leukotriene-c4 and Acute-Disease

A 32-year-old man with glutathione synthetase deficiency developing an acute metabolic crisis is described. During this acute episode, intracellular glutathione content in erythrocytes was below the detection limit (<0.3 mmol/L). Leukotriene C4 in CSF and urinary leukotriene E4 were massively decreased, indicating an imparied synthesis of cysteinyl leukotrienes. Clinical recovery after one week was accompanied by a clear improvement of these biochemical parameters. The highly disturbed glutathione synthesis is postulated to be the reason for a deficient synthesis of cysteinyl leukotrienes, which may at least in part be responsible for the severe clinical symptoms.

Topics: Acute Disease; Adult; Glutathione; Glutathione Synthase; Humans; Leukotriene C4; Male; Metabolism, Inborn Errors

Leukotrienes (LT) are potent lipid mediators synthesized by the 5-lipoxygenase pathway of arachidonic acid (AA) metabolism. LT have been implicated in a broad spectrum of inflammatory processes. To investigate the influence of genetic factors on the contribution of LT to acute inflammation, we generated congenic 5-lipoxygenase-deficient 129, C57BL/6 (B6), and DBA/1Lac (DBA) mouse lines. Topical application of AA evoked a vigorous inflammatory response in 129 and DBA mice, whereas only a modest response was seen in B6 animals. The response to AA in 129 and DBA strains is LT dependent. In contrast, LT make little contribution to this response in B6 mice. AA-induced inflammation in B6 mice is prostanoid dependent, since this response was substantially reduced by treating B6 mice with a cyclooxygenase inhibitor. These data suggest that prostanoids are essential for AA-induced cutaneous inflammation in B6 mice, whereas LT are the major mediators of this response in 129 and DBA strains. In contrast, the response to AA in the peritoneal cavity is robust in the 129 and B6 strains, but was significantly blunted in DBA mice, showing that strain differences in the response to AA are tissue specific. Variations in these and other experimental models of inflammation appear to correlate directly with the ability of a particular mouse strain and a specific tissue to respond to LT, specifically LTC4. Taken together, these findings indicate that the relative contribution of prostanoids and LT to inflammatory responses is variable not only between strains but also between different tissues within these inbred mouse lines.

Topics: Acute Disease; Animals; Arachidonate 5-Lipoxygenase; Arachidonic Acid; Crosses, Genetic; Ear, External; Edema; Indomethacin; Inflammation; Leukotriene C4; Leukotrienes; Mice; Mice, Congenic; Mice, Inbred C57BL; Mice, Inbred DBA; Mice, Mutant Strains; Peritonitis; Species Specificity; Zymosan

A prospective, randomized, blinded experimental trauma study.. The effect of adenosine on arachidonic acid metabolites and lipid peroxidation was investigated in induced spinal cord injury.. Effects of adenosine in ischemia-reperfusion models have been studied, but no studies of adenosine's effect on direct trauma to the spinal cord have been reported.. Thirty-seven adult Wistar albino rats were randomly divided into four groups and underwent laminectomy. Group 1 underwent a sham operation. Group 2 received an intravenous adenosine infusion of 100 micrograms/kg per minute for 30 minutes. In Group 3, a standard spinal cord trauma of 50 g.cm strength was established at the lower thoracic level with a "weight-drop" technique, and Group 4 received an infusion of adenosine (100 micrograms/kg per minute) for 30 minutes after the trauma.. Tissue prostaglandin E2 activity was significantly higher in adenosine-treated trauma groups when compared with that in other groups (P < 0.0001). The difference in tissue leukotriene C4 activity between control and trauma groups was significant (P < 0.05). Adenosine infusion after trauma limited the increases in lipid peroxidation, with the difference approaching significance at P = 0.06. The structure of myelin was well preserved in the adenosine-treated trauma group. However, the changes were irreversible in severely damaged areas.. After acute spinal cord trauma, intravenous adenosine infusion of 100 micrograms/kg per minute could attenuate progression to secondary injury, but adenosine alone was not effective yet.

Topics: Acute Disease; Adenosine; Animals; Arachidonic Acid; Dinoprostone; Disease Models, Animal; Laminectomy; Leukotriene C4; Lipid Peroxidation; Male; Myelin Sheath; Nerve Compression Syndromes; Random Allocation; Rats; Rats, Wistar; Spinal Cord; Spinal Cord Injuries; Vasodilator Agents

To determine the role of inflammatory products of phospholipid metabolism in acute otitis media (AOM), we infected 128 chinchillas with Streptococcus pneumoniae and randomly assigned them to one of four equal-sized treatment groups receiving intramuscular ampicillin sodium (control) or intramuscular ampicillin plus receptor blockers of platelet activating factor (WEB 2086, 5 mg/d orally), of leukotriene (MK 571, 0.5 mg/d orally), or of thromboxaneA2 (GR 32191B, 5 mg/d orally). All treatments were begun on day 2 postinoculation and continued for 10 days. On days 3, 6, 9, and 12, 8 animals from each group were sacrificed. Effusions were recovered for biochemical assay, and the right middle ears were prepared for histologic study. Differences among groups in the number of ears with effusion or in effusion volume were not statistically significant. In comparison to the control group, mucosal thickness and the number of ears with histopathologic signs of inflammation were significantly less in the GR and WEB treatment groups, but not the MK group. Also, effusion concentrations of free fatty acids, protease, and hydrolytic enzymes were significantly less in those groups. These results show that the addition of a receptor blocker for either platelet activating factor and/or thromboxane to ampicillin in the treatment of AOM reduces mucosal inflammation and decreases the production of other inflammatory chemicals. The failure of a receptor blocker of leukotrienes to moderate disease expression suggests either a less important role for these chemicals in AOM or an insufficient bioavailability of the specific MK 571 inhibitor. These results confirm that platelet activating factor and thromboxane are active mediators of inflammation in AOM.

Topics: 6-Ketoprostaglandin F1 alpha; Acute Disease; Animals; Azepines; Biphenyl Compounds; Chinchilla; Dinoprostone; Ear, Middle; Fatty Acids, Nonesterified; Heptanoic Acids; Hydrolases; Leukotriene Antagonists; Leukotriene C4; Mucous Membrane; Otitis Media; Phospholipids; Platelet Activating Factor; Platelet Membrane Glycoproteins; Pneumococcal Infections; Propionates; Quinolines; Receptors, Cell Surface; Receptors, G-Protein-Coupled; Receptors, Thromboxane; Thromboxane B2; Triazoles

Leukotrienes (LT) are inflammatory mediators which can also exert regulatory effects on human myelopoiesis. We have studied the LT-producing capacity of freshly isolated leucocyte suspensions (containing blast cells in variable proportions) from 41 patients with acute myeloid leukaemia (AML) or chronic myeloid leukaemia (CML) in blast crisis (CMLbc) at diagnosis or relapse/resistant disease. Leucocyte suspensions from 19/29 AML patients (66%), and 2/12 CMLbc patients (17%; P = 0.012) demonstrated deficient capacity to synthesize LT from endogenous substrate after ionophore A23187 stimulation. Thus, these cells produced < 8 pmol LTB4+LTC4/10(6) cells (< 20% of mean LT formation in leucocyte suspensions from 18 healthy subjects). Addition of exogenous arachidonic acid did not normalize the LT synthesis in poor-producing cell suspensions. Purified, morphologically mature granulocytes from two AML patients also failed to produce normal amounts of LT. In leucocyte suspensions from the remaining 20 AML/CMLbc patients A23187 provoked LT biosynthesis, with markedly increased production of LTC4, but decreased LTB4 formation. Furthermore, elevated conversion of exogenous LTA4 to LTC4 was noted in the patient samples, independent of their capacity to produce LT after A23187 stimulation. The percentage of blast cells in patient white blood cell differential counts correlated inversely with ionophore-induced LT synthesis, but positively with the conversion of exogenous LTA4 to LTC4. The results suggest elevated LTC4 synthase activity and suppressed 5-lipoxygenase activity as novel enzymatic features of myeloid leukaemia patients with immature phenotype.

Topics: Acute Disease; Adolescent; Adult; Aged; Blast Crisis; Female; Glutathione Transferase; Granulocytes; Humans; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukemia, Myeloid; Leukocytes; Leukotriene A4; Leukotriene C4; Leukotrienes; Male; Middle Aged; Tumor Cells, Cultured

Leukotrienes may mediate bronchoconstriction in asthma. Cysteinyl leukotriene production rises in vivo after allergen challenge, but few reports describe leukotriene concentrations in clinical asthma or in children. Using high performance liquid chromatography/radioimmunoassay, plasma and urinary leukotrienes in asthmatic children (aged 5-10 years) were measured during an acute exacerbation (peak expiratory flow (PEF) < 65%, n = 10) and one month later (PEF 74-169%, n = 9), and in non-atopic normal children (aged 1.3-13.2 years). In the asthmatics, geometric mean (95% confidence interval) plasma leukotriene B4 (LTB4) was 746 pg/ml (398 to 1403) acutely and 1026 pg/ml (662 to 1593) in remission, compared with 369 pg/ml (167 to 728) in the normal children (n = 14). Plasma cysteinyl leukotrienes were low or undetectable, but urinary leukotriene E4 (LTE4) was higher in the asthmatics during an acute episode (210 pmol/mmol creatinine, 101 to 454) and at follow up (179 pmol/mmol, 110 to 293), compared with the normal children (98 pmol/mmol, 81 to 118, n = 41). This persistent increase in plasma LTB4 and urinary LTE4 concentrations one month after a severe asthmatic episode suggests leukotriene production is related to chronic inflammation rather than to acute bronchoconstriction.

Topics: Acute Disease; Adolescent; Asthma; Child; Child, Preschool; Chromatography, High Pressure Liquid; Humans; Leukotriene B4; Leukotriene C4; Leukotriene E4; Radioimmunoassay