Journal of lipid mediators最新文献

A complex interaction of mechanical, hormonal, vasoactive, morphological and gaseous factors is responsible for the transitional period and maintenance of these changes in the newborn period. Vasoactive eicosanoids, formed at multiple sites in the lungs exert multiple effects on the perinatal pulmonary circulation. By direct, as well as indirect interaction with other systems, eicosanoids appear to have a role in the rearrangement of the circulation at birth. At this time PGE1, acetylcholine, bradykinin, and endothelin appears to work, at least in part, to cause fetal pulmonary vasodilation via the release of EDRF. Products of the lipoxygenase pathway are powerful vasoconstrictors, but may not be important in regulation of high fetal pulmonary vascular tone or the pulmonary pressor response to hypoxia.

The potency and selectivity of A-78773, a newly discovered 5-lipoxygenase inhibitor, were examined. The compound was significantly more potent than zileuton in inhibiting leukotriene formation in cell free lysates and in isolated human neutrophils. A-78773 inhibited a RBL cell lysate 5-lipoxygenase at concentrations 2 orders of magnitude lower than those required to inhibit rabbit reticulocyte 15-lipoxygenase or human platelet 12-lipoxygenase. The compound was also a potent, long lasting, orally active inhibitor of leukotriene formation ex vivo in dogs and in vivo in the rat. In experiments where leukotriene formation was completely inhibited, no increase in eicosanoids from other pathways was observed. A-78773 should prove to be a valuable clinical tool in treating leukotriene mediated diseases.

The regulatory role of prostanoids in acute cerebrovascular adaptations in newborns was determined using awake neonatal piglets (ages 0-5 days, n = 60). Cerebral blood flow (CBF) was measured by radiolabelled microspheres before and 45 s after intracarotid injections of PGE1 (0.1-10 micrograms/kg, n = 6), PGE2 (0.01-2 micrograms/kg, n = 6), PGF2 alpha (0.01 microgram/kg, n = 8) and PGI2 (0.1 microgram/kg, n = 6). CBF increased with PGE1 (10 micrograms/kg) by 39.5% and with all doses of PGE2 (p < 0.01) compared to zero dose. PGF2 alpha, a known adult vasoconstrictor increased total CBF from 97 +/- 8 to 130 +/- 14 ml/min per kg. PGI2 also increased CBF by 27% (p < 0.01). When CBF and prostanoid levels were measured with balloon catheters placed at the aortic root and the descending aorta and were inflated to adjust arterial blood pressure (BP) from 17 to 117 mmHg, sagittal sinus concentrations of prostanoids inversely correlated with total CBF (for PGs, tau = -0.52 to -0.66, p < 0.001; for TXB2, tau = -0.91 to 0.99, p < 0.0001). During hypotension (MABP < 50 mmHg) PGE, PGF2(2)alpha, 6-keto-PGF1 alpha and TXB2 increased by 311 +/- 56, 330 +/- 50, 301 +/- 44 and 658 +/- 44%, respectively. Net cerebrovascular production [total CBF x (sagittal sinus-arterial plasma prostanoid concentration)] of PGE, PGF2 alpha, and 6-keto-PGF1 alpha and TXB2 increased during hypotension compared to normotension (BP = 50-90 mmHg). At MABP = 91-117 mmHg, net production of prostanoids increased by 142-31%.(ABSTRACT TRUNCATED AT 250 WORDS)

Plasmid vectors were constructed which allowed expression of the mouse prostaglandin endoperoxide (PGH) synthase-1 and PGH synthase-2 isozymes in cos-1 cells. Efficient expression of the PGHS-2 isozyme required the truncation of the entire 3'-untranslated region of the PGHS-2 cDNA, possibly due to the presence of multiple AUUUA sequences which may destabilize the PGHS-2 mRNA. The length of the 3'-untranslated regions of the murine and ovine PGHS-1 isozymes, which do not contain AUUUA sequences, did not affect the efficiency of expression of these proteins. The murine PGHS-2 isozyme catalyzes the same cyclooxygenase and hydroperoxidase activities as the ovine and murine PGHS-1 isozymes. The maximal activities of the mouse enzymes expressed in cos-1 cells was about equal, but both were only about a third that seen with the sheep enzyme. Whether this reflects differences in the turnover rate of the mouse and sheep enzymes, or differences in the efficiency of expression in cos-1 cells is not known.

Lysophospholipases participate in the regulation of the levels of lysophospholipid, compounds with pleiotropic biological effects. Lysophospholipases were purified from a macrophage cell line (WEHI 265.1), a myelocytic leukemia cell line (HL-60) and peripheral blood eosinophils. WEHI 265.1 cells contain three lysophospholipases 28, 27 and 110 kDa as determined by polyacrylamide gel electrophoresis. The 110 kDa lysophospholipase also exhibits phospholipase A2 activity and appears to be identical to a previously described 110 kDa phospholipase A2. Similarly, the HL-60 cells have three lysophospholipases, the largest again a 110 kDa enzyme with phospholipase A2 activity and the smaller are 20 and 21 kDa. The low molecular mass lysophospholipases have distinctive chromatographic properties and amino acid compositions. However, the two low molecular mass enzymes from a given cell type are not radically different, e.g., 15 of the 20 amino acids of the C-terminal sequences of the HL-60 enzymes are identical. A single lysophospholipase, approx. 15 kDa, is a major eosinophil protein. This enzyme is different from those described above.

Although the function of prostaglandins in fish reproduction has not been well studied, it is becoming increasingly clear that prostaglandin F2 alpha or a compound closely resembling it serves three critical roles mediating reproductive activities in teleost fish. First, it appears to play a paracrine role in the ovary stimulating and/or modulating follicular rupture. Second, circulating levels of F prostaglandins rise at the time of ovulation and travel to the brain where they elicit female sexual behavior. Third, recent studies indicate that F prostaglandin is metabolized and released to the water where it functions as a sex pheromone stimulating male sexual behavior. Although these roles have been best characterized in the goldfish, ongoing studies indicate that metabolites of prostaglandin F2 alpha may commonly function as pheromones in many fish. Many questions remain about the identity(ies), origins, and species-specificity of the prostaglandin pheromone.

The cDNA encoding the platelet-activating factor (PAF) receptor was cloned from a guinea pig lung cDNA library by using a Xenopus laevis oocyte expression system. The human PAF receptor cDNA was isolated from a human leukocyte cDNA library using a 0.8-kbp fragment of the guinea pig PAF receptor cDNA as a probe. Both receptors have the same number of amino acids (342 residues) with seven putative transmembrane spanning domains, and belong to the G-protein-linked receptor superfamily. Overall amino acid identity between the two receptors was 83%:91% in the transmembrane domains. Seven threonine and three serine residues conserved in the cytoplasmic loops of both receptors may function as phosphate acceptors, as related to the homologous desensitization of the receptor. Activation of the PAF receptor yielded inositol 1,4,5-trisphosphate production in the PAF receptor expressed COS-7 cells and oocytes, and guanosine 5'-O-(2-thio)bisphosphate injected into the oocytes inhibited PAF-induced Cl- current, providing evidence that PAF stimulates phosphoinositide turnover via G-protein(s).

The research of the last two decades in the field of SRS-A and peptidoleukotriene (pLT) antagonists has provided information for the design of potent pLT antagonists, which share some or all of the following structural elements: (1) a lipophilic anchor, which fits into the lipophilic pocket of the LTD4 receptor; (2) a central lipophilic unit mimicking the tetraene system of LTD4; (3) one or two acidic groups, as mimics of the cysteinyl-glycine unit and/or the carboxylic group in the eicosanoid backbone of LTD4; (4) spacers connecting these elements. Potent pLT antagonists lacking a second polar binding group compensate by stronger interaction in other regions of the receptor. Identification of pLT antagonists is based on lead optimisation, preparation of pLT analogs and on the knowledge of the pLT receptor.