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Despite its crucial role in the health of both the fetus and the pregnant woman, the placenta is the least understood human organ. Since a growing body of evidence also underscores the importance of placental development in the lifelong health of both mother and offspring, this lack of knowledge about placental structure and function is particularly concerning. Given modern approaches and technologies and the ability to develop new methods, we propose a coordinated "Human Placenta Project", with the ultimate goal of understanding human placental structure, development, and function in real time.

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The pathogenesis of most chronic wounds is unknown. In this report, we summarize several areas of investigation which appear ready for further progress and which were discussed at a recent National Institutes of Health workshop on this subject. Of note were presentations of research on the role of fibrosis in wound healing, interaction of cytokines, hypoxia, extracellular matrix formation, keratinocyte migration, and involvement of proteases and neuropeptides in chronic wounds.

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Segments of rat aortic arch were studied to determine the existence of sexual dimorphism. The influence of the endothelium in mediating gender differences in contractility (maximum tension, Tmax) and sensitivity (ED50) to prostaglandin F2 alpha was measured. This was done in both intact and denuded vascular ring preparations which were dissected from adult male and female rats. Group I comprised untreated male and female rats; Groups II and III were treated with testosterone (10 mg/kg i.m.) or 17 beta-estradiol (2.5 mg/kg i.m.), respectively, on days 1, 3 and 6 and sacrificed on day 7. Intact vascular ring preparations from untreated females were significantly less sensitive (P less than .01) and less contractile (P less than .025) than those from the males. After the intimal surface of the aortic arch rings was rubbed the rings from females exhibited a significant increase in Tmax. However, in vessels from males endothelial denudation had no effect on either Tmax or ED50. Testosterone treatment of female rats significantly increased Tmax (P less than .01) and decreased the ED50 (P less than .01) when compared to rings from untreated females. Testosterone treatment did not significantly affect either parameter in vessels from females which had been rubbed. Testosterone treatment also had no significant effect in either intact or rubbed vessels from males. Estrogen treatment significantly increased the Tmax (P less than .05) of intact vessels from females and had no effect on other vessel segments. Thus, the gender difference in Tmax may relate to an attenuating effect of the endothelium on contractility in the rings from females.(ABSTRACT TRUNCATED AT 250 WORDS)

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A number of beta adrenergic blocking drugs were evaluated on ring preparations of endothelium intact and denuded segments of the rat aorta. The preparations were preconstricted under isometric conditions with an EC80 dose of phenylephrine. Labetalol (10(-7)-10(-5) M), MK-761 10(-7)-10(-5) M), timolol (10(-7)-10(-4) M) and propranolol (10(-6)-10(-4) M) relaxed both endothelium intact and denuded vessels in a dose-dependent manner. Spirendalol (2.8 X 10(-8)-8.1 X 10(-6) M), a specific beta-2 receptor antagonist and L643717 (1.8 X 10(-7)-3.6 X 10(-6) M), a specific beta-1 receptor antagonist did not elicit relaxation. Labetalol, MK-761, timolol and propranolol promoted relaxation only when vascular segments were preconstricted with phenylephrine or norepinephrine and failed to do so when prostaglandin F2 alpha or U46619 were used. This indicates a possible displacement of alpha adrenergic agonists with the beta antagonists. The degree of relaxation induced by labetalol, MK-761, timolol and propranolol was significantly less (P less than .05) when the endothelium was removed. Eicosatetraynoic acid (3.2 X 10(-5) M) significantly attenuated the relaxation response to labetalol, MK-761 and timolol in the intact but not in denuded vascular preparations. These studies suggest that some of the vascular effects of beta blockers may relate to the endothelium.

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Prostacyclin (PGI2) relaxes vascular smooth muscle in several species but, in high doses, PGI2 has been reported to contract several isolated arteries. Vascular endothelium is known to be obligatory for the vasodilatory responses to acetylcholine and several other substances. We therefore investigated the contractile effect of various prostanoids on rat abdominal aorta in which the endothelium was left intact or was removed. PGI2 (4-2000 ng/ml), 6-keto-prostaglandin (PG) E1, PGE1 and PGE2 (4-800 ng/ml) contracted both intact and de-endothelialized aortic segments in a dose-dependent manner. PGI2 (8-2000 ng/ml) increased the force generated by aortic rings with intact endothelium from 77.3 +/- 24.6 to 685 +/- 99.2 mg. The response to similar doses of PGI2 in aortic rings with the endothelium removed was reduced significantly (22.7 +/- 14.1 to 260 +/- 116.4 mg). This contractile response to PGI2 in both intact and de-endothelialized aortic rings was abolished by indomethacin pretreatment (20 micrograms/ml for 30 min) and was also blocked completely by the thromboxane receptor antagonist SQ 29548 (100 ng/ml). In contrast, the thromboxane synthase inhibitor OKY 1581 (2.5 micrograms/ml) did not significantly reduce the contractile response to PGI2. Unlike PGI2, the force generated by PGE2 (4-800 ng/ml) in aortic rings with intact endothelium (0-550.0 +/- 107.2 mg) was not significantly different from that generated by aortic rings without endothelium (35.0 +/- 23.6 to 650.0 +/- 193.2 mg).(ABSTRACT TRUNCATED AT 250 WORDS)

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Human peritoneal eosinophils were obtained from the waste dialysis bags of patients undergoing continuous ambulatory peritoneal dialysis. The number of eosinophils obtained from each bag varied from 3 X 10(7) to 288 X 10(7). The cells were incubated for 1 h in tissue culture medium and prostaglandin E2 (PGE2), 6-keto-prostaglandin F1 (6-keto-PGF1), and thromboxane B2 (TXB2) were determined by radioimmunoassay of the supernatant. The basal release as well as the stimulated release from the purified eosinophils of TXB2 were five times greater than the release of PGE2 and thirty times greater than the release of 6-keto-PGF1. A dose-response curve was achieved for all three cyclooxygenase products with the calcium ionophore A23187. The release of TXB2 was inhibited in a dose-dependent manner by the specific thromboxane A2 (TXA2) synthase inhibitor OKY-1581 and a corresponding increase in PGE2 and 6-keto-PGF1 was obtained. Indomethacin (5.6 X 10(-6) M) inhibited the cyclooxygenase products to almost undetectable levels.

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The pulmonary arteries of rats were studied in order to determine the existence of sexual dimorphism. Gender differences, in the sensitivity (EC50) and maximum contractility (Tmax) of ring preparations of the main pulmonary arteries of adult male and female rats, were evaluated with the synthetic endoperoxide analog [(15S)]-hydroxy-11 alpha,9 alpha-(epoxymethano)-prosta-5Z, 13E-dienoic acid,] (U46619) and norepinephrine. There were no significant gender differences in the Tmax values obtained with either U46619 or norepinephrine. However, when the intimal surface of vessel segments from female rats was rubbed, U46619 but not norepinephrine elicited a significantly lower Tmax. In contrast, no change in Tmax was observed with denuded vessel segments from males. Removal of the endothelium did not significantly affect the EC50 of U46619 or norepinephrine in segments from either sex. The inhibitory effect of verapamil on the U46619-induced contractile response was studied on both intact and denuded vessels from rats of both gender. The Tmax of intact vessels from males but not females was significantly attenuated by verapamil (P less than .05). The EC50 values with verapamil were not significantly different in any of the vessel preparations. We suggest that the endothelium of the pulmonary artery of female rats significantly potentiates the contractile response to U46619 and attenuates the inhibitory effect of verapamil.

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The routine availability of nucleated human cells for experimental use in limited in the absence of venipuncture. In this paper we have demonstrated that macrophages may be harvested routinely from the waste dialysis bags of patients undergoing continuous ambulatory peritoneal dialysis. These cells were identified as macrophages by morphology, adherence, phagocytosis, chemotaxis, non-specific esterase staining and peroxidase staining. Macrophages from patients with end-stage renal disease produced arachidonate cyclo-oxygenase products in a pattern similar to that of ascites macrophages obtained from patients with normal kidney function. Arachidonate metabolism was shown to be manipulatable. Thus, indomethacin blocked synthesis of cyclooxygenase products, and OKY-1581, a specific thromboxane synthase inhibitor, increased the release of prostaglandin E2 and prostacyclin, measured as its stable breakdown product 6-keto-prostaglandin F1, whereas the thromboxane B2 synthesis was effectively inhibited.

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Macrophages were isolated from the dialysis fluid of patients undergoing continuous ambulatory peritoneal dialysis and separated by gradient centrifugation and purification on 50% Percoll. The cells were prelabeled with [14C]arachidonic acid for 1.5 h. The labeled cells were then incubated with calcium ionophore A23187 (1 microM), serum-treated zymosan (200 micrograms/ml), and a lipoxygenase inhibitor, nordihydroguairetic acid (1 X 10(-5) M). The arachidonate metabolites in the medium were separated on Sep-Pak columns, and finally purified by reverse-phase high-pressure liquid chromatography (HPLC). The labeled products co-chromatographed with authentic leukotriene B4 and leukotriene C4 standards. Serum-treated zymosan and A23187 significantly stimulated and nordihydroguairetic acid significantly inhibited leukotriene synthesis. Leukotriene D4 was not detected, which suggests that these cells contain low gamma-glutamyltranspeptidase or high dipeptidase activity. These results establish, for the first time, that human peritoneal macrophages synthesize the lipoxygenase products, leukotriene B4 and leukotriene C4.

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Morphologic functional, and biochemical studies were performed on pseudointima obtained from woven Dacron aortic prostheses harvested from eight dogs 2 to 3 years after placement. In vivo platelet reactivity with prostheses was assessed by serial 51Cr-platelet survival measurements which documented that platelet survival returned towards normal but never attained preoperative levels. The extent of luminal coverage of prosthesis with pseudointima of the time of harvest was 60.3% +/- 2.4%. Morphologic techniques, including conventional light microscopy, immunoperoxidase light microscopy for endothelial factor VIII-related antigen, and scanning and transmission electron microscopy, demonstrated that pseudointima was composed of endothelial cells of varying maturity lining mesenchymal tissue. Areas of the prostheses with poorly formed pseudointima containing exposed Dacron fibers were covered with exuberant, platelet-rich thrombi. Ability of pseudointima to produce prostacyclin was assessed by bioassay of platelet antiaggregatory activity and radioimmunoassay of 6 keto PGF1 alpha, a metabolite of prostacyclin. These experiments confirmed that pseudointima produced abundant prostacyclin, although not as much as native aortic tissue. These studies document that vascular prosthetic pseudointima is nonreactive with platelets, presumably because of prostacyclin generation.

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1. Isolated perfused lungs from mature male rats show greater conversion of 14C Arachidonic Acid to cyclo-oxygenase products than females. 2. Following unlabelled arachidonate infusion, the male lungs release more 6-K-PGF1 alpha and TxB2 than females. 3. Aortic rings from male rats release more PGI2-like material and 6-K-PGF1 alpha than the females. 4. These data indicate an elevated PG synthetase activity in male rats as compared with females.

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Comparison of uptake between fed and fasted animals indicates that short-term changes in nutritional states significantly affects AA uptake and the effect of testosterone upon uptake. Consequently, the tradition of fasting animals prior to experimental manipulation may obscure not only sex differences but other factors as well. Clearly the experimental data obtained on fasted animals may not be a good model for Western man.

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