leukotriene-b4 and Syndrome

Neutrophil activation with the release of intracellular granule contents has been observed in sickle cell disease (SCD). Because leukotriene B(4) (LTB(4)), a 5-lipoxygenase metabolite of arachidonic acid in neutrophils, is a chemoattractant and enhances neutrophil adhesion to endothelium, we assessed plasma levels of this metabolite in controls (n = 9) and individuals with SCD, SS genotype, both in basal "steady state" (n = 37) and during episodes of vaso-occlusion (n = 10) and acute chest syndrome (n = 5). Thirteen patients with SCD, SC genotype, in steady state were also studied. Although no significant differences were noted between the control (136 +/- 32 fmol/mL) and SC genotype (177 +/- 83 fmol/mL, P >.15), LTB(4) levels were markedly increased in patients with SS genotype in basal steady state (207 +/- 64 fmol/mL, P <.003) compared with those in controls. Values were further increased during vaso-occlusion (264 +/- 94 fmol/mL) and acute chest syndrome (363 +/- 124 fmol/mL). These levels were significantly different from measurements taken during steady state (P <.04 and P <.0001, respectively). No correlation was noted between LTB(4) level and total white cell or neutrophil count. Additionally, the significant correlation noted in SCD between increased levels of plasma LTB(4) and soluble L-selectin (P <.03) reflects neutrophil activation. We also observed an effect of LTB(4) on red cell-endothelial adhesion at concentrations that appear clinically relevant (1-10 pmol/mL) with concomitant up-regulation of mRNA for the endothelial vitronectin receptor. These properties of LTB(4) are relevant to disease pathophysiology, providing further evidence of the contribution of the neutrophil to the proinflammatory and proadhesive phenotype in SCD.

Topics: Adolescent; Adult; Anemia, Sickle Cell; Cell Adhesion; Chest Pain; Child; Child, Preschool; Endothelium, Vascular; Erythrocytes; Fetal Hemoglobin; Gene Expression; Genotype; Hemoglobins; Humans; L-Selectin; Leukocyte Count; Leukotriene B4; Neutrophils; Pain; Receptors, Vitronectin; Reference Values; Reticulocyte Count; RNA, Messenger; Syndrome; Vascular Diseases

Organic dust toxic syndrome (ODTS) is associated with inhalation of high concentrations of organic materials and is a noninfectious illness characterized by fever, malaise, myalgia, and neutrophilic inflammation of the lower respiratory tract. Studies in our laboratory of fungi in fresh lumber have demonstrated that yeasts may predominate and have raised the issue of potential exposure of sawmill workers to yeasts. Zymosan, a cell wall preparation from Saccharomyces cerevisiae, is a potent stimulator of alveolar macrophages (AM). In the present study, preparations from the cell walls of Pichia fabianii, Candida sake, Trichosporon capitatum, Rhodotorula glutinis, and Cryptococcus laurentii were compared with zymosan and beta-1,3-glucan for their ability to stimulate AM and activate complement. All species activated complement. P. fabianii, C. sake, T. capitatum, R. glutinis, C. laurentii, as well as zymosan and glucan, stimulated superoxide anion and leukotriene B4 production in a dose-dependent fashion, but R. glutinis and C. laurentii were much less active. Zymosan, glucan, P. fabianii, and R. glutinis treatment of AM resulted in increased phagocytosis of labeled sheep RBCs, whereas there was no effect with C. sake or C. laurentii and T. capitatum significantly inhibiting phagocytosis. These results suggest that exposure to high concentrations of yeast could provoke pulmonary inflammation resulting in an episode of ODTS.

Topics: Agricultural Workers' Diseases; Animals; Dose-Response Relationship, Drug; Dust; Leukotriene B4; Lung; Macrophages, Alveolar; Phagocytosis; Pneumonia; Rats; Rats, Sprague-Dawley; Sheep; Superoxides; Syndrome; Tumor Necrosis Factor-alpha; Yeasts; Zymosan

The eicosanoids are a family of lipid-derived autocoids that are released in response to a variety of physical and hormonal stimuli. In this study, prostaglandin E2 (PGE2) and leukotriene B4 (LTB4) were measured in the digital veins of clinically normal horses and horses with chronic laminitis to determine whether these arachidonic acid metabolites have a role in mediating signs of hoof pain and lesions associated with chronic laminitis. Horses were evaluated at rest and after a brief exercise period, to determine whether eicosanoids are released into the circulation after mild concussion. Digital vein eicosanoid concentrations in horses with signs of hoof pain attributable to chronic laminitis were not different than those in clinically normal horses. There was no difference in resting and postexercise PGE2 or LTB4 concentrations. Mean digital vein PGE2 concentration for the 2 groups was 187.18 pg/ml, whereas mean digital vein LTB4 concentration for the 2 groups was 74.71 pg/ml. These data do not support the hypothesis that PGE2 and LTB4 have a role in mediating the signs of pain and pathologic features of chronic laminitis.

Topics: Analysis of Variance; Animals; Chronic Disease; Dinoprostone; Eicosanoids; Female; Foot; Horse Diseases; Horses; Leukotriene B4; Male; Orchiectomy; Reference Values; Syndrome; Vascular Diseases; Veins

We have identified a patient with a number of neutrophil dysfunctions. The patient was a female baby who lived for 8 months. During her life, she developed severe bacterial infections and showed omphalitis, impaired wound healing, and a pronounced leukocytosis. She was not a patient with leukocyte adhesion deficiency, because all leukocyte CD18 complex proteins were expressed at normal levels. Yet, neutrophil polarization and chemotaxis to platelet-activating factor, leukotriene B4, or formyl-methionyl-leucyl-phenylalanine (FMLP) were completely absent. We found a strong defect in actin polymerization in response to chemotactic stimuli, but only a retarded or even normal reaction with other stimuli. This indicates that the cellular dysfunctions were not due to an intrinsic defect in actin metabolism. Instead, the regulation of actin polymerization with chemotactic stimuli seemed to be defective. We concentrated on FMLP-induced responses in the patient's neutrophils. Functions dependent on activation of complement receptor type 3, such as aggregation or adherence to endothelial cells, were normally induced. Binding to serum-coated coverslips was normal in cell number; however, spreading was not observed. Exocytosis from the specific granules was readily induced. In contrast, FMLP failed to induce a respiratory burst activity or degranulation of the azurophil granules. FMLP induced a normal increase in free intracellular Ca2+, but a decreased formation of diglycerides (especially the 1-O-alkyl,2-acyl compounds). Thus, we have described a patient whose neutrophils show a severe defect in functional activation via chemotaxin receptors, resulting in a selective absence of NADPH oxidase activity, exocytosis from the azurophil granules, and actin polymerization. Our findings show that actin polymerization for neutrophil spreading and locomotion is regulated differently from that for phagocytosis. Also, the release of azurophil and specific granule contents is clearly shown to be regulated in a different way.

Topics: Actins; Antigens, CD; Calcimycin; Calcium; CD18 Antigens; CD4 Antigens; CD8 Antigens; Cell Adhesion; Cell Aggregation; Chemotaxis, Leukocyte; Cytochalasin B; Endothelium, Vascular; Female; Humans; Immunologic Deficiency Syndromes; In Vitro Techniques; Infant, Newborn; Kinetics; Leukocyte Count; Leukotriene B4; N-Formylmethionine Leucyl-Phenylalanine; Neutrophils; Oxygen Consumption; Platelet Activating Factor; Reference Values; Sepsis; Syndrome; T-Lymphocyte Subsets

Persistent lymph node syndrome, epidemiologically related to acquired immune deficiency syndrome, is characterized by reactive lymphadenopathy and an increased incidence of localized bacterial, viral, and fungal infections. Seven typical patients were found to have a localized infection every 4.5 +/- 2.0 months (mean +/- SD) since onset of adenopathy. Because recurrent bacterial infections may be associated with defective polymorphonuclear leukocyte (PMNL) function, studies of PMNL function in these patients were undertaken. The patients' PMNLs had diminished chemotactic responses to high concentrations of two structurally distinct chemotactic factors, leukotriene B4 and N-formylmethionylleucylphenylalanine. The patients' PMNLs also had deficient degranulating responses to the former but not to the latter. Diminished PMNL function may contribute to the observed increased incidence of localized infections, which are a major source of morbidity, in these patients.

Topics: Adult; Chemotaxis, Leukocyte; Glucuronidase; Homosexuality; Humans; Leukotriene B4; Lymphatic Diseases; Lysosomes; Male; N-Formylmethionine Leucyl-Phenylalanine; Neutrophils; Syndrome

The formation of 5- and 15-lipoxygenase products of arachidonic acid metabolism was examined in human peripheral blood eosinophils obtained from five normal individuals and five patients with the hypereosinophilic syndrome (HES). Normal and HES eosinophils after stimulation with the calcium ionophore A23187 produced in comparable amounts leukotriene (LT)C4, LTD4, LTB4 and two of its isomers (5-(S),12-(R)-6-trans-LTB4 and 5-(S), 12-(S)-6-trans-LTB4), 15-hydroxy-eicosatetraenoic acid (HETE), 5,15-di-HETE and 8,15-di-HETE. No single lipoxygenase product predominated in the absence of added arachidonic acid whereas 15-HETE was the major product formed when either normal or HES eosinophils were stimulated with A23187 in the presence of added arachidonic acid (10(-4) M).

Topics: Arachidonate Lipoxygenases; Arachidonic Acids; Calcimycin; Chromatography, High Pressure Liquid; Eosinophilia; Eosinophils; Humans; Leukotriene B4; Lipoxygenase; SRS-A; Syndrome