Prostaglandins最新文献

8-Iso-prostaglandin (PG)E₂ and 8-iso-PGF_2α are members of the isoprostane class of prostanoids which are formed by free radical mediated oxidation of arachidonic acid. Both E₂- and F₂-isoprostanes are potent vasoconstrictors and are believed to act through the prostanoid TP-receptors or a closely related receptor. In lightly anaesthetised, spontaneously breathing rabbits, aerosolised administration of histamine ( (1.25–40 mg ml⁻¹, n = 8) caused a modest dose-dependent increase in total lung resistance (R_L) and a concomitant fall in dynamic lung compliance (C_{L dyn}). Aerosolised methacholine (0.625 – 20 mg ml⁻¹, n = 6) caused considerable bronchoconstriction, with a dose-dependent increase in R_L, and a corresponding fall in C_{L dyn}. In contrast, intratracheal administration of either 8-iso PGE₂ or 8-iso-PGF_2α (1ng ml⁻¹, − 100μg ml⁻¹, n = 8) had no significant effect on lung function. The TP-receptor agonist, U-46619, was similarly inactive in this model when given by aerosol. Intravenous administration of histamine or 8-iso PGF_2α, had no significant effect on the lung indices, R_L and C_{L dyn}, or on the pulmonary and systemic vasculature (n = 4 per drug group). 8-Iso PGE₂ caused a concentration-dependent decrease in the right ventricular systolic pressure from 3 nmol kg⁻¹ to 100 nmol kg⁻¹ (n = 4, p < 0.05), but showed no other activity. In contrast, U-46619 given intravenously caused an increase in transpulmonary pressure (n = 4, p < 0.05), but had no effect on airflow. At higher doses, it did cause a significant drop in both systemic and right ventricular systolic pressures (n = 4, p < 0.05), which were probably due to an interaction with platelets. The isoprostanes had no effect on the rabbit airway up to a concentration of 3μM. In contrast, 3μM U-46619 caused a modest contraction of tracheal smooth muscle, whilst 3μM methacholine was at least five-fold more potent in contracting the same tissues.

We conclude that the aerosolised isoprostanes are not broncho-constriciting agents in the rabbit in vivo.

The inducible form of prostaglandin endoperoxide-2 (PGS-2) is transiently induced by activators of the protein kinase A and protein kinase C systems in rat preovulatory (PO) granulosa cells. This induction is suggested to play an important role in the ovulatory process, which shares many of the characteristics of an inflammatory reaction. The purpose of the present study was to explore the role of progesterone (P₄) as an “anti-inflammatory” steroid for the regulation of PGS-2 and the synthesis of prostaglandins in the PO follicle. Isolated rat PO follicles were preincubated with different amounts of exogenous P₄ before the addition of luteinizing hormone (LH) and 3-isobutyl-1-methylxanthine (IBMX) (LH+I). Medium levels of prostaglandin E₂ (PGE₂) were measured by RIA and the protein contents of PGS-1 and PGS-2 were determined by immunoblotting. LH+I. Both the content of PGS-2 and the synthesis of (PGE₂) were decreased. The content of PGS-1 demonstrated only minor changes in response to P₄. These results showed a dual regulation of PGS-2 in the rat PO follicle with both stimulatory and inhibitory pathways. One of the “anti-inflammatory” actions exerted by P₄ in the present study was to reduce the expression of PGS-2 and the follicular production of prostaglandins. This action might be of importance for restriction and control of the inflammatory response in the ovulatory process in vivo.

In 1990, prostaglandin (PG) F₂-like compounds were discovered to be produced in abundance in vivo by a free radical mechanism independent of the cyclooxygenase enzyme. Because these compounds are isomeric to cyclooxygenase-derived PGF_2α, they were termed F₂-isoprostanes (F₂-ISOP's). Subsequently, it was also demonstrated that PGD₂-like compounds (D₂-IsoP'S) and PGE₂-like compounds (E₂-IsoP's) are also produced in vivo as products of this pathway. Four different regioisomers of each of these classes of ISOP'S are formed, each of which can be comprised of eight racemic diastereomers. Thus, 64 different F₂-IsoP's, E₂-IsoP's, and D₂-IsoP's can be formed. Interest in these molecules stems not only from the fact that quantification of IsoP'S can provide a valuable index of free radical-induced lipid peroxidation in vivo but also from the fact that it has been shown that these compounds are capable of exerting potent biological activity. Because of this potential for exerting biological activity, the chemical syntheses of various IsoP compounds for biological testing has been initiated. As a result, a need for a systematic nomenclature for these compounds has evolved. A facile nomenclature that will allow rational differentiation and designation of each of the isomeric structures comprising the family of IsoP'S is presented.

Lipid-derived mediators play critical roles in inflammation and other multicellular vascular processes, including atherosclerosis and thrombosis (1). The lipoxins (LXs) were first isolated in 1984 (2), and have continued to show intriguing and potentially important biological roles. These compounds carry a trihydroxytetraene structure and are both structurally and functionally unique among arachidonic acid-derived bioactive products (Fig. 1). The availability of synthetic materials for evaluation of bioactions as well as appropriate methods of detection to determine when and where LX are generated has, in recent studies, catapulted our understanding of the formation and actions of the lipoxins. This mini-review addresses new concepts in the formation and biological roles of these lipid-derived mediators and considers whether the lipoxins and the newly discovered aspirin-triggered lipoxins (ATL) represent novel approaches for therapeutic opportunities. Recent findings indicate that select cytokines and aspirin initiate and regulate LX biosynthetic events. These circuits involve cell-cell interfacing that facilitates transcellular events to form LX that display anti-inflammatory actions in both in vitro and in vivo models. These recent results suggest that LX biosynthetic circuits assemble to evoke anti-inflammatory actions and generate LX that can serve as “stop signals” in appropriate microenvironments.

Numerous transcription response elements (e.g. AP-1, AP-2, GRE, CREB, as well as DRE) have been identified in the transcription regulation region of the PHS-2 gene in both mouse and human. The discovery of a DRE in the region raised the possibility that PHS-2 could be induced by TCDD, a dioxin compound. The time course and dose dependence of TCDD induction of PHS-2 mRNA expression were observed in HUVEC, primary human epithelial cells. In the observed time range (0–24 hours) the steady-state mRNA expression levels of PHS-2, as well as of mRNA for CYPlA1, increased with time at a TCDD dose of 20 nM. At the 24 hour time point, TCDD-treated cells displayed significant dose-dependent elevation of PHS-2 over the range of 0–40 nM TCDD. The increases in PHS-2 mRNA in both the time course and dose dependence experiments were consistent with that of CYPIAI. In contrast, mRNA for PHS-1, the constitutively expressed isoform of PHS, did not show significant changes under the conditions tested. These results are the first to indicate that TCDD can elevate PHS-2 mRNA level in a time and dose dependent manner. Further work needs to be done to learn the molecular mechanism of activation of PHS-2 by TCDD and the relation of TCDD action with other regulatory factors in the control of PHS-2 expression.

[3-(4-(4,5-diphenyl-2-oxazolyl)-5-oxazolyl]phenoxy]acetic acid (BMY 45778) inhibits human (IC₅₀ = 35 nM), rabbit (136 nM) and rat (1.3 μm) platelet aggregation. This compound activates adenylyl cyclase (ED⁵⁰= 6−10 nM) and stimulates GTPase in human platelet membrane preparations. The potency (EC₅₀) of BMY 45778 stimulating adenylyl cyclase is comparable to iloprost. However, maximal stimulation of GTPase by BMY 45778 is approximately half the iloprost-stimulated activity, and BMY 45778 limits the GTPase stimulation by iloprost suggesting that BMY 45778 is a partial agonist at the IP receptor. BMY 45 778 completely prevents [³H]Iloprost binding to platelet membranes (IC₅₀ = 7 nM). In whole platelets, BMY 45 778 causes elevation of platelet cAMP levels (cAMP content doubles at 13 nM) and activation of the cAMP dependent protein (cAMP-protein kinase ratio is twice basal at 2 nM). BMY 45778 treatment of whole platelets also desensitizes the adenylyl cyclase activation by iloprost. These results indicate that BMY 45778, which is structurally different from prostacyclin and most prostacyclin agonist, acts by stimulating prostacyclin (IP) receptors.

Prostaglandins (PGs) affect various aspects of gastric functions. In the present study the orally administered PGI₂ derivative beraprost sodium (TRK-100, I μg per kg body weight) decreased oxyntic histidine decarboxylase activity without changing serum gastrin levels. Antral pH increased 4 hr after treatment. Beraprost also decreased the pentagastrininduced histidine decarboxylase activity at the same dose. Serum levels of secretin, somatostatin and glucose, and oxyntic mucosal levels of histamine and somatostatin, showed no significant change after treatment with beraprost. These results suggest that the response of oxyntic histidine decarboxylase to gastrin is modified by one or more prostanoids including PGI₂. This mechanism might play a role in gastric mucosal protection.

Plasma iPGE₂ and i6-keto PGF_1α were measured with an EIA assay in twenty patients with alcohol-related liver cirrhosis (ALC group) and 13 patients with hepatitis B virus as an etiologic factor of liver cirrhosis (HLC group). Significant increase of both prostanoids was observed irrespectively of the etiology of liver cirrhosis. Their levels increased depending on the degree of liver insufficiency with the highest values in patients classified as Child-Pugh C class. A significant, positive correlation with Child-Pugh score was found regarding PGE₂ (r = 0,657; p < 0,001) as well as 6-keto PGF_1α (r = 0, 736; p < 0,001). Correlation (r = 0, 789, p < 0,001) was also observed between levels of both prostaglandins. In conclusion we have shown that plasma iPGE₂ and i6-keto PGF_1α arise simultaneously with the degree of liver insufficiency, that can be a result of activation of non-parenchymal liver cells accompanying hepatic fibrosis.

This paper reports on the involvement of c-MYB in the regulation of 5-lipoxygenase gene expression during differentiation of human HL-60 cells. We demonstrate that c-MYB binds, the 5-lipoxygenase promoter in undifferentiated cells but not in DMSQ-diif ferentiated cells. Also, we show that overexpression of c-myb cDNA in differentiated HL-60 cells represses the 5-lipoxygenase gene expression.