or chronic infection, foals born prematurely are often viable and exhibit signs of precocious maturity (Rossdale, 1993). In a recent in vitro study, it was demonstrated that IL-10 expression was significantly reduced in placental tissue from mothers with chorioamnionitis–associated preterm delivery and that IL-10 treatment of these explants reduced cyclo-oxygenase-2 expression (Hanna et al., 2006), an important component of the prostaglandin cascade associated with labor. It is important to note at this point that both horses and sheep (ruminants) possess epitheliochorial placentation (Senger, 2003).


Biophotonics and real time imaging

Biophotonics involves the union of photonics and biology, and deals with the interactions between light, biological matter and its application to biomedical science. Nature has harnessed the photon (light) in many ways as a basic principle of life; whether through photosynthetic pathways in plants, as methods of communication among insects (e.g., firefly) or a multitude of other examples from across the natural world.

The use of photonics in experimental models of human conditions has become a key diagnostic and research tool for understanding physiological systems in normal and diseased states that were not previously attainable with other detection systems. Manipulation of light as a tool that can be adapted to biomedical models of disease and for understanding the symmetry and asymmetry of physiological systems, employing a wide variety of molecular spectroscopic techniques, including the use of fluorescence and bioluminescence, are being developed and employed for applications in disease monitoring and drug discovery (Vo-Dinh, 2003).

In mainstream science, photonics has found a niche as an indicator used to monitor gene activity (e.g., gene promotor-reporter systems) or as fluorescent or bioluminescent chemical indicators (e.g., replacing many radioactive-based assays). Using the current array of ultrasensitive photon detectors, photons emitted from several centimeters within tissues can be detected; permitting activity in lymph nodes, circulatory pathways and/or tissues/organs of the peritoneal or cranial cavities to be imaged non-invasively.

The last 10 years has seen unprecedented adaptations of this technology for investigating a variety of physiologically relevant systems in situ, including single cell (Willard et al., 1997; 1999a,b), whole plants (Anderson et al., 1995), Drosophila (Brandes et al., 1996), rodents (Contag et al., 1995; 1997; Youngblood, 2004; Ryan et al., 2005a) and, more recently, large animal models of disease (Willard et al., 2002; 2003; Ryan et al., 2006).

The advantages of this technology are that it provides dynamic, real time and over time assessments of the physiological event(s) under study and in the case of in vivo animal models can dramatically reduce the number of animals needed to answer the questions posed. This approach replaces the static endpoints (e.g., traditional messenger ribonucelic acid and protein quantitation) with fluid endpoints that are more relevant to what is happening, or may happen, in the context of converging events representative of dynamic (living) environments.

This allows for the creation of physiologically relevant models of disease that incorporate a dynamic systems approach that does not dissociate pathways or events, but rather permits the complexity of a living system to be studied with high definition and precision in context.

Real time imaging technology using luciferase reporter genes (i.e., lux gene) to monitor physiological events in vivo has become an important and meaningful approach to studying, in real time and over time, biological responses including efficacy of drugs for cancer therapy, pathogenesis of bacterial pathogens or the regulation and expression of specific genes during specific physiological event(s).

Current research in our laboratory employs bioluminescent indicators to evaluate the pathogenesis of specific bacterial organisms (i.e., Salmonella typhimurium) in neonatal pigs in which luciferase and its accessory genes encoding for the enzyme substrate are constitutively expressed (Willard et al., 2002).

More recently, we have employed a transgenic mouse model (Zhang et al., 2004) in which a promoter region of the vascular endothelial growth factor receptor 2 (VEGF-R2) gene is cloned upstream of the luciferase gene and, when activated in the presence of exogenous substrate (luciferin), can be non-invasively monitored using a highly sensitive imaging system to study regulation of vascular development under normal and abnormal (i.e., exposure to an endocrine disrupter such as xenoestrogenic pesticides) physiological conditions (Youngblood et al., 2004; Ryan et al., 2005).

In sheep and mare uterine infection studies during late gestation we have employed E. coli transformed with a pAK-lux1 plasmid (E. coli-lux; ~1 x 106 CFU) for generation of photonic images of pathogen progression. The plasmid (11,904 bp) used is a broadhost- range cloning vector with numerous plasmid replicons and the luciferase gene is constitutively expressed in the living bacteria and acts as a marker for pathogen progression in the infected animal.


STUDIES USING EXPERIMENTALLY INFECTED PREGNANT EWES AND MARES

Due to the high incidence of preterm labor associated with placental infections (i.e., S. equi; E. coli), the high costs of treating premature foals to assure survival and the poor prognosis of these foals becoming viable or competitive athletes (Steel et al., 1999; Smith et al., 2004), there is a need to develop effective therapeutic strategies to ensure a successful pregnancy outcome.

Currently, effective strategies do not exist that address both the infection and sustain pregnancy to term (LeBlanc, 1997; 2004; Palmer et al., 2002; Frazer, 2004). Therefore, these strategies must include not only effective treatment of the infectious organisms or uterine/placental insult, but also agents (i.e., immunomodulators) that will stabilize the pregnancy by attenuating the inflammatory response.

Recent studies have demonstrated, using rat (Bennett et al., 2000) and rhesus monkey (Sadowsky et al., 2003) models, that the combined treatment of antibiotics with the anti-inflammatory cytokine IL-10 or the synthetic corticoid dexamethasone reduced the incidence of preterm labor in rats subjected to intra-uterine E. coli exposure (Rodts-Palenik et al., 2003; 2004) or monkeys exposed to inflammatory cytokines (Sadowsky et al., 2003).

The focus of our research at Mississippi State University is to develop appropriate animal models to test novel therapeutic strategies to prevent uterineplacental infection-induced preterm labor. Furthermore, we wish to understand pathogen progession and localization in fetal tissues so as to better understand the etiology of neurological damage seen in many preterm offspring. To meet this goal we are currently employing lux-gene modified organisms and bioluminescence imaging technology. An important beneficial outcome from the studies in the mare will be the reduction in the incidence of neurological abnormalities in foals born to dams treated for uterine infections (i.e., placentitis).

Our underlying hypothesis in these studies is that immunomodulators such as IL-10, an anti-inflammatory cytokine, and altrenogest, a synthetic progestin, or dexamethasone, a synthetic corticosteroid, administered in combination with antibiotics will prevent preterm labor in mares subjected to intra-uterine exposure with an infectious organism or intrauterine placental insult, and reduce the incidence of fetal neurological damage (fetal brain lesions).

Moreover, the ability to track pathogen progression using transformed organisms with the lux gene (i.e., E. coli-lux) and biophotonic imaging during the disease process gives researchers the ability to obtain information on progression and pathogen localization that previously could not be determined until the fetus and placental tissues were presented for necropsy.

In 2005 we performed a series of preliminary studies (Ryan et al., 2005b; 2006), using the pony mare placentitis experimental model described by McGlothlin et al. (2004) with some modifications, to evaluate the use of antibiotics alone and in combination with immunomodulators (Terrone et al., 2001; Rodts-Palenik et al., 2003; 2004) such as progestins (i.e., altrenogest; Ousey et al., 2005) and dexamethasone (Sadowsky et al., 2003) for the treatment of uterine infections and prevention of preterm labor in the mare.

Furthermore, progesterone (17α-hydroxy-progesterone) has recently been shown to be effective in preventing preterm labor in women with a history of preterm delivery, women with uterine infections and women with multiple fetus pregnancies (Meis, 2005; Meis et al., 2003).

In addition, RegumateTM, a commercially available preparation of the synthetic progestin altrenogest, is used in equine medicine to help support mares with high risk pregnancies. Placental infection due to opportunistic pathogens (i.e., S. equi) is the single most common cause of abortion, stillbirth and premature delivery in horses (Giles et al., 1993). Moreover, increasing evidence demonstrates that placentitis increases pro-inflammatory cytokine expression in the fetal membranes and fluids (Jacobsson et al., 2003; Hanna et al., 2006), which in turn may activate the prostaglandin cascade leading to premature delivery.

By inhibiting or blocking the pro-inflammatory cytokine responses with combinatorial drug therapy, it was hoped that the incidence of preterm labor in experimentally infected mares would be reduced. Thus, the objective of these pilot studies was to induce ascending placentitis and evaluate two therapeutic strategies to prevent cytokine-induced preterm birth in late gestation mares.

To this end, in Experiment 1 six ponies (~290 d gestation) were infected intra-cervically with ~2 x 106 colony forming units (CFU) of a clinical strain of S. equi and assigned (n=3/group) to receive either trimethroprim sulfamethoxazole (TMS; 30 mg/kg BW, BID) alone or in combination with RegumateTM (altrenogest; TMS+R; 2.0 mg/50 kg BW, SID). Drug sensitivity tests confirmed that this strain of S. equi was sensitive to TMS.

In Experiment 2, 12 late term-pregnant mares were assigned to one of three experimental groups. Eight mares were inoculated trans-cervically with S. equi (~2 x 106 CFU) as in Expt. 1 and were assigned to receive either antibiotics alone (TMS: 30 mg/kg BW, BID) or in combination with dexamethasone (TMS+DEX) while four mares served as non-infected, non-medicated controls (CON).

DEX was administered daily over a six-day period with decreasing doses every two days from 40, 35 to 25 mg, respectively. Blood samples were collected prior to infection and at 12, 24, 48, 72 h post infection and three times weekly thereafter until delivery and macrophage cytokine mRNA, relaxin and progesterone (P4) levels were determined.

Fetal and placental well-being were evaluated daily by transrectal ultrasonography.

Treatment (TMS, TMS+R or TMS+DEX) commenced upon initial signs of vaginal discharge and/or placental changes. TMS was maintained through to delivery and for seven days post partum. Blood was collected from foals at 0 and 24 h post partum for CBC (neutrophil:lymphocyte ratio), immunoglobulin G (IgG) and P4 analysis as indices of maturity. Placentae and fetuses were submitted for necropsy and histopathology.

In Experiment 1 all six mares showed signs of vaginal discharge and/or placental changes within 36 h of inoculation. Three aborted 11, 12 and 14 days post-inoculation, two from the TMS+R group and one from the TMS group; the remaining three mares carried to near-term delivering viable foals. Mean birth weight of TMS and TMS+R foals was 19.55 ± 1.82 and 17.55 ± 1.71 kg, respectively. Placental thickening increased (P<0.001) from 0.77 ± 0.04 cm at pre-inoculation to 1.17 ± 0.06 cm at 48 h post inoculation. Pathology confirmed ascending necrosuppurative placentitis and bronchopneumonia in aborted fetuses. Culture of stomach contents of aborted fetuses revealed heavy growth of S. equi.

In Expt. 2, the mean gestational stage at time of S. equi inoculation was 297 ± 2.6 for infected vs. 307 ± 3.4 days for control mares. The average stage of gestation at time of delivery for CON, TMS and TMS+DEX mares was 340 ±7.6, 319 ± 6.4 and 293 ± 3.7 days, respectively.

All CON mares delivered normal viable foals while two of the inoculated mares aborted dead fetuses, one from each treatment group.

Of the remaining infected mares, six produced live pre-term foals (3 from TMS, 3 from TMS+DEX) five of which were viable while one from the TMS+DEX group was euthanized due to poor viability indices. Mean days at which pre-term delivery occurred for CON, TMS and TMS+DEX mares were -0.25 ± 7.6, 20.8 ± 6.3 and 37.3 ± 3.2 days, respectively. Mean birth weight of CON, TMS, TMS+DEX foals was 47.2 ± 1.8, 41.0 ± 3.6 and 34.9 ±2.3 kg, respectively. Pathology of placentae from infected mares showed varying degrees of lesions and edema consistent with ascending placentitis.

Due to low experimental numbers, the data are inconclusive as to whether the combinatorial therapy of TMS+R or TMS+DEX is more effective in the prevention of preterm delivery than TMS alone. Cytokine and blood hormone analyses are pending and should reveal a clearer picture of the underlying physiological responses in the face of uterine infections during late gestation. We plan on expanding these studies to obtain definitive answers on the merits of the above described therapeutic approaches to prevent pre-term labor in mares with uterine infections.

In an effort to understand pathogen progression in the disease process, we inoculated two mares with E. coli-lux (1 x 106 CFU) via ultrasound-guided transabdominal injection of the amnion to localize the pathogen in fetal tissues and organs using biophotonic imaging (Ryan et al., 2005c). The results of this experiment demonstrated that the pathogen once it is in the fetal fluids is aspirated into the lungs and ingested in the gastrointestinal tract where it colonizes the stomach, small and large intestines. While the organism was found to colonize the nares and sinuses of foals, it was absent from brain tissue.

In comparative studies, we used the late-term pregnant ewe as the model (Moulton et al., 2006; Ryan et al., 2005c). Ewes were infected via ultrasound-guided transabdominal inoculation of the amnion and incidence of preterm delivery in response to different inoculum concentrations ranging from 1 x 106 – 20 x 106 CFU of E. coli-lux was determined in addition to evaluating pathogen invasion of fetal lamb tissues. Preterm birth was observed in 20% of sham-inoculated control ewes (2/10), in 60% of ewes infected with 1.2 x 106 (3/5), 4 x 106 (3/5), or 5.6 x 106 CFU, respectively, and 80% of ewes infected with 20 x 106 CFU E. coli-lux.

In all lambs imaged for pathogen localization, organisms were found in the heart, lungs, gastrointestinal tract, nares and sinuses, but not in the brain. In addition, histopathology of cortical brain sections showed a high incidence of neurological damage of white matter in lambs that delivered preterm to ewes experimentally infected with E. coli-lux.

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