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E J Goetzl

Publications and source records attributed to E J Goetzl.

At least 145 records · Page 8Linked to original sources
PubMed1986

Development of receptors for leukotriene B4 on HL-60 cells induced to differentiate by 1 alpha,25-dihydroxyvitamin D3.

The incubation of HL-60 human promyelocytic leukemia cells for 7 days with 100 nM 1 alpha,25-dihydroxyvitamin D3 [1,25(OH)2D3] induced differentiation into monocyte-like cells, as assessed by morphologic and biochemical characteristics. Stereospecific receptors for leukotriene B4 (LTB4) developed on the surface of the HL-60 cell-derived monocytes that had the capacity to transduce LTB4 stimulation of a transient increase in the cytosolic concentration of calcium ([Ca+2]in). HL-60 cell-derived monocytes, but not undifferentiated HL-60 cells, expressed a high affinity subset of 6400 +/- 3700 receptors per cell with a dissociation constant (Kd) of 2.3 +/- 1 nM (mean +/- SD, n = 3) and a low affinity subset of approximately 2.2 X 10(6) receptors per cell with an apparent Kd of 680 +/- 410 nM. Derivatives of LTB4 inhibited the binding of [3H]LTB4 to HL-60 cell-derived monocytes with a rank order of potency of LTB4 greater than 20-OH-LTB4 greater than 3-aminopropyl amide-LTB4, which is similar to the order for LTB4 receptors of human blood PMNL. In contrast, leukotrienes C4 and D4 and formyl-methionyl chemotactic peptides did not inhibit the binding of [3H] LTB4, which demonstrates the specificity of these receptors for isomers of 5,12-dihydroxy-eicosatetraenoic acid. LTB4 stimulated an increase in [Ca+2]in in HL-60 cell-derived monocytes which reached 50% of the maximal level at an LTB4 concentration of 0.5 nM (EC50). Preincubation of HL-60 cell-derived monocytes with 10 nM LTB4 resulted in a selective loss of high affinity receptors, as assessed by binding of [3H]LTB4, and a 200-fold increase in the EC50 for stimulation by LTB4 of increases in [Ca+2]in, without alterations in either the low affinity receptors for LTB4 or the responsiveness of [Ca+2]in to formyl-methionyl chemotactic peptides. HL-60 cells that are induced to differentiate into monocytes thus develop stereospecific receptors for LTB4 with binding and transductional characteristics similar to those of human blood PMNL.

Calcitriol↗
PubMed1986

Leukotrienes in the aqueous humor of patients with uveitis.

Utilizing chromatographic and radioimmunoassay techniques, we measured the concentration of leukotriene (LT) B4 and LTC4/D4/E4 in the aqueous humor of 14 patients with uveitis and seven patients undergoing penetrating keratoplasty or routine cataract extraction. Leukotriene B4 was detected in 11 of 14 patients with uveitis (mean, 0.96 pmole/mL), and LTC4/D4/E4 was found in 12 of 14 patients with uveitis (mean, 2.0 pmole/mL). In the control group, LTB4 was detected in six of seven patients (mean, 0.57 pmole/mL), and LTC4/D4/E4 was found in six of seven patients (mean, 1.9 pmole/mL). Leukotriene levels did not correlate with clinically assessed aqueous cell and flare. Mean levels of LT in patients with uveitis receiving corticosteroids were nearly double those found in non-steroid-treated patients. Despite apparent differences in LT levels, none of the above differences reached statistical significance.

Adrenal Cortex Hormones↗
PubMed1986

Alterations in human leukocyte function induced by ingestion of eicosapentaenoic acid.

Two groups of six adults with persistent asthma, who were identical clinically, received 0.1 or 4 g of purified eicosapentaenoic acid ethyl ester (EPA) daily for 8 weeks. Both doses increased significantly the generation of leukotriene B5 (LTB5) from EPA by polymorphonuclear (PMN) and mononuclear leukocytes, while only the high dose decreased leukocyte arachidonic acid (AA) and the generation of LTB4 and prostaglandin E2 from AA. Only the high dose led to inhibition of PMN leukocyte chemotaxis to multiple stimuli by a mean of 57-70% (P less than 0.01), without altering monocyte chemotaxis, the production of platelet-activating factor by mononuclear leukocytes, or the IgE-dependent release of histamine from basophils. Both doses of EPA increased the responses of T lymphocytes to phytohemagglutinin by a mean of 73% or more (P less than 0.01) without modifying the numbers of helper and suppressor T lymphocytes. EPA affects the functions of several types of leukocytes critical to inflammation and immunity.

Administration, Oral↗
PubMed1986

Abnormal responses to aspirin of leukocyte oxygenation of arachidonic acid in adults with aspirin intolerance.

The effect of 1 microM and 5 microM aspirin on oxygenation of arachidonic acid in vitro by basophils stimulated with anti-IgE was assessed with basophil-enriched suspensions of mononuclear leukocytes from five patients with asthma and hypertrophic allergic rhinitis and one patient with rhinitis alone who had recent adverse pulmonary reactions to aspirin, four aspirin-tolerant patients with asthma receiving therapy similar to that of the aspirin-sensitive patients, and eight normal subjects who resembled the patients with respect to sex and age. As quantified by the combined application of high-performance liquid chromatography and radioimmunoassays, the generation of the principal products prostaglandin E2 (PGE2) and leukotriene D4 was modified differently by aspirin but not sodium salicylate in the aspirin-sensitive patients. The alterations of PGE2 generation and of the ratio of leukotriene D4 to PGE2 generation by aspirin were much greater for basophil-containing leukocytes of aspirin-sensitive patients than those of the two control groups. Although the basic mechanism and relevance to pulmonary reactions of the observed effects of aspirin were not elucidated, aspirin clearly modifies the leukocyte oxygenation of arachidonic acid differently in aspirin-sensitive patients.

Adult↗
PubMed1986

Neuroimmunology.

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Brain↗
PubMed1986

In vivo and in vitro assessment of the role of leukotriene B4 as a mediator of rat cutaneous late-phase reactions.

Mast cell-dependent late-phase reactions (LPR) occur in rat skin and are characterized histologically by an early (1 to 8 hours) neutrophil-rich infiltrate, which is essential to a later (24 hours) infiltration by mononuclear cells. Although the ability of preformed mast cell-granule constituents alone to elicit LPR is clearly established, the relative pathogenetic contributions of newly generated lipid mediators to rat LPR are unknown. Leukotriene B4 (LTB4) may be generated by stimulated mast cells in a number of species and might potentially contribute to the neutrophil ingress. In order to examine this possibility in a well-characterized animal model of LPR, the capacity of LTB4 to influence rat cutaneous inflammation was studied. LTB4 (0.1 to 100 ng) alone did not induce vasopermeability in rat skin nor potentiate the blueing response to histamine. Intracutaneous LTB4 (0.1 to 100 ng) did not cause significant infiltration of neutrophils 3 to 4, 6 to 8, or 24 hours after injection; increased numbers of mononuclear leukocytes were not appreciated through 24 hours. In the same animals intracutaneous anti-IgE and intact mast cell granules both produced intense biphasic infiltration characteristic of rat LPR. In order to examine if rat polymorphonuclear leukocytes were capable of responding to LTB4, several in vitro studies were performed. Rat peritoneal and peripheral blood neutrophils migrated toward formyl-methionyl-leucyl-phenyl-alanine in vitro but not to purified human or synthetic LTB4. Rat peripheral blood and elicited peritoneal neutrophils bound only 32% and 27%, respectively, of the quantity of [3H]LTB4 bound by human neutrophils.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1986

Hyperalgesic properties of 15-lipoxygenase products of arachidonic acid.

Induction of hyperalgesia by leukotriene B4 (LTB4), a potent chemotactic factor for polymorphonuclear leukocytes (PMNLs), depends on the generation by cutaneous PMNLs of mediators that are probably derived from the 15-lipoxygenation of arachidonic acid. The capacity of dihydroxyeicosatetraenoic acid (diHETE) products of the 15-lipoxygenation of arachidonic acid in PMNL to elicit hyperalgesia was evaluated by assessing the effects of intradermal injection of synthetic diHETEs on the pressure nociceptive threshold in rats. (8R,15S)-Dihydroxyeicosa-(5E-9,11,13Z)-tetraenoic acid [(8R,15S)-diHETE] produced a dose-dependent hyperalgesia, as measured by decrease in threshold for paw withdrawal. The isomer (8S,15S)-diHETE antagonized in a dose-dependent manner this hyperalgesia due to (8R,15S)-diHETE but did not suppress prostaglandin E2-induced hyperalgesia. (8S,15S)-DiHETE produced a dose-dependent hypoalgesia, as reflected by an increase in nociceptive threshold, suggesting a contribution of endogenous (8R,15S)-diHETE to normal nociceptive threshold. The hypoalgesic effect of (8S,15S)-diHETE was blocked by corticosteroids but not by the cyclooxygenase inhibitor indomethacin. Neither (8R,15S)-dihydroxyeicosa-(5,15E-9,11Z)-tetraenoic acid nor (8R,15S)-dihydroxyeicosa-(5,11E-9,13Z)-tetraenoic acid exhibited any hyperalgesic or hypoalgesic activity. The stereospecificity of the effect of (8R,15S)-diHETE suggests that the induction of hyperalgesia is a receptor-dependent phenomenon and that (8S,15S)-diHETE may be an effective receptor-directed antagonist. The (8R,15S)-diHETE and (8S,15S)-diHETE from PMNL, keratinocytes, and other epithelial cells may modulate normal primary afferent function and contribute to inflammatory hyperalgesia.

Animals↗
PubMed1986

Leukotriene C4 transport and metabolism in the central nervous system.

The transport and metabolism of radiolabeled leukotriene (LT) C4 in the CNS were investigated after intraventricular injection. Under thiopental (Pentothal) anesthesia, New Zealand white rabbits were injected intracerebroventricularly with 0.2 ml of artificial CSF containing 2.5 microCi of [3H]LTC4 (36 Ci/mmol), 0.3 microCi of [14C]mannitol, and, in some cases, 0.9 mg of probenecid, 1.8 mg of cysteine, 1.4 micrograms of unlabeled LTC4, or 2 mg of tolazoline HCl. After 2 h, the conscious rabbits were killed, and the quantity and nature of the 3H and 14C were determined in CSF, choroid plexus, and brain. The [3H]LTC4 recovered in CSF and brain was not extensively metabolized, as greater than 70% of the 3H remained [3H]LTC4, although some spontaneous conversion to 11-trans-[3H]LTC4 occurred. Oxidized forms of [3H]LTC4, [3H]LTD4, and [3H]LTE4 did not exceed 18% in CSF and brain. After intraventricular injection of [3H]LTC4, 3H was transferred from the CSF to blood by a probenecid-sensitive, but tolazoline-insensitive, transport system in the CNS much more rapidly than mannitol. Cysteine decreased the retention of [3H]LTC4 in brain. These results are consistent with previous in vitro observations that [3H]LTC4 is transferred from CSF into blood by an efficient transport system for LTC4 in choroid plexus.

Animals↗
PubMed1986

O3-induced change in bronchial reactivity to methacholine and airway inflammation in humans.

The increase in airway responsiveness induced by O3 exposure in dogs is associated with airway epithelial inflammation, as evidenced by an increase in the number of neutrophils (polymorphonuclear leukocytes) found in epithelial biopsies and in bronchoalveolar lavage fluid. We investigated in 10 healthy, human subjects whether O3-induced hyperresponsiveness was similarly associated with airway inflammation by examining changes in the types of cells recovered in bronchoalveolar lavage fluid obtained after exposure to air or to O3 (0.4 or 0.6 ppm). We also measured the concentrations of cyclooxygenase and lipoxygenase metabolites of arachidonic acid in lavage fluid. We measured airway responsiveness to inhaled methacholine aerosol before and after each exposure and performed bronchoalveolar lavage 3 h later. We found more neutrophils in the lavage fluid from O3-exposed subjects, especially in those in whom O3 exposure produced an increase in airway responsiveness. We also found significant increases in the concentrations of prostaglandins E2, F2 alpha, and thromboxane B2 in lavage fluid from O3-exposed subjects. These results show that in human subjects O3-induced hyperresponsiveness to methacholine is associated with an influx of neutrophils into the airways and with changes in the levels of some cyclooxygenase metabolites of arachidonic acid.

Adult↗
PubMed1986

Mediation of pulmonary immunity and hypersensitivity by neuropeptides.

Noxious challenges and inflammatory reactions in pulmonary tissue selectively stimulate different subsets of peptidergic nerve fibers to release distinct neuropeptides, that elicit local and systemic responses similar to those of immediate hypersensitivity. The sensory neuropeptides affect functions of leukocytes, epithelial glands, and smooth muscle cells directly through receptor-medicated processes, and indirectly, through the actions of mediators released from mast cells stimulated by the peptides. The specificity of neuropeptide recognition by pulmonary lymphocytes, smooth muscle cells, mast cells and basophils, and the functional diversity of these neuropeptides suggests that the nervous system modulates immediate and delayed hypersensitivity responses in the lung by unique mechanisms.

Animals↗
PubMed1985

Selective expression of 15-lipoxygenase activity by cultured human keratinocytes.

Human keratinocytes isolated from neonatal skin express 15-lipoxygenase activity at a level far greater than that of any of the other pathways for lipoxygenation of arachidonic acid. The 10,000 x g supernatant of sonicates of 10(6) keratinocytes generates 15-hydroxy-eicosatetraenoic acid from 5 micrograms/ml of arachidonic acid at a mean maximum rate of 38 ng/30 min at 37 degrees C, that is similar to the activity of the 15-lipoxygenase of human airway epithelial cells and greater than that of endothelial cells and leukocytes. The unique mediators derived from the 15-lipoxygenation of arachidonic acid, that stimulate secretion and exert hyperalgesic effects, may achieve a concentration in skin sufficient to regulate local cellular and neural functions.

Animals↗
PubMed1985

Pertussis toxin inhibition of chemotactic factor-induced calcium mobilization and function in human polymorphonuclear leukocytes.

Chemotactic factors stimulate a rapid increase in the cytosolic concentration of intracellular calcium ions ([Ca2+]in) in human polymorphonuclear leukocytes (PMNL), which may be an event that is critical to the expression of chemotaxis and other PMNL functions. Treatment of PMNL with pertussis toxin catalyzes ADP-ribosylation of a protein similar or identical to the inhibiting regulatory protein of adenylate cyclase, Gi, and suppresses the increase in [Ca2+]in elicited by leukotriene B4(LTB4) and formyl-methionyl-leucyl-phenylalanine. Chemotactic migration and lysosomal enzyme release elicited by chemotactic factors were inhibited by pertussis toxin with a concentration-dependence similar to that for inhibition of the increase in [Ca2+]in, without an effect on lysosomal enzyme release induced by the ionophore A23187 and phorbol myristate acetate. Activated pertussis toxin catalyzed the [32P]ADP-ribosylation of a 41 kD protein in homogenates of PMNL. The extent of [32P]ADP-ribosylation of this protein was reduced 59% by pretreatment of intact PMNL with pertussis toxin. Pertussis toxin selectively decreased the number of high-affinity receptors for LTB4 on PMNL by 60% without altering the number or binding properties of the low-affinity subset of receptors. Pertussis toxin modification of a membrane protein of PMNL analogous to Gi thus simultaneously alters chemotactic receptors and attenuates the changes in cytosolic calcium concentration and PMNL function caused by chemotactic factors.

Adenosine Diphosphate Ribose↗
PubMed1985

Leukotriene C4 transport by the choroid plexus in vitro.

Nanomolar concentrations of peptidoleukotrienes evoke sustained cerebral edema and arterial constriction. Peptidoleukotrienes are thus considered to play an important role in eliciting cerebral edema after cerebral ischemia and vasospasm after subarachnoid hemorrhage. It was hypothesized that the choroid plexus, the locus of the blood-cerebrospinal fluid barrier, might minimize the vasoactivity of locally generated or systemically derived leukotrienes by transporting leukotrienes from cerebrospinal fluid into the blood. Consistent with this hypothesis, leukotriene C4 in vitro was transported into and released from isolated rabbit choroid plexus by a system that was specific, energy-dependent, probenecid-sensitive, and depressed by cold temperatures. The accumulation of leukotriene C4 in the choroid plexus was not dependent on tissue binding or metabolism of leukotriene C4.

Animals↗
PubMed1985

Predominant generation of 15-lipoxygenase metabolites of arachidonic acid by epithelial cells from human trachea.

Epithelial cells of 99% purity and 92% viability were isolated from human tracheas obtained post mortem, and the cellular pathways for lipoxygenation of arachidonic acid were examined in vitro. The lipoxygenase metabolites were identified by comparison with synthetic standards during reversed-phase and straight-phase high-pressure liquid chromatography, UV spectroscopy, and gas chromatography/mass spectrometry. Epithelial cells incubated without arachidonic acid failed to generate detectable quantities of metabolites, while cells incubated with arachidonic acid at 1-50 micrograms/mf for 1-30 min invariably generated predominantly 15-lipoxygenase products, including 15-hydroxyicosatetraenoic acid (15-HETE), four isomers of 8,15-dihydroxyicosatetraenoic acid (two 8,15-diHETES and two 8,15-leukotrienes), at least one isomer of 14,15-dihydroxyicosatetraenoic acid, and smaller amounts of 12-HETE and 8-HETE, but little or no detectable 5-HETE or 5,12-diHETEs. The capacity of epithelial cells from human pulmonary airway to selectively generate 15-lipoxygenase metabolites of arachidonic acid suggests a potential role for the products as mediators of airway epithelial function.

Arachidonate Lipoxygenases↗
PubMed1985

Inflammation and hypersensitivity.

The leukotrienes are a family of potent mediators of hypersensitivity and inflammation. The application of sensitive and specific radioimmunoassays for leukotrienes has revealed the generation of significant quantities of several leukotrienes by leukocytes exposed to natural stimuli in the absence of exogenous arachidonic acid. The C6 peptide leukotrienes, LTC4 and LTD4, are potent vasoactive and smooth muscle contractile factors. LTB4 and other di-HETEs stimulate polymorphonuclear leukocyte function and suppress T-lymphocyte activities. The effects of LTB4 on T lymphocytes are subset-specific and include the activation of suppressor and cytotoxic T cells. Receptors for LTB4 on polymorphonuclear leukocytes are specific but exhibit considerable heterogeneity of binding affinity and may mediate different functional effects. The complexity of the pathways of generation and metabolism of leukotrienes, and of the leukotriene receptors, suggest that carefully defined systems will be needed to test the effects of pharmacological inhibitors and antagonists.

Arachidonic Acid↗
PubMed1985

Accumulation of leukotriene C4 and histamine in human allergic skin reactions.

To determine whether lipoxygenase products of arachidonic acid metabolism are released in vivo during human allergic cutaneous reactions, we serially assayed chamber fluid placed over denuded skin sites for the presence of both C-6 peptide leukotrienes (e.g., LTC4, LTD4, and LTE4) and leukotriene B4 (LTB4), using radioimmune assay and HPLC separation, and compared it to histamine (assayed radioenzymatically) in 13 atopic and two nonatopic volunteers. Skin chamber sites challenged with ragweed or grass pollen antigen (250-750 protein nitrogen units/ml) for the first hour and phosphate-buffered saline (PBS) for the next 3 h were assayed hourly and compared to sites challenged with PBS alone. As assessed by HPLC, LTC4 composed greater than 85% of the C-6 peptide leukotriene released at any skin site, whereas little LTD4 or LTE4 was detected. LTC4 was present in significantly greater concentrations at antigen sites as compared to PBS-challenged sites throughout the 4-h period. Minimal concentrations of LTB4 were found throughout this time period and were not different at antigen or PBS sites. Histamine was present in significantly greater concentrations at antigen rather than PBS sites, but the pattern of release was different from that of LTC4. Peak histamine release invariably occurred during the first hour and decreased progressively thereafter, whereas the greatest amounts of LTC4 were detected during the 2nd to 4th hours. The amount of LTC4 accumulating at the site was dependent upon the dosage of antigen used in the epicutaneous challenge. We have demonstrated in this study that of the leukotrienes assessed LTC4 is released in the greatest quantity in situ during in vivo allergic cutaneous reactions and that it is present at such sites for at least 4 h after antigen challenge. Since intradermal injection of LTC4 in humans induces wheal and flare responses that persist for hours, our findings support the hypothesis that LTC4 is an important mediator of human allergic skin reactions.

Chromatography, High Pressure Liquid↗
PubMed1985

Modulation of lymphocyte function by sensory neuropeptides.

Neuropeptides present in the peripheral nervous system (PNS) and central nervous system (CNS) modify diverse functions of human, murine and guinea pig mononuclear leukocytes in vitro and in vivo by receptor-mediated mechanisms. Both stimulatory and inhibitory effects on lymphocytes and macrophages have been demonstrated for different neuropeptides in vitro at concentrations which are similar to those in the circulation and in tissues. The dissociation constant (KD) for the binding of a neuropeptide to its lymphocyte receptor is within the range of concentrations that evoke lymphocyte responses critical to immunity and hypersensitivity. The receptor-mediated interactions of diverse neuropeptides with immunocompetent cells provide one mechanism through which the PNS may influence localized immune responses and the CNS may alter systemic immunity.

Animals↗