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abstract / Pharmacology and Pharmacy / Doctoral / Doctor of Philosophy

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Natural killer (NK) cells are important in limiting tumor dissemination. The NK activity in C57B1/6 mice bearing Lewis lung carcinoma (LLC) was monitored during tumor development. During the initial period of tumor growth, NK activity was enhanced. As tumor growth progressed, NK activity became suppressed. Depletion of macrophages from the spleen cells of tumor-bearing mice restored the NK cytotoxic response. Plasma prostaglandin E2 (PGE2) concentrations were measured by a radioimmunoassay and found to become elevated during the course of tumor growth. To determine whether the suppressed NK activity might have been a result of the elevated levels of PGE2, mice were treated with a prostaglandin synthesis inhibitor, indomethacin. Indomethacin treatment prevented the rise in plasma PGE2 concentrations and the suppression in NK activity. These results support the hypothesis that the suppression of NK activity in tumor bearers is mediated by PGE2 which might be produced by the host's suppressor macro-phages.

The incidence of preterm labor has risen over recent decades and preventative antibiotic treatment is ineffective. Associated with a 40% increased risk of preterm birth, bacterial vaginosis is characterized by a decrease in lactobacilli and increase in pathogenic bacteria in the vaginal flora. Ascent of bacterial products to the intrauterine environment stimulates cytokine and prostaglandin secretion from invading immune cells and gestational tissues. Probiotic lactobacilli modulate the immune responses in mouse macrophages and human placental trophoblast cells. The focus of this thesis was to determine the influence of Lactobacillus rhamnosus GR-1 (GR-1) on cytokines and prostaglandins which are part of the activated pathway in infection and/or inflammation mediated preterm labour. GR-1 increased amnion chemokine and reduced pro-inflammatory cytokine release. GR-1 elevated prostaglandin E2 release that was paralleled by an increase in mPGES2 expression. It is possible that t that GR-1 may enhance the host defense barriers of the amnion to pathogenic bacteria.

The incidence of preterm labor has risen over recent decades and preventative antibiotic treatment is ineffective. Associated with a 40% increased risk of preterm birth, bacterial vaginosis is characterized by a decrease in lactobacilli and increase in pathogenic bacteria in the vaginal flora. Ascent of bacterial products to the intrauterine environment stimulates cytokine and prostaglandin secretion from invading immune cells and gestational tissues. Probiotic lactobacilli modulate the immune responses in mouse macrophages and human placental trophoblast cells. The focus of this thesis was to determine the influence of Lactobacillus rhamnosus GR-1 (GR-1) on cytokines and prostaglandins which are part of the activated pathway in infection and/or inflammation mediated preterm labour. GR-1 increased amnion chemokine and reduced pro-inflammatory cytokine release. GR-1 elevated prostaglandin E2 release that was paralleled by an increase in mPGES2 expression. It is possible that t that GR-1 may enhance the host defense barriers of the amnion to pathogenic bacteria.

The objectives were: (1) to determine the pre-ovulatory changes in plasminogen activator (PA) and (PA) inhibitor (PAI) activities in the porcine follicle, and, (2) to determine if changes in the PA/plasmin system associated with ovulation were prostaglandin (PG)-dependent. PA activity (change in absorbance/h/mg wet tissue weight, three gilts per treatment group) was elevated in both granulosa cells (GC) and theca interna cells (TIC) prior to human chorionic gonadotropin (hCG) administration (0.582 $ pm$ 0.171 and 0.718 $ pm$ 0.221, respectively) but returned to basal levels in these two compartments (0.023 $ pm$ 0.013 and 0.052 $ pm$ 0.024, respectively) at 29 h post-hCG. PA activity remained basal thereafter in GC but increased approximately ten-fold in the TIC (0.549 $ pm$ 0.239) at the time of ovulation (three gilts at 41 h and one of three gilts at 38 h). PAI activity did not change in TIC over the pre-ovulatory period but increased in GC as ovulation approached. PAI activity in GC peaked at 38 h (being significantly different (p $<$ 0.05) to all other times except 41 h). Although indomethacin (INDO) effectively inhibited both PG synthesis (1.1 $ pm$ 0.2 vs. 9.2 $ pm$ 0.9 ng/ml in controls) and ovulation (0 vs. 27-61% in controls), elevated PA activity (0.801 and 0.349) was detected in the TIC of two out of nine INDO-treated gilts. Levels were basal (0.074 $ pm$ 0.028) in the other gilts. These inconclusive results are believed to reflect the occurrence of ovulation earlier than predicted, in as many as 40% of control gilts, and the short duration of increased PA activity at this time. In conclusion, elevated PA activity, in GC and TIC prior to ovulation induction, may play a role in follicular development. Elevated TIC PA activity may play an important role in the ovulatory process, but is probably PG-independent.

Thesis (M.D.)--University of Adelaide, Dept. of Medicine and Pathology, 1985. / Includes bibliographical references (leaves 161-204).