Arachidonic acid metabolites on peripheral blood plasma in patients with bronchial asthma

To assess the role of arachidonic acid metabolites in pathogenesis of bronchial asthma, we measured thromboxane B2 (TxB2), 6-keto PGF1 alpha, leukotriene (LT) C4, and LTB4 in venous blood plasma in patients with bronchial asthma and in controls. The level of TxB2 was significantly higher in 18 asthmatics with attacks than that in 11 controls (77.3 +/- 48.8 pg/ml vs 48.8 +/- 9.4 pgml). The levels of 6-keto PGF1 alpha in both asthmatics with attacks (17.8 +/- 6.7 pg/ml) and without an attack (16.4 +/- 9.7) were significantly higher than that in controls (11.6 +/- 3.9 pg/ml). The levels of LTC4 in asthmatics with attacks (0.84 +/- 0.11 ng/ml, n = 11) were significantly higher than that in controls, furthermore the level of LTC4 in asthmatics without an attack. The level of LTB4 was significantly higher in asthmatics with attacks (295.0 +/- 160.7 pg/ml, n = 26) than that in controls (161.7 +/- 25.3 pg/ml, n = 12) and asthmatics without an attack (182.4 +/- 97.9 pg/ml, n = 22). These findings suggest that the arachidonic acid metabolites are related to the asthma attack and are associated with the pathogenesis of bronchial asthma.     

Alteration of prostaglandin production and agonist responsiveness by n-6 polyunsaturated fatty acids in endometrial cells from late-gestation ewes

We investigated the effect of n-6 polyunsaturated fatty acids (PUFAs) on prostaglandin (PG) production by the uterus. A mixed population of endometrial cells (epthelium and stroma) from late-gestation ewes were cultured in defined medium containing linoleic acid (LA, 18:2, n-6), gamma-linolenic acid (GLA, 18:3, n-6) or arachidonic acid (AA, 20:4, n-6) in concentrations of 0 (control), 20 or 100 microM. After 45 h in test medium with or without added PUFAs, cells were challenged with control medium (CM), oxytocin (OT, 250 nM), lipopolysaccharide (LPS, 0.1 micro g/ml) or dexamethasone (DEX, 5 microM) for 22 h in the continued presence of the same concentration of PUFA and the medium was collected for measurement of PGF(2alpha) and PGE(2). Supplementation with LA inhibited the production of PGF(2alpha) but did not alter PGE(2), whereas GLA and AA increased production of both PGs. All PUFA supplements thus increased the ratio of PGE(2) to PGF(2alpha) (E:F ratio) two- to threefold. In control cells, OT and LPS challenges stimulated the production of PGF(2alpha) and PGE(2). In all challenge groups, the concentrations of PGF(2alpha) in response to PUFAs followed the same pattern - LA相似文献   

Production of an interleukin-1 inhibitory factor by human alveolar macrophages from normals and allergic asthmatic patients

In order to study the possible role of alveolar macrophages (AMs) in the development of local immune responses, we compared interleukin-1 (IL-1) production by peripheral blood monocytes and AMs from 17 allergic asthmatics and 32 controls. When stimulated by lipopolysaccharide, alveolar macrophages and blood monocytes from controls released IL-1 (127 +/- 74.6 and 178.8 +/- 120 IL-1 units/ml, respectively) in the same amounts as AMs and blood monocytes from allergic asthmatics (148 +/- 47.5 and 160.5 +/- 78.3 IL-1 units/ml, respectively). After stimulation by anti-IgE or the specific allergen, asthmatic blood monocytes released IL-1-like activity (71.8 +/- 46.4 and 45.4 +/- 25.9 IL-1 units/ml, respectively). In contrast, asthmatic AM supernatants contained no detectable IL-1-like activity after stimulation by allergen or anti-IgE. The same pattern was observed with monocytes and AMs from controls after passive cell sensitization with 20% of IgE-rich serum. In a second step, the effect of supernatants of IgE-dependent stimulated AMs was tested on thymocyte proliferation induced by a purified IL-1, permitting the demonstration of an IL-1 inhibitory factor released by the AMs while these supernatants didn't modify the IL-2-dependent proliferation of a CTL-L line. The use of indomethacin and assessment of PGE2 levels in AM supernatants made it possible to discard the role of prostaglandins in this inhibitory effect. Moreover this activity, which is resistant to heat and trypsin treatment, has a molecular mass between 40 and 50 kD and did not correspond to serum proteases, alpha-1-antiproteinase, and arginase.(ABSTRACT TRUNCATED AT 250 WORDS)     

Allergic and nonallergic asthmatics have distinct patterns of T-cell activation and cytokine production in peripheral blood and bronchoalveolar lavage.

Activation of lymphocyte subpopulations was determined in conjunction with levels of cytokines in peripheral blood and bronchoalveolar lavage (BAL) of asthmatics. Allergic asthmatics had increased numbers of CD4+ IL-2R+ T cells in peripheral blood and BAL, and T-cell activation closely correlated with numbers of low-affinity IgE receptor (CD23) bearing B cells. In contrast, in nonallergic asthmatics both CD4+ and CD8+ T cells from blood and BAL had increased expression of IL-2R, HLA-DR, and VLA-1. Furthermore, in the nonallergic asthmatics CD8+ T cells were decreased in blood but increased in BAL. Cytokine levels were determined in BAL fluid and supernatants from purified peripheral blood T cells and enriched BAL lymphocyte preparations. Allergic asthmatics were characterized by increased levels of IL-4 and IL-5, and this elevated IL-4 contributed to the elevated IgE levels found in these allergic subjects. In contrast, nonallergic asthmatics had elevated levels of IL-2 and IL-5, with IL-2 contributing to T-cell activation. In both types of asthma, the close correlation of IL-5 levels with eosinophilia suggests that IL-5 is responsible for the characteristic eosinophilia of asthma. Thus, we provide evidence of distinct T-cell activation resulting in different spectra of cytokines in allergic and nonallergic asthma.     

Cholinergic and alpha-adrenergic stimulation of prostaglandin release by dog thyroid in vitro.

Dog thyroid slices released in their incubation medium prostaglandins E2 (PGE2), F2 alpha (PGF2 alpha), 15-keto-13,14-dihydro-F2 alpha, and thromboxane B2 (TxB2), as measured by direct RIA. This release could be inhibited by indomethacin and naproxen, indicating that it corresponded to a neosynthesis. Carbamylcholine (2--100 microns) stimulated the release of PGE2, PGF2 alpha, and TxB2, whereas epinephrine (20 microns to 1 nM) enhanced the release of PGE2 and PGF2 alpha but had no effect on TxB2. These stimulations were inhibited by atropine and dihydroergocryptine, respectively, suggesting that a muscarinic and an alpha-adrenergic receptor were involved. The ionophore A23187 reproduced these stimulations, and the stimulatory effects of carbamylcholine and epinephrine were inhibited in the absence of exogenous Ca++ and after EGTA depletion. Ca++ thus appears as a major regulator of PG production in the thyroid. TSH (0.06--10 MU/ml) and dibutyryl cAMP had no effect on the release of PGE2, PGF2 alpha, or TxB2 by dog thyroid in vitro.     

Ovine allantoic fluid inhibition of prostaglandin synthesis in cotyledonary microsomes

Inhibition of microsomal prostaglandin (PG) biosynthesis by allantoic fluid, obtained from ewes at 80-120 days of gestation, was examined. Inhibition of cotyledonary microsomal PGE2 and PGF2 alpha biosynthesis by lyophilized allantoic fluid occurred in a dose-dependent manner. The concentration of allantoic fluid required to inhibit PGE2 and PGF2 alpha production by 50% averaged 17.9 +/- 3.2 (S.E.M.) mg dry weight/ml (n = 5). Microsomal PG biosynthesis was markedly enhanced by the addition of arachidonic acid (30 mumol/l). Synthesis of PGE2 and PGF2 alpha was increased to 245 +/- 65% and 184 +/- 14% of control (P less than 0.05, n = 5) respectively. Treatment of cotyledonary microsomes with porcine phospholipase A2 (PLA2; 0.125 units/ml) also stimulated PG synthesis, PGE2 increasing to 216 +/- 27% and PGF2 alpha to 172 +/- 14% of control (P less than 0.05, n = 5) respectively. Allantoic fluid (20 mg dry weight/ml) inhibited arachidonic acid-stimulated PG synthesis (PGE2 by 48.6 +/- 13.8% and PGF2 alpha by 44.2 +/- 7.7%) and PLA2-stimulated PG synthesis (PGE2 by 60.6 +/- 11.6% and PGF2 alpha by 74.8 +/- 8.5%). Allantoic fluid, however, did not affect PLA2-stimulated release of arachidonic acid from microsomes, thus negating the possibility that allantoic fluid suppresses PG synthesis by inhibiting PLA2 activity. These data indicate that allantoic fluid inhibits PG production at the level of PG synthase enzymes. Prostaglandin inhibitor(s) in allantoic fluid may play a role in maintaining uterine quiescence throughout gestation and its withdrawal, at term, may be involved in the initiation of labour.     

Differences in prostaglandin E2, prostaglandin F2 alpha and prostacyclin contents and their response to thyrotrophin stimulation and in prostaglandin-stimulated cyclic AMP response in normal and Grave's thyroid slices

The human thyroid contained prostaglandin (PG) E2, PGF2 alpha and 6-oxo-PGF1 alpha, an end-metabolite of prostacyclin (PGI2), the 6-oxo-PGF1 alpha content being the highest of these prostaglandins. Graves's thyroid contained a significantly higher amount of PGF2 alpha and lower amounts of PGE2 and 6-oxo-PGF1 alpha than the normal thyroid. Thyrotrophin acutely augmented the thyroid contents of PGE2, PGF2 alpha and 6-oxo-PGF1 alpha. The TSH-stimulated increases in PGE2 and 6-oxo-PGF1 alpha were lower but the TSH-stimulated increase in PGF2 alpha was significantly higher in Graves's thyroid than in the normal thyroid. Prostaglandin E2 and PGI2 stimulated human thyroid cyclic AMP synthesis, with the magnitudes of PGE2- and PGI2-stimulated increases in cyclic AMP being equal in normal and Graves's thyroid. Prostaglandin F2 alpha did not stimulate cyclic AMP synthesis significantly. These results provide evidence that prostaglandins play important roles in thyroid physiology and the pathophysiology of Graves's disease.     

Secretion of progesterone and prostaglandins by cells of bovine corpora lutea from three stages of the luteal phase

The secretion of prostaglandins (PGs) by bovine corpora lutea was investigated. Corpora lutea from the early, early-mid and late-mid stages of the luteal phase were dissociated by collagenase treatment and cultured in monolayer in Dulbecco's modified Eagle's medium containing 10% (v/v) fetal calf serum. Treatment with either LH (100 ng/ml) or dibutyryl cyclic AMP (dbcAMP; 1 mmol/l) had no effect on progesterone secretion by early luteal phase cells but stimulated progesterone secretion two- to fourfold by cells from the latter stages. The secretion rates, per microgram cell protein, of 6-keto-PGF1 alpha, PGE2 and PGF2 alpha were substantially greater in cells from the early luteal phase than in those from the latter stages, however, all changes in PG secretion in response to treatments were qualitatively similar between cells from the three stages of the luteal phase. The secretion rate of 6-keto-PGF1 alpha was greater than that of PGE2 or PGF2 alpha and was inhibited by treatment with indomethacin (28 mumol/l) but unaltered by treatment with LH, dbcAMP or butyrate (1 mmol/l). Secretion of PGE2 was inhibited by indomethacin but stimulated two- to threefold by treatment with either dbcAMP or butyrate. Secretion of PGF2 alpha was minimal and not inhibited further by treatment with indomethacin, but was stimulated 10- to 40-fold with dbcAMP. Indomethacin treatment inhibited the stimulatory effect of dbcAMP; butyrate had no effect on PGF2 alpha secretion. Treatment with LH had no effect on any of the PGs measured. In these experiments the secretion of progesterone appeared unrelated to any changes in the secretion of PGs.(ABSTRACT TRUNCATED AT 250 WORDS)     

IL-4 receptor genetic polymorphisms and asthma in Asian populations

BACKGROUND: IL-4 receptor alpha chain is crucial for the binding and signaling of IL-4, which mediates isotype switching and IgE production. The gene of IL-4 receptor alpha chain is a candidate gene for asthma and atopy. OBJECTIVES: To determine whether Ile50Val and Q576R polymorphisms of IL-4 receptor alpha chain gene were associated with asthma and higher level of total IgE in Chinese, Malay and Indian populations. METHODS: About 303 physician-diagnosed asthmatic subjects (145 Chinese, 73 Malay, 85 Indian) and 355 unselected blood donors (157 Chinese, 98 Malay, 100 Indian) were recruited. Total serum IgE level was measured by ELISA. Genotypes of Ile50/Val and Q576R were determined by PCR and restriction enzyme length polymorphism (RFLP). RESULTS: Ile50Val heterozygote is less frequent in asthmatics than in controls in Malay population (P=0.007). No difference was found in Chinese and Indian population. Ile50/Ile50 was more prevalent in higher total serum IgE group (IgE>100IU/ml) in Malay. The prevalence of Ile50/R576 haplotype was lower in asthmatics than controls in Chinese (P=0.046); while the prevalence of Ile50/Q576 haplotype was lower in asthmatics than in controls in Malay (P=0.048). The frequencies of the two single nucleotide polymorphisms (SNPs) and haplotypes vary among ethnicities (P<0.05). CONCLUSION: IL-4RA gene polymorphisms and its haplotypes showed ethnic variations. The association between IL-4RA gene polymorphisms, its haplotypes and asthma differed from ethnicities.     

Prostaglandins E1 and E2 interact with prostaglandin F2alpha to regulate initiation of DNA replication and cell division in swiss 3T3 cells.

Prostaglandin (PG) E1 or E2 added at 2-1,000 ng/ml to quiescent cultures of Swiss 3T3 cells synergistically enhanced the rate of initiation of DNA replication stimulated by PGF2 alpha alone or with insulin. Neither PGD2 nor PGF1 alpha had any effect with PGF2 alpha. An increase in the rate of entry into S phase also occurred when PGE1 or PGE2 was added 8 or 15 hr after addition of PGF2 alpha. However, adding PGE1 and PGE2 together with PGF2 alpha did not further enhance the synergistic effect observed with PGE1 or PGE2 separately. The synergistic effect was also observed in stimulation of 2-deoxyglucose uptake but not in early changes of intracellular levels of cAMP. These results may be relevant in understanding the control of fibroblastic proliferation in wound healing and may provide an alternative mechanism for oncogenic transformation.     

Absence of prostacyclin involvement in angiotensin-induced aldosterone secretion in rat adrenal cells

The role of prostaglandins (PGs) in aldosterone secretion was studied in isolated rat adrenal glomerulosa cells. [14C]Arachidonic acid was metabolized to [14C]6-keto-PGF1 alpha, [14C]PGF2 alpha, [14C]PGE2, and [14C]PGD2. Pretreatment with indomethacin (5 X 10(-5) M) or U-51605 (5 micrograms/ml) inhibited the synthesis of these metabolites. Angiotensin II (AII) stimulated a concentration-related release of aldosterone and 6-keto-PGF1 alpha, but not PGE2. Significant increases in aldosterone and 6-keto-PGF1 alpha occurred at AII concentrations of 0.2 and 2 nM. The increases in 6-keto PGF1 alpha concentrations after AII treatment were small, however (278 +/- 33 pg/10(6) cells X h for control vs. 581 +/- 90 after 2 nM AII). At higher concentrations, AII further stimulated aldosterone, but 6-keto PGF1 alpha levels declined. AII stimulated the synthesis of aldosterone and 6-keto PGF1 alpha in parallel with time of incubation. Indomethacin (3 microM) decrease basal and AII-stimulated aldosterone release by 40% and 23%, respectively, and inhibited the synthesis of PGs. U-51605 (5 micrograms/ml) failed to alter aldosterone release. Arachidonic acid increased the synthesis of PGE2 and 6-keto-PGF1 alpha in a concentration-related manner without altering the synthesis of aldosterone. In contrast, PGH2 stimulated the release of PGE2, 6-keto-PGF1 alpha, and aldosterone. PGI2 and PGE2 stimulated aldosterone secretion, which was concentration related. Threshold stimulation by PGI2 and PGE2 occurred at 0.5 and 5 nM, respectively. Maximal stimulation occurred at 5 nM for PGI2 and at 5000 nM for PGE2, with PGE2 producing the greater maximal response. Treatment of the cells with trypsin eliminated the steroidogenic response to PGE2. These findings indicate that PGI2 and PGE2 are produced by the adrenal glomerulosa cells, and the synthesis of PGI2 may be stimulated by AII. However, the concentrations of PGI2 synthesized are not adequate to stimulate aldosterone secretion. Thus, PGI2 does not appear to mediate angiotensin-induced aldosterone secretion.     

Inhibition of prostaglandin-enhanced release of LH by antiserum to luteinizing hormone releasing hormone.

Prostaglandin E2 (PGE2), PGF2alpha, PGF2beta was infused into a lateral ventricle of the brain of adult male rats, after pretreatment with normal rabbit serum (NRS) or anti-LH-RH serum, and the concentration of LH in arterial plasma was determined. I.v. administration of anti-LH-RH serum 2.5 min prior to the infusion of 2 microgram or 20 microgram of PGE2 significantly inhibited the PGE2-induced rise of plasma LH. Intraventricular infusion of 20 microgram of PGF2alpha or PGF2beta into NRS-pretreated animals caused a marked increase in the plasma LH concentration; whereas, prior i.v. administration of anti-LH-RH serum blocked the PG-induced rise in plasma LH levels. It is concluded that PGE2, PGF2alpha, and PGF2beta stimulate the release of LH primarily by enhancing the release of LH-RH.     

The effects of lipopolysaccharide and interleukins-1alpha, -2 and -6 on oxytocin receptor expression and prostaglandin production in bovine endometrium

Up-regulation of endometrial oxytocin receptor (OTR) expression followed by an increase in pulsatile endometrial prostaglandin (PG) F(2alpha) secretion causes luteolysis in cattle. Inhibition of luteolysis is essential for the maternal recognition of pregnancy but also occurs in association with endometritis. The factors regulating OTR expression at this time are unclear. The OTR gene promoter region contains binding elements for acute phase proteins but their function has not been established. This study investigated the effects of various cytokines on OTR expression and on PGF(2alpha) and PGE(2) production in explant cultures of bovine endometrium. Endometrium was collected in the late luteal phase (mean day of cycle 15.4+/-0.50) or early luteolysis (mean day of cycle 16.4+/-0.24) as determined by the initial concentration of endometrial OTR. Explants were treated for 48 h with: (i) lipopolysaccharide (LPS) and/or dexamethasone (DEX), (ii) ovine interferon-tau (oIFN-tau), or (iii) human recombinant interleukin (IL)-1alpha, -2 or -6. OTR mRNA was then measured in the explants by in situ hybridisation and the medium was collected for measurement of PGF(2alpha) and PGE(2) by RIA. LPS treatment stimulated production of PGF(2alpha), whereas DEX either alone or in combination with LPS was inhibitory to both PGF(2alpha) and PGE(2). Neither of these treatments altered OTR mRNA expression. oIFN-tau reduced OTR mRNA expression but stimulated production of both PGF(2alpha) and PGE(2). In endometrial samples collected in the late luteal phase, IL-1alpha, -2 and -6 all inhibited OTR mRNA expression, but IL-1alpha and -2 both stimulated PGF(2alpha) production. In contrast, when endometrium was collected in early luteolysis, none of the interleukins altered OTR expression or caused a significant stimulation of PGF(2alpha) production but IL-2 increased PGE(2). Neither IL-1alpha nor -2 altered OTR promoter activity in Chinese hamster ovary cells transfected with a bovine OTR promoter/chloramphenicol acetyl transferase reporter gene construct. In conclusion, the action of interleukins on both OTR mRNA expression and endometrial prostaglandin production alters around luteolysis. Pro-inflammatory interleukins suppress OTR expression in the late luteal phase, while LPS stimulates PGF(2alpha) without altering OTR mRNA expression. IL-I and -2 and LPS are therefore unlikely to initiate luteolysis but may cause raised production of PGF(2alpha) during uterine infection.     

Prostaglandin synthesis by isolated rat renal glomeruli.

The PGE2, PGF2 alpha and 6-keto-PGF1 alpha contents of the incubation medium of glomeruli isolated from rat kidney were measured at different times with or without addition of arachidonic acid. These prostaglandins accumulated progressively with time and reached equilibrium after 60--120 min incubation. Synthesis of the 3 prostaglandins was inhibited when indomethacin was added whereas it was markedly enhanced, mainly for PGE2, at increasing doses of arachidonic acid. Plateaus were reached above 5 micrograms/ml and concentrations corresponding to 50% of the maximum values were 2 micrograms/ml for PGE2 and PGF2 alpha, and 0.8 microgram/ml for 6-keto-PGF1 alpha. There were strictly linear relationships between PGE2 or PGF2 alpha productions and the concentration of glomerular protein. PGE2 and PGF2 alpha synthesis with or without arachidonic acid were maximum at 30--37 degrees C. PGE2 glomerular content was almost undetectable initially and increased with time. These data demonstrate that PGE2, PGF2 alpha and PGI2, in order of decreasing abundance, are synthesized by the glomerular cells and suggest that PGE2 and PGI2-sensitive glomerular adenylate cyclase activities and PGE2-sensitive renin synthesis may be stimulated by prostaglandins formed in the glomeruli themselves.     

Smoking Affects Eotaxin Levels in Asthma Patients

Background. Chronic airway inflammation is most important pathological finding in asthma. Cigarette smoking may modify type of inflammation as well as may influence disease severity and response to the treatment. Objective. Thus the aim of this study was to investigate whether cigarette smoking may have an influence on the levels of eotaxin-1, eotaxin-2, eotaxin-3 and IL-5 in patients with stable mild/moderate asthma. Methods. 45 steroid naive asthmatics (mean age: 55.2 ± 2.2 yrs) and 23 “healthy” smokers and non-smokers control subjects (mean age: 54.4 ± 9.7 yrs) were investigated. Asthmatics were divided into two subgroups according to their smoking histories: asthmatic smokers (n = 19) who currently smoke and have a history of > 10 pack-years and asthmatic never-smokers (n = 26). BAL and induced sputum were performed. Cytospins of induced sputum and BAL were stained with May-Grünwald-Giemsa for differential cell counts. Eotaxin-1, eotaxin-2, eotaxin-3 and IL-5 concentrations in serum, sputum and BAL supernatant was measured using a commercial ELISA kit. Results. In sputum supernatant from asthma smokers was significantly higher concentration of eotaxin-1 than in non-smokers asthmatics (203.4 ± 10.0 vs. 140.2 ± 9.5 respectively, p < 0.05). In non-smokers asthma patients levels of BAL eotaxin-1 strongly related to percent and absolute numbers of BAL eosinophils and neutrophils (Rs = 0.737 and Rs = 0.514 respectively, p < 0.05). The number and percent of sputum neutrophils and eosinophils, obtained from smokers asthmatics, significantly correlated with eotaxin-2 concentration in sputum supernatant (Rs = 0.58 and Rs = 0.75 respectively, p < 0.05). IL-5 levels in the serum and sputum from asthmatic never-smokers were significantly higher than they were from asthmatic smokers and “healthy” smokers. Asthmatic never-smokers showed a significantly higher amount of IL-5 in serum and sputum than the asthmatic smokers showed. Conclusions. This study showed the elevated levels of sputum eotaxin-1 as well as serum, sputum and BAL eotaxin-2 in asthmatic smokers without a significant increase of eosinophils compared to asthmatic never-smokers. The eotaxin concentrations were related not only with number of eosinophils but also with the number of neutrophils in all the studied tissue compartments. The data herein permits a suggestion that smoking may influence change in asthmatic airway inflammation by stimulating the production of eotaxins.     

Effects of prostaglandin F2 alpha on bone formation and resorption in cultured neonatal mouse calvariae: role of prostaglandin E2 production

Although most studies show that prostaglandin E2 (PGE2) is the most potent and effective of the prostanoids in bone, recent data in cell culture suggest that PGF2 alpha may have unique effects, particularly on cell replication. The present study was undertaken to compare the effects of PGF2 alpha and PGE2 in cultured neonatal mouse parietal bones by simultaneous measurement of bone resorption as release of previously incorporated 45Ca, bone formation as incorporation of [3H]proline into collagenase-digestible (CDP) and noncollagen protein, and DNA synthesis as incorporation of [3H]thymidine. PGF2 alpha was less effective than PGE2 as a stimulator of bone resorption, and its effects were partially inhibited by indomethacin and markedly inhibited by glucocorticoids. In contrast, the resorptive response to PGE2 was unaffected by indomethacin and only partially inhibited by cortisol. PGF2 alpha had little effect on bone formation, in contrast to the biphasic effect of PGE2, which inhibited labeling of CDP in the absence of cortisol and stimulated CDP labeling in the presence of cortisol. PGF2 alpha increased thymidine incorporation into DNA, but the effect was smaller than that of PGE2 and was inhibited by indomethacin. These observations suggested that PGF2 alpha might act in part by stimulating PGE2 production. By RIA, PGE2 concentrations were increased in the medium of bones treated with PGF2 alpha, and this increase was blocked by indomethacin. By HPLC, bones prelabeled with [3H]arachidonic acid showed an increase in labeled PGE2 release, and RIA showed an increase in PGE2 after PGF2 alpha treatment. These results indicate that PGF2 alpha is a relatively weak agonist in bone compared to PGE2 and that some of the effects of PGF2 alpha on bone resorption, formation, and cell replication may be mediated by an increase in endogenous PGE2 production.     

Increased interleukin-4 and decreased interferon gamma production in children with asthma: function of atopy or asthma?

Both atopy and asthma are claimed to be associated with a Th-2 cytokine pattern. We sought to determine the contribution of atopy and asthma to the observed Th-2/Th-1 imbalance in these conditions. Of 60 children aged 6-16 years that were included in the study, 13 were nonatopic nonasthmatic, 15 atopic nonasthmatic, 14 nonatopic asthmatic, and 18 atopic asthmatic. Atopic children had positive skin prick tests to grass pollens only. All children were studied after an asymptomatic and drug-free period of at least three months. Total IgE was measured in serum. Peripheral blood mononuclear cells were cultured and stimulated in vitro with phytohemagglutinin and interferongamma (IFN-gamma) and interleukin-4 (IL-4) measured in the supernatants. Total IgE was significantly higher in atopic asthmatics compared to nonatopic asthmatics (p = 0.004), and nonatopic nonasthmatics (p = 0.001), but was not different from atopic nonasthmatics (p >0.05). On the other hand, IL-4 was significantly elevated in atopic asthmatics and in nonatopic asthmatics compared to nonatopic nonasthmatics (p = 0.037 and p = 0.009, respectively). Although atopic asthmatics had lower IFN-gamma values than nonatopic asthmatics, the difference did not reach statistical significance. No correlation was detected between any two parameters. Our results suggest that both atopy and asthma contribute to the increased levels of IL-4 and that, whereas nonatopic asthma is associated with increases in both IL-4 and IFN-gamma release by mononuclear cells, only atopic asthma is characterized by a Th-2 type cytokine dominance.     

Mechanism of the rapid antigonadotropic action of prostaglandins in cultured luteal cells

A reproducible method for dissociation and culture of rat luteal cells is described. The concentration of LH required to produce half-maximal stimulation of progesterone secretion was 50 ng/ml. The effects of prostaglandin E(2) (PGE(2)) and prostaglandin F(2alpha) (PGF(2alpha)) on basal and luteinizing hormone (LH)-stimulated progesterone production were examined. Both prostaglandins stimulated basal progesterone production but PGE(2) was about twice as active, showing a 2-fold maximal stimulation at 0.75 muM. When either prostaglandin was incubated simultaneously with LH, a dose-dependent inhibition of progesterone secretion occurred; PGF(2alpha) was 4 times more active than PGE(2), showing 50% inhibition at a concentration of 40 x nM. Thus, both prostaglandins are more active as antagonists than as agonists of LH with respect to progesterone secretion. PGF(2alpha) also inhibited LH-stimulated adenylate cyclase activity and cyclic AMP accumulation. The block in progesterone secretion was reversed by addition of dibutyryl cyclic AMP (1 mM) but not by theophylline (5 mM) alone. These data and the finding that PGF(2alpha) did not affect the specific binding activity of the LH receptor in intact luteal cells indicate that the rapid action of prostaglandins in luteal cells is due to a block of LH-dependent production of cyclic AMP which results in a decrease in progesterone secretion.     

Prostaglandin E1 enhances the histamine induced stimulation of the mucociliary activity in the rabbit maxillary sinus

Inflammatory mediators are released in the airways during both inflammatory and allergic reactions, and many of these mediators affect mucociliary activity. To discover whether mucociliary activity is changed by a combination of mediators, the interaction between prostaglandins and histamine or methacholine was studied in vivo in the rabbit maxillary sinus. We used a photoelectric technique and recorded frequency changes induced by tested substances. Prostaglandins E1 and F2 alpha (PGE1 and PGF2 alpha) were given as ia. infusions followed by bolus injections of histamine or methacholine. Infusion with PGE1 (0.1 microgram.kg-1) enhanced the stimulating effect of a subsequent injection of histamine (10 micrograms.kg-1), maximum stimulation being 33 +/- 6% compared to 14 +/- 4% after histamine alone (p = 0.02). When the histamine injection was given 20 min after PGE1 no enhancement was observed. PGE1 did not enhance the stimulating effect of methacholine. In contrast to PGE1, PGF2 alpha failed to enhance the effect of histamine. It is proposed that a role of PGE1 is to modify the mucociliary response to other mediators released during inflammatory and allergic reactions.