Epidemiological studies have shown a potential association between maternal periodontitis and pregnancy complications. We used a pregnant murine model to study the effect of infection with the periodontal pathogen Porphyromonas gingivalis on pregnancy outcomes. Female BALB/c mice were inoculated with heat-killed P. gingivalis (10 9 CFU) in a subcutaneous chamber and mated 2 weeks later. At gestation day (GD) 7.5, mice were challenged with live P. gingivalis ( Maternal liver, uterus, and spleen samples were examined for P. gingivalis DNA using a PCR technique. Of the eight challenged mice with FGR fetuses, three had PCR signals for P. gingivalis in liver and uterus, but not in the spleen. Liver, uterus, and spleen were negative for P. gingivalis DNA among all other challenged and control mice. In serum of dams with FGR fetuses, tumor necrosis factor alpha levels were elevated significantly, while interluekin-10 levels were significantly reduced compared to levels in dams with normal fetuses. P. gingivalis-specific serum immunoglobulin G levels were significantly elevated in dams with FGR fetuses compared to dams without any FGR fetuses. These data demonstrate that P. gingivalis-induced murine FGR is associated with systemic dissemination of the organism and activated maternal immune and inflammatory responses.

Leukotriene B4 (LTB4) is a product of the 5-lipoxygenase pathway of arachidonic acid metabolism. LTB4 is a potent chemotactic factor for neutrophils and has been postulated to play an important role in a variety of pathological conditions including rheumatoid arthritis (RA), psoriasis, and inflammatory bowel disease. Rheumatoid arthritis (RA) is a chronic inflammatory polyarthritis that is inadequately treated with currently available drugs (1). One potential strategy to better treat this disease is to reduce the influx of leukocytes into the joint, since recent studies have shown that the extent of neutrophil infiltration into the joints of RA patients precedes clinical signs of inflammation and is predictive of pain (2). There are a number of mediators of the inflammatory response that could potentially be responsible for neutrophil accumulation, but leukotriene B4 (LTB4) is an attractive target since it is a potent chemotactic agent for human neutrophils (3), is produced in large amounts by these cells, and is found in the synovial fluid of patients with RA (4).In this paper, we describe experiments to assess the role of LTB4 in a murine model of RA, collagen-induced arthritis. The immunological and histological features of this model resemble those seen in RA patients. The strategy we employed was to use a LTB4 receptor antagonist to block the biological effects of endogenously produced LTB4. Several potent and selective LTB4 receptor antagonists, with a variety of structural types, have been reported (reviewed in ref. 5). However, there are no data on the efficacy of these agents in models of arthritis. CP-105,696, (+)-1-(3S,4R)-[3-(4-phenylbenzyl)-4-hydroxychroman-7-yl]cyclopentane carboxylic acid, is a newly discovered LTB4 receptor antagonist that has a high affinity OH for human and mouse LTB4 receptors and has a long plasma half-life in the mouse, which allows the maintenance of pharmacologically relevant concentrations of the drug with a once daily dosing protocol. Here we report the use of CP-105,696 to demonstrate the importance of LTB4 as a critical mediator in the pathogenesis of murine collagen-induced arthritis. MATERIALS AND METHODSIn Vitro LTB4 Receptor Ligand Binding Assays. The procedure for [3H]LTB4 binding was adapted from the method of Cheng and co-workers (6). Binding was performed in 150 ,ul in a buffer containing 50 mM Tris HCl (pH 7.3), 10 mM MgCl2, 9% methanol, 0.7 nM [3H]LTB4 (5920-7400 GBq/ mmol; New England Nuclear), and either 0.83 mg (murine spleen) or 0.13 mg (human neutrophil) of membrane per ml. Unlabeled LTB4 was added at a concentration of 5 ,uM to determine nonspecific binding. Incubations were carried out in microtiter plates at 4°C for 30 min and the bound ligand was separated from the free ligand with a Betaplate apparatus (Pharmacia LKB) with double-thickness glass fiber filter mats.In Vitro Chemotaxis Assay. Chemotaxis assays were performed as described by Harvath and co-workers (7). Neutrophils were isolated according to the procedure of Ferrante and Thong (8...

CDP870 is effective, was very well tolerated in this small study, and has an extended duration of action following one or more intravenous doses.

To investigate the effects of bisphenol A (BPA) on embryo and uterine factors in embryo implantation, timed pregnant C57BL6 females were treated subcutaneously with 0, 0.025, 0.5, 10, 40, and 100 mg/kg/day BPA from gestation days 0.5 to 3.5. In 100 mg/kg/day BPA-treated females, no implantation sites were detected on day 4.5 but retention of embryos in the oviduct and delayed embryo development were detected on day 3.5. When untreated healthy embryos were transferred to pseudopregnant females treated with 100 mg/kg/day BPA, no implantation sites were detected on day 4.5. In 40 mg/kg/day BPA-treated females, delayed implantation and increased perinatal lethality of their offspring were observed. Implantation seemed normal in the rest BPA-treated groups or the female offspring from 40 mg/kg/day BPA-treated group. These data demonstrate the adverse effects of high doses of BPA on processes critical for embryo implantation: embryo transport, preimplantation embryo development, and establishment of uterine receptivity.

Our previous animal studies showed that maternal Porphyromonas gingivalis infection in a subcutaneous chamber is associated with hepatic and uterine translocation, as well as systemic induction of maternal inflammatory responses, both of which were associated with fetal growth restriction (FGR). However, P. gingivalis-challenged dams had fetuses with either FGR (2 standard deviations below mean weight of nonchallenged dams) or normal weight. Therefore, the objective of this study was to determine whether maternal infection with P. gingivalis compromises normal fetal development via direct placental invasion and induction of fetus-specific placental immune responses characterized by a proinflammatory Th1-type cytokine profile. P. gingivalis-specific DNA was detected in placentas and fetuses of FGR and normal littermates from P. gingivalisinfected dams. Th1-and Th2-type cytokine mRNA as well as tumor necrosis factor alpha and transforming growth factor ␤2 mRNA were examined in placental tissue by using reverse transcription-PCR to determine Th1/Th2 ratios. For eight litters containing both normal-weight and FGR fetuses, P. gingivalis DNA was detected only in the placentas of FGR fetuses. All fetuses and all amniotic fluid samples from infected and control dams were negative for P. gingivalis DNA. mRNA levels of gamma interferon and interleukin-2 (IL-2) were significantly increased in placentas of FGR fetuses, while expression of IL-10 was significantly decreased in the same group. These data indicate that, in P. gingivalis-challenged dams, within each litter there is placenta-specific translocation of P. gingivalis that results in growth restriction of the targeted fetus, which is associated with a shift in the placental Th1/Th2 cytokine balance.