Platelet-activating factor (PAF) is a pro-inflammatory lipid which is a potent inducer of vascular permeability that has been implicated as an essential component of pre-implantation stages of pregnancy. Both embryo- derived and uterine PAF have been suggested as key regulators for establishment of pregnancy. However, these claims are controversial. In some instances, published claims have been unable to be confirmed. We have established that PAF levels in rabbit endometrium change during early pregnancy and pseudopregnancy, and that rabbit endometrial membranes have high affinity binding sites for PAF. Furthermore, human endometrial stromal cells in culture make PAF, and their cellular content of PAF can be elevated by progesterone, and further amplified by prostaglandin E2 (PGE2). Conversely, in endometrial epithelial cells, PGE2 secretion is increased and PGF2alpha secretion inhibited by addition of PAF, suggesting the presence of a paracrine control mechanism between epithelial and stromal cells. Isolated rabbit endometrial cells also produce PAF in response to A23187 treatment, and there appears to be a difference in responsiveness between cells derived from day-6 of pregnancy and pseudopregnancy. We have further shown that a PAF antagonist CV3988 can inhibit implantation in rabbits, probably by an endometrial action, and that day-6 blastocysts respond to PAF in vitro by phospholipid turnover and increased intracellular calcium levels. The present research will determine the significance of PAG in the implantation process in rabbits. Various PAF antagonists, that compete or do not compete, with endometrial PAF receptors will be tested for ability to interfere with implantation when given at various times during pre- implantation pregnancy. Reversal of any such inhibition will be attempted by concomitant administration of a non-metabolizable PAF analog. These experiments will determine the specificity of this inhibitory action and at what stage of early pregnancy these antagonists are most effective. To define further the influence of these antagonists on the two components - embryo and endometrium - embryo transfer experiments of treated embryos to untreated pseudopregnant recipients and vice versa are proposed. To examine in more detail the physiological action of PAF on rabbit embryos, other experiments to study phospholipid turnover, second messenger generation and changes in intracellular calcium in response to PAF in embryos of various stages of development are proposed. Taken together, these experiments will define the role of PAF in the implantation process in rabbits and elucidate whether it is actions on the embryo or endometrium or both that are important for successful implantation. This information will be of importance for treatment of infertility due to failure of blastocyst growth and development and implantation, and for improving the success rate in patients requiring treatment with assisted reproductive technology.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
2R01HD014048-11A1
Application #
3312446
Study Section
Reproductive Biology Study Section (REB)
Project Start
1980-04-01
Project End
1993-02-28
Budget Start
1992-07-01
Budget End
1993-02-28
Support Year
11
Fiscal Year
1992
Total Cost
Indirect Cost
Name
University of Texas Health Science Center San Antonio
Department
Type
Schools of Medicine
DUNS #
800772162
City
San Antonio
State
TX
Country
United States
Zip Code
78229
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Yang, Z M; Chen, D B; Le, S P et al. (1996) Differential hormonal regulation of leukemia inhibitory factor (LIF) in rabbit and mouse uterus. Mol Reprod Dev 43:470-6
Yang, Z M; Le, S P; Chen, D B et al. (1995) Leukemia inhibitory factor, LIF receptor, and gp130 in the mouse uterus during early pregnancy. Mol Reprod Dev 42:407-14
Chen, D B; Hilsenrath, R; Yang, Z M et al. (1995) Leukaemia inhibitory factor in human endometrium during the menstrual cycle: cellular origin and action on production of glandular epithelial cell prostaglandin in vitro. Hum Reprod 10:911-8
Kudolo, G B; Yang, Y Q; Chen, D B et al. (1995) Differential metabolism of exogenous platelet-activating factor by glandular epithelial and stromal cells of rabbit endometrium. J Reprod Fertil 105:315-24
Yang, Z M; Chen, D B; Le, S P et al. (1995) Interleukin-1 alpha in the rabbit uterus during early pregnancy. Early Pregnancy 1:201-5
Yang, Z M; Le, S P; Chen, D B et al. (1995) Expression patterns of leukaemia inhibitory factor receptor (LIFR) and the gp130 receptor component in rabbit uterus during early pregnancy. J Reprod Fertil 103:249-55
Kudolo, G B; Harper, M J (1995) Lyso-PAF:acetyl-CoA acetyltransferase and CDP-choline cholinephosphotransferase activities in the rabbit endometrium. J Lipid Mediat Cell Signal 11:145-58
Yang, Z M; Le, S P; Chen, D B et al. (1994) Temporal and spatial expression of leukemia inhibitory factor in rabbit uterus during early pregnancy. Mol Reprod Dev 38:148-52
Norris, C J; Peairs, W A; Kudolo, G B et al. (1994) Platelet-activating factor antagonists and implantation in rabbits. J Reprod Fertil 100:395-401

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