leukotriene-b4 and Neutropenia

Topics: Animals; Calcium; Guinea Pigs; Humans; In Vitro Techniques; Leukotriene B4; Neutropenia; Neutrophils; Phenylpropionates

Cuprophane membranes elict intense blood-surface interactions during clinical hemodialysis. The goal of the present studies was to determine whether calcium channel blockade may alter hemodialysis-related leukotriene B4 (LTB4) generation and neutropenia in 12 patients with end-stage renal failure. The patients were randomized to receive either placebo or nitrendipine for six weeks. Compared with untreated patients, the calcium channel blocker treatment group had significantly lower predialysis plasma LTB4 levels, Nitrendipine reduced both the magnitude of LTB4 generation and of neutropenia during the early phase of hemodialysis, but did not alter the close temporal relation of LTB4 accumulation and neutrophil activation. Therefore, the generation and release of LTB4 by neutrophils may be a calcium-dependent event. Furthermore, these results suggest that activation of neutrophil 5-lipoxygenase may contribute to the alterations in neutrophils of hemodialysis patients.

Topics: Aged; Aprotinin; Cellulose; Female; Humans; Kidney Failure, Chronic; Leukotriene B4; Male; Membranes, Artificial; Middle Aged; Neutropenia; Nitrendipine; Radioimmunoassay; Renal Dialysis

Antibodies to the pan-leukocyte adhesion-GPCR CD97 efficiently block neutrophil recruitment in mice, thereby reducing antibacterial host defense, inflammatory disease, and hematopoietic stem cell mobilization. Here, we investigated the working mechanism of the CD97 antibody 1B2. Applying sterile models of inflammation, intravital microscopy, and mice deficient for the CD97L CD55, the complement component C3, or the FcR common γ-chain, we show that 1B2 acts in vivo independent of ligand-binding interference by depleting PMN granulocytes in bone marrow and blood. Granulocyte depletion with 1B2 involved FcR but not complement activation and was associated with increased serum levels of TNF and other proinflammatory cytokines. Notably, depletion of granulocytes by CD97 antibody required acute inflammation, suggesting a mechanism of conditional, antibody-mediated granulocytopenia.

Topics: Animals; Antibodies, Blocking; Antibody Specificity; CD55 Antigens; Cell Adhesion; Cell Movement; Cytokines; Granulocytes; Humans; Inflammation; Leukotriene B4; Lipopolysaccharides; Membrane Glycoproteins; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Neutropenia; Peritonitis; Receptors, Fc; Receptors, G-Protein-Coupled; Tumor Necrosis Factor-alpha

Neutropenic patients often develop bacterial or fungal infections not responding to broad-spectrum antibacterial or antifungal agents. Clinical efforts were made with transfusion of granulocyte concentrates; however, functions of granulocytes after multiple G-CSF stimulations and after apheresis are not yet investigated and described sufficiently.. The aim of this study was to characterize functional and immunologic variables of granulocytes in blood samples drawn from donors before and after each stimulation episode with G-CSF, in the resulting granulocyte concentrates and in the patients 8 hours after transfusion.. Chemotaxis was not influenced, neither by G-CSF application nor by apheresis. Multiple G-CSF stimulations enhanced oxidative burst and phagocytosis of Escherichia coli in donor granulocytes. These values returned to basal levels in granulocyte concentrates. Expression of granulocytic surface antigens was downregulated after application of G-CSF but returned to normal and in part enhanced values in concentrates. A clinically relevant increase of proinflammatory cytokines could not be detected. Leukotriene B4 production was reduced after the fourth G-CSF stimulation in the donor blood and enhanced in the granulocyte concentrate after apheresis. Results in recipients indicate that changes of granulocyte function noted in concentrates were only transient.. Stimulation of healthy donors with repeated G-CSF injections and subsequent granulocyte apheresis does not dramatically change decisive functions of granulocytes.

Topics: Adult; Antigens, Surface; Chemotaxis, Leukocyte; Escherichia coli; Female; Granulocyte Colony-Stimulating Factor; Granulocytes; Hematologic Neoplasms; Hematopoietic Stem Cell Mobilization; Humans; Interleukin-1; Interleukin-6; Leukapheresis; Leukotriene B4; Male; Neutropenia; Phagocytosis; Respiratory Burst; Tissue Donors; Tumor Necrosis Factor-alpha

The roles of neutrophil aggregation, inducible nitric oxide synthase activation and chemoattractant, leukotriene B4, in potentiation of the cigarette smoke effect on ethanol-induced gastric mucosal damage were studied. Smoke exposure markedly increased gastric lesion formation following ethanol administration and this was accompanied by substantial increase in gastric mucosal leukotriene B4 concentration, myeloperoxidase and inducible nitric oxide synthase activities. Antineutrophil serum or aminoguanidine pretreatment significantly attenuated both gastric mucosal lesion formation and inducible nitric oxide synthase activity. The increased myeloperoxidase activity was abolished by antineutrophil serum but not by aminoguanidine. These data indicated that both neutrophil mobilization and inducible nitric oxide synthase activation in the gastric mucosa play an important role in the potentiating action of cigarette smoke on ethanol-induced gastric mucosal lesion formation. Increased synthesis of nitric oxide from inducible nitric oxide synthase during gastric damage may be secondary to neutrophil infiltration in the gastric mucosa. Chemoattractant leukotriene B4 could also contribute to neutrophil recruitment in the tissue.

Topics: Animals; Antibodies; Cell Aggregation; Central Nervous System Depressants; Enzyme Inhibitors; Ethanol; Gastric Mucosa; Leukotriene B4; Male; Neutropenia; Neutrophils; Nitric Oxide; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Peroxidase; Rats; Rats, Sprague-Dawley; Smoking; Stomach Ulcer

Topics: Animals; Arachidonic Acid; Ear, External; Edema; Leukotriene B4; Metalloendopeptidases; Mice; Mice, Inbred BALB C; Neutropenia; Protease Inhibitors; Rats; Receptors, Leukotriene B4; Succinates

An animal model of leukotriene B4- (LTB4) induced neutropenia has been developed to evaluate LTB4 receptor antagonists in vivo. LTB4, a potent chemotactic inflammatory mediator, when administered intravenously, induces a profound, rapid, and transient redistribution of blood neutrophils from the circulating pool to the marginated pool. This phenomenon is applied in the neutropenia model whereby circulating blood neutrophil counts prior to and after intravenous infusion of LTB4 are compared. Kinetics of LTB4-induced neutrophil responses are determined through the use of a Technicon H*1 automated blood cell analyzer. LTB4 receptor antagonists are identified by inhibition of LTB4-induced neutropenia. Standard antiinflammatory compounds including BW-755C, Abbott A-64077 (zileuton), dexamethasone-21-acetate, indomethacin, and naproxen did not affect LTB4-induced neutropenia. A potent LTB4 receptor antagonist, designated "RPR," inhibited LTB4-induced neutropenia following oral administration in a dose-dependent fashion.

Topics: 4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-3-amine; Animals; Anti-Inflammatory Agents, Non-Steroidal; Biological Availability; Dexamethasone; Hydroxyurea; Indomethacin; Leukocyte Count; Leukotriene B4; Male; Models, Biological; Naproxen; Neutropenia; Neutrophils; Rats; Rats, Sprague-Dawley; Receptors, Leukotriene B4

Bolus injections of leukotriene B4 (LTB4) at 30-min intervals repeatedly induced similar profound and reversible neutropenias. In contrast, after a 30-min infusion of LTB4, the neutropenia induced by bolus injections of LTB4 was inhibited in a dose-dependent manner; a threshold inhibition was seen at the infusion rate of 10 ng LTB4/min/kg, whereas almost complete inhibition was observed at 50 ng LTB4/min/kg. Steady state arterial plasma concentrations of LTB4 increased proportionally to LTB4 infusion rate, ranging from 0.15 +/- 0.01 nM (control) to 2.80 +/- 0.16 nM (100 ng/min/kg). Extending the infusion period of LTB4 up to 330 min did not result in an enhanced inhibition of the neutropenia in response to bolus injections of LTB4. Reversibility of the desensitization was shown by an almost complete recovery of the neutropenic response within 30 min after cessation of the infusion. The desensitization achieved towards LTB4 showed some specificity, inasmuch as a profound and reversible neutropenia was observed in response to a bolus of either FMLP or C5a under conditions in which sensitivity to LTB4 was lost. These findings suggest that a specific desensitization to LTB4 is feasible in vivo and may constitute a useful approach, in addition to the use of 5-lipoxygenase inhibitors and LTB4 antagonists, to delineate the significance of LTB4 as a mediator of inflammation.

Topics: Animals; Desensitization, Immunologic; Drug Administration Schedule; Infusions, Intravenous; Leukotriene B4; Male; N-Formylmethionine Leucyl-Phenylalanine; Neutropenia; Rabbits

ONO-4057(5-[2-(2-Carboxyethyl)-3-[6-(4-methoxyphenyl)-5E- hexenyl]oxyphenoxy]valeric acid), an orally active leukotriene B4(LTB4) antagonist, displaced the binding of [3H] LTB4 to the LTB4 receptor in human neutrophil (Ki = 3.7 +/- 0.9 nM). ONO-4057 inhibited the LTB4-induced rise in cytosolic free calcium (the concentration causing 50% inhibition (IC50) = 0.7 +/- 0.3 microM) and inhibited human neutrophil aggregation, chemotaxis or degranulation induced by LTB4 (IC50 = 3.0 +/- 0.1, 0.9 +/- 0.1 and 1.6 +/- 0.1 microM) without showing any agonist activity at concentration up to 30 microM. ONO-4057 did not inhibit fMLP or C5a-induced neutrophil activation at concentrations up to 30 microM. In the in vivo study, ONO-4057 given orally, prevented LTB4-induced transient neutropenia or intradermal neutrophil migration in guinea pig (the dose causing 50% efficacy (ED50) = 25.6mg/kg or 5.3mg/kg). Furthermore, ONO-4057 given topically, suppressed phorbol-12-myristate-13-acetate (PMA)-induced neutrophil infiltration in guinea pig ear (the effective dose = 1 mg/ear). These results indicate that ONO-4057 is a selective and orally active LTB4 antagonist and may be a potential candidate for the treatment of various inflammatory diseases.

Topics: Animals; Calcium; Cell Aggregation; Chemotaxis, Leukocyte; Complement C5a; Cytoplasmic Granules; Guinea Pigs; Humans; Inflammation; Leukotriene B4; Male; N-Formylmethionine Leucyl-Phenylalanine; Neutropenia; Neutrophils; Phenylpropionates; Receptors, Immunologic; Receptors, Leukotriene B4; Tetradecanoylphorbol Acetate

Neutrophils from patients suffering from severe congenital neutropenia (SCN), who were receiving recombinant human granulocyte colony-stimulating factor (rhG-CSF), were investigated in order to analyze the previously described decrease in chemotaxis. This study demonstrated the decreased chemotaxis to five well-known chemoattractants, FMLP, C5a, IL-8, LTB4 and PAF. To further investigate this impairment of patients' neutrophils, receptors and receptor turnover for chemoattractants were examined using flow cytometry. We found 1) increased FMLP receptor and decreased C5a receptor expression, 2) a normal expression of intracellular FMLP receptors after incubation with PMA, 3) increased loss and decreased re-expression of FMLP receptors after incubation with this peptide, 4) normal expression of adhesion glycoproteins CR3 (CD11b/CD18) and LFA1 (CD11a/CD18), 5) further signs of in vivo preactivation: high expression of Fc gamma-RI (CD64) and Fc gamma-RII (CD32), decreased expression of Fc gamma-RIII (CD16), increased expression of CD14, and low expression of HLA-DR. These data demonstrate that the decrease of chemotaxis of neutrophils from SCN patients is not due: a) to a decrease in the number of intra- or extracellular FMLP receptors; b) to a decrease of adhesion molecules. However, the decreased chemotaxis could result from an altered FMLP receptor turnover. The relevance of the altered Fc gamma-receptor pattern for the in vivo occurrence of side-effects, e.g. the necrotic vasculitis, of G-CSF treatment is discussed.

Topics: Antibodies, Monoclonal; Antigens, Differentiation; Antigens, Surface; Chemotaxis, Leukocyte; Complement C5a; Fluorescein-5-isothiocyanate; Granulocyte Colony-Stimulating Factor; HLA-DR Antigens; Humans; Immunoglobulin G; In Vitro Techniques; Interleukin-8; Leukotriene B4; N-Formylmethionine Leucyl-Phenylalanine; Neutropenia; Neutrophils; Receptors, Fc; Receptors, Formyl Peptide; Receptors, IgG; Receptors, Immunologic; Recombinant Proteins; Reference Values; Tetradecanoylphorbol Acetate

Topics: Animals; Binding, Competitive; Cell Aggregation; Guinea Pigs; Humans; Leukotriene B4; Lung; Muscle Contraction; Muscle, Smooth; Neutropenia; Neutrophils; Peroxidase; Phenylpropionates; Rats; Receptors, Immunologic; Receptors, Leukotriene B4; Skin

The ability of various leukotrienes, platelet-activating factor and N-formyl-methyl-leucyl-phenylalanine to augment colonic damage induced by 30% ethanol was investigated in the rat. Each of the mediators was tested at a dose of 2 nmol, administered intracolonically in the ethanol vehicle. When colonic damage was assessed 72 hr later, only leukotriene B4 significantly augmented damage compared to the controls. The incidence of ulcers increased from 35% in the control group to 90% in the group receiving leukotriene B4. Leukotriene B4 administration also resulted in significant increases in colonic myeloperoxidase activity and colonic leukotriene B4 synthesis. To assess the possible contribution of infiltrating neutrophils to the increase in colonic leukotriene B4 synthesis that accompanies colonic inflammation, colitis was induced in normal and neutropenic rats by intracolonic administration of trinitrobenzene sulfonic acid. Neutropenia was achieved by treatment with an antineutrophil serum. In the neutropenic animals killed 4 hr after induction of colitis significant changes in leukotriene B4 synthesis were not observed, whereas a fourfold increase was observed in the controls. From these studies we conclude the following: (1) leukotriene B4, at a dose of 2 nmol, can significantly potentiate the colonic ulceration induced by 30% ethanol; (2) this action of leukotriene B4 is not shared by the same dose of the other inflammatory mediators tested; and (3) infiltrating neutrophils are the major source of colonic leukotriene B4 synthesis in a rat model of colitis.

Topics: Administration, Rectal; Animals; Colitis; Drug Synergism; Ethanol; Leukotriene B4; Leukotrienes; Male; N-Formylmethionine Leucyl-Phenylalanine; Neutropenia; Platelet Activating Factor; Rats; Rats, Inbred Strains; Ulcer

The hypothesis that neutrophils play an important role in the pathogenesis of gastric ulceration induced by nonsteroidal anti-inflammatory drugs (NSAIDs) was tested in rats. Rats made neutropenic by prior treatment with an antibody to rat neutrophils raised in goat were found to be significantly more resistant to the gastric-damaging actions of indomethacin or naproxen than were control rats or rats pretreated with normal goat serum. The reduction of damage in neutropenic rats was not due to effects of the antineutrophil serum on either gastric acid secretion or the ability of indomethacin or naproxen to inhibit prostaglandin synthesis. Gastric cyclooxygenase activity was inhibited by greater than 95% in both normal and neutropenic rats that received indomethacin or naproxen. Reduction of circulating neutrophil numbers by treating rats with methotrexate also resulted in a significant reduction in the susceptibility to gastric damage induced by indomethacin. Since activation of circulating neutrophils appeared to be important in the development of gastric erosions after administration of indomethacin, and in the significant changes in vascular endothelial integrity (Monastral Blue staining) observed within 15 min of indomethacin administration, we investigated the possibility that leukotrienes (LTs) and platelet-activating factor (PAF) might be involved in the pathogenesis of indomethacin-induced ulceration. Changes in gastric LTB4 synthesis were not observed after indomethacin administration. Pretreatment with either an LTD4 antagonist or a PAF antagonist was without significant effect on the extent of gastric damage induced by indomethacin. These results suggest an important role for neutrophils in the pathogenesis of NSAID-induced gastric ulceration. Neutrophils may be important in the vascular injury that occurs early after administration of these compounds.

Topics: Animals; Immune Sera; Indomethacin; Leukotriene B4; Male; Methotrexate; Muscle, Smooth; Neutropenia; Neutrophils; Rats; Rats, Inbred Strains; Reference Values; Stomach; Stomach Ulcer

Biosynthesis of leukotriene B4 (LTB4) was studied in ten patients with end-stage renal failure undergoing chronic hemodialysis with a cuprophane membrane. As compared to healthy subjects the low basal plasma levels of LTB4 quantified by radioimmunoassay after extraction and purification by HPLC showed no significant difference. The time-course of LTB4 release after contact of the blood with the dialysis membrane without further in vitro stimulation was characterized by a rapid increase by about 500% within the first 10 min, appearing approximately at the same time as the known fall of white blood cell count which reaches its nadir after 20 min. Analysis of further release showed a decline of LTB4 biosynthesis to basal levels at the end of hemodialysis. These results indicate that activation of the 5-lipoxygenase pathway is involved in hemodialysis-associated leukopenia and may contribute to the alterations in neutrophils of patients with chronic dialysis therapy.

Topics: Arachidonate 5-Lipoxygenase; Enzyme Activation; Female; Humans; Kidney Failure, Chronic; Kinetics; Leukotriene B4; Male; Middle Aged; Neutropenia; Renal Dialysis

This study investigated the possible contribution of neutrophils to development of reexpansion pulmonary edema (RPE) in rabbits. Rabbits' right lungs were collapsed for 7 days and then reexpanded with negative intrathoracic pressure for 2 h before study, a model that creates unilateral edema in the reexpanded lungs but not in contralateral left lungs. Two hours after lung reexpansion, significant increases in lavage albumin concentration (17-fold), percent neutrophils (14-fold), and total number of neutrophils (7-fold) recovered occurred in the reexpanded lung but not in the left. After 2 h of reexpansion increased leukotriene B4 was detected in lavage supernatant from right lungs (335 +/- 33 pg/ml) compared with the left (110 +/- 12 pg/mg, P less than 0.01), and right lung lavage acid phosphatase activity similarly increased (6.67 +/- 0.35 U/l) compared with left (4.73 +/- 0.60 U/l, P less than 0.05). Neutropenia induced by nitrogen mustard (17 +/- 14 greater than neutrophils/microliters) did not prevent RPE, because reexpanded lungs from six neutropenic rabbits were edematous (wet-to-dry lung weight ratio 6.34 +/- 0.43) compared with their contralateral lungs (4.97 +/- 0.04, P less than 0.01). An elevated albumin concentration in reexpanded lung lavage from neutropenic rabbits (8-fold) confirmed an increase in permeability. Neutrophil depletion before reexpansion did not prevent unilateral edema, although neutrophils were absent from lung sections and alveolar lavage fluid from neutropenic rabbits.

Topics: Acid Phosphatase; Animals; Leukotriene B4; Male; Neutropenia; Neutrophils; Permeability; Pulmonary Alveoli; Pulmonary Edema; Rabbits

Leukotriene C4 and its immediate metabolites leukotriene D4 and E4 are potent inducers of macromolecular leakage from postcapillary venules by a direct, immediate type of action. Leukotriene B4 specifically promotes leukocyte adhesion to the vascular endothelium, with subsequent diapedesis and further migration in the extravascular space. In addition, leukotriene B4 elicits a delayed type of plasma exudation that apparently is secondary to recruitment of polymorphonuclear leukocytes from the circulation. Considered together, the microvascular effects of the leukotrienes documented here strongly support the possibility that these substances are significant mediators of tissue edema and granulocyte accumulation, characteristics of the acute inflammatory reaction.

Topics: Animals; Cell Adhesion; Cheek; Cricetinae; Leukocytes; Leukotriene B4; Microcirculation; Neutropenia; SRS-A

Arachidonic acid is metabolized to prostaglandins and thromboxane via the cyclooxygenase pathway and to leukotrienes B4, C4, D4, and E4 via the lipooxygenase pathway. A possible role played by leukotrienes in cardiogenic shock resulting from anaphylaxis prompted us to investigate the action of these compounds on coronary vessels and myocardial contractility. In this study leukotriene B4 (LTB4) and C4 (LTC4) were injected directly into the left circumflex (LCx) coronary artery of nine anesthetized Suffolk sheep. LTB4 had no effect on coronary artery blood flow or myocardial contractility, but 3 X 10(-9) mole induced profound transient circulating neutropenia, reflecting the potent chemotactic and chemokinetic properties of this compound. Injecting as little as 1.6 X 10(-11) mole of LTC4 caused a 14.5 +/- 4.3% (mean +/- SE) reduction of LCx coronary artery flow while 1.6 X 10(-10) mole caused a 26.5 +/- 3.7% decrease of LCx coronary artery flow and an 18.1 +/- 3.2% decrease in systolic shortening of the myocardial region supplied by the LCx coronary artery. Since the decrease in systolic shortening was far greater than that expected on the basis of the reduction in coronary artery flow, we postulate that LTC4 has a direct negative inotropic effect. FPL 55712, a receptor antagonist of leukotrienes C4, D4, and E4, blocked the vasoconstriction induced by LTC4 but only partially blocked the negative inotropic effects of LTC4. LTC4 is a potent vasoconstrictor and negative inotropic agent and may play an important role in anaphylactic shock.

Topics: Animals; Cardiac Catheterization; Chromones; Coronary Circulation; Dose-Response Relationship, Drug; Female; In Vitro Techniques; Leukotriene B4; Male; Myocardial Contraction; Neutropenia; Sheep; SRS-A

Leukotriene B4 (LTB4), a metabolite of arachidonic acid, is known to be a potent chemotactic and chemokinetic substance. We have used the hamster cheek pouch microcirculation model to study the effect of LTB4 on vascular permeability and the involvement of neutrophil granulocytes in this response. Intravascular fluorescein-labeled dextran (mol wt 150,000) was used as a tracer of macromolecular permeability. Topical application of LTB4 (150 nM-5 microM) to the hamster cheek pouch resulted in an immediate increase in adhering leukocytes in postcapillary venules and later venules. Leukocyte accumulation was reversible, but continued longer the higher the dose of LTB4 used. Subsequently, a dose-dependent increase in vascular permeability was seen at post-capillary and larger venules, with a maximum 10-20 min after application; the maximum occurred later the higher the dose of LTB4. Depletion of neutrophil granulocytes by pretreatment of the animals with antineutrophil serum obtained from immunized rabbits significantly decreased the permeability response to LTB4, whereas the response to histamine was unaffected. These results suggest that neutrophil granulocytes play a role in LTB4-mediated permeability increase. LTB4 may be of importance both for the leukocyte accumulation and for the edema formation seen in inflammatory reactions.

Topics: Animals; Antilymphocyte Serum; Arachidonic Acids; Capillary Permeability; Chemotaxis, Leukocyte; Cricetinae; Dextrans; Dose-Response Relationship, Drug; Fluorescein-5-isothiocyanate; Fluoresceins; Leukocyte Count; Leukotriene B4; Male; Neutropenia; Neutrophils; Rabbits; Time Factors

5(S), 12(S)-Dihydroxy-cis-14,trans-6,8,10-eicosatetraenoate (compound I), 5(S),12(R)-dihydroxy-cis-14,trans-6,8,10-eicosatetraenoate (compound II), and 5(S),12(R)-dihydroxy-cis-6,14,trans-8,10-eicosatetraenoate (compound III) were prepared from rabbit peritoneal neutrophils challenged with arachidonic acid plus ionophore A23187. Each arachidonate metabolite caused rabbit neutrophils to aggregate and, in cells treated with cytochalasin B, release granule-bound enzymes. Compound III was 10- to 100-fold more potent than compounds II and I. When intravenously infused into rabbits at doses of 100--1,000 ng/kg, compound III induced abrupt, profound, transient neutropenia associated with a rapidly reversing accumulation of neutrophils in the pulmonary circulation. This in vivo action correlated closely with the ability of the fatty acid to activate neutrophils in vitro: neutropenia, aggregation, and degranulation occurred at similar doses of stimulus and the rapid, reversing kinetics of the neutropenic response paralleled the equally rapid, reversing formation of aggregates. The fatty acid did not alter the circulating levels of lymphocytes or platelets and did not aggregate platelets in vitro. At comparable doses (i.e., 100--1,000 ng/kg), compounds I and II did not cause neutropenia. Thus, compound III possesses a high degree of structural and target-cell specificity in stimulating neutrophils in vitro and in vivo. Clinical and experimental syndromes associating neutropenia with increased levels of circulating arachidonate metabolites may involve compound III as a mediator of neutrophil sequestration in lung.

Topics: Agranulocytosis; Animals; Arachidonic Acids; Dose-Response Relationship, Drug; Infusions, Parenteral; Leukotriene B4; Lung; Neutropenia; Neutrophils; Rabbits