leukotriene-e4 and Respiratory-Distress-Syndrome

Acute respiratory distress syndrome (ARDS) is an acute lung injury of high mortality rate, and sepsis syndrome is one of the most frequent causes of ARDS. Metabolites of arachidonic acid, including thromboxanes and leukotrienes, are proinflammatory mediators and potentially involved in the development of ARDS. A key enzyme for the production of these inflammatory mediators is cytosolic phospholipase A(2) (cPLA(2)). Recently, it has been reported that arachidonyl trifluoromethyl ketone (ATK) is a potent inhibitor of cPLA(2). In the present study, we hypothesized that pharmacological intervention of cPLA(2) could affect acute lung injury. To test this hypothesis, we examined the effects of ATK in a murine model of acute lung injury induced by septic syndrome. The treatment with ATK significantly attenuated lung injury, polymorphonuclear neutrophil sequestration, and deterioration of gas exchange caused by lipopolysaccharide and zymosan administration. The current observations suggest that pharmacological intervention of cPLA(2) could be a novel therapeutic approach to acute lung injury caused by sepsis syndrome.

Topics: Animals; Arachidonic Acids; Bronchoalveolar Lavage Fluid; Cytosol; Enzyme Inhibitors; Leukotriene C4; Leukotriene D4; Leukotriene E4; Lipopolysaccharides; Lung; Male; Mice; Mice, Inbred C57BL; Peroxidase; Phospholipases A; Phospholipases A2; Respiratory Distress Syndrome; Sepsis; Sodium Chloride; Thromboxane B2; Zymosan

Bleomycin and asparaginase are widely used antineoplastic agents which may induce allergic or inflammatory side-effects. Mast cells are implicated as effector cells in allergic and inflammatory responses. The aim of this study was to establish whether bleomycin or asparaginase modulate leukotriene production in vitro and in vivo. Leukotriene C4 (LTC4) production by murine bone marrow-derived mast cells (BMMC) was determined by radioimmunoassay (RIA). Leukotriene production in patients was assessed by determining leukotriene E4 and N-acetyl-leukotriene E4 in urine by means of combined HPLC and RIA. Bleomycin induced an up to 2.1-fold increase in LTC4 production both in unstimulated and in calcium ionophore-stimulated mast cells. In 3 of 7 patients treated with bleomycin, a greater than 2-fold increase in endogenous leukotriene production was observed. This effect was associated with febrile responses and was most pronounced in a patient who developed an Adult Respiratory Distress Syndrome (ARDS). Asparaginase increased leukotriene production up to 10-fold in stimulated but not in unstimulated BMMC. In a patient who developed an anaphylactic reaction after treatment with asparaginase, a pronounced increase in urinary leukotriene concentration was observed. In contrast to bleomycin or asparaginase, a number of other cytostatic agents did not significantly change leukotriene production by BMMC. Our data indicate that some of the inflammatory and allergic side-effects of bleomycin and asparaginase could be mediated by leukotrienes, a possible source of which may be mast cells.

Topics: Adult; Anaphylaxis; Animals; Antineoplastic Agents; Asparaginase; Bleomycin; Calcimycin; Drug Hypersensitivity; Humans; In Vitro Techniques; Inflammation; Ionophores; Leukotriene C4; Leukotriene E4; Leukotrienes; Lymphoma, Non-Hodgkin; Mast Cells; Mice; Mice, Inbred BALB C; Respiratory Distress Syndrome

The conventional method for measuring urinary leukotriene E4 (LTE4) is by reversed-phase high-performance liquid chromatography (RP-HPLC), followed by radioimmunoassay (RIA) or enzyme immunoassay (EIA). We measured urinary LTE4 levels by two methods, HPLC with EIA and EIA alone after initial crude extraction of urine using an octadecyl reversed-phase extraction cartridge (Sep-Pak). Ninety-three urine samples from normal subjects and patients with bronchial asthma and adult respiratory distress syndrome were tested. The results showed that urinary LTE4 levels measured by EIA significantly correlated with those measured by HPLC plus EIA in the three groups (r = 0.88, 0.85, 0.68). The absolute values of urinary LTE4 measured by EIA without HPLC purification were higher than by EIA with HPLC purification. This suggests that HPLC may not be necessary for routine urinary LTE4 quantitation in different clinical situations.

Topics: Adult; Asthma; Chromatography, High Pressure Liquid; Humans; Immunoenzyme Techniques; Leukotriene E4; Respiratory Distress Syndrome

In an experimental model of adult respiratory distress syndrome (ARDS) we have investigated the release of several vasoactive mediators since the rapid and severe increase in pulmonary arterial pressure is known to be a key feature in this condition. Intravenous injection of oleic acid (OA) into rats resulted in the development of a syndrome similar to ARDS characterized by severe hypoxia. As early as 15 min after OA injection elevated levels of 11-deoxy-15-keto-13,14-dihydro-11,16-cyclo-prostaglandin (PG) E2 (DKH2-cyclo-PGE2) as an indicator of endogenous PGE2 formation could be observed. Similarly, elevated levels of cysteinyl-leukotrienes (LT), determined as immunoreactive (ir) LTE4, and ir-endothelin (ET) could be detected. These mediators were found to be elevated in plasma samples for at least 3 h. In addition, rather large amounts of ir-ET could be detected in bronchoalveolar lavage (BAL) fluid samples between 1 h and 3 h. Thus, it seems possible that cysteinyl-LT and peptides of the ET family, both known for their vasoactivity, might be involved in the pathophysiological process of ARDS.

Topics: Animals; Eicosanoids; Endothelins; Leukotriene E4; Male; Radioimmunoassay; Rats; Rats, Inbred Strains; Respiratory Distress Syndrome; SRS-A

The time course of leukotriene generation in the adult respiratory distress syndrome (ARDS) was investigated by measurement of urinary leukotriene E4 (LTE4) excretion, the major urinary LT metabolite in humans. Sequential measurements were made in nine subjects entered into the study within 48 h of the onset of ARDS, defined by an arterial/alveolar PO2 ratio of less than 0.3 and radiographic evidence of diffuse bilateral pulmonary edema. Initial urinary LTE4 excretion was significantly elevated (1.250 +/- 0.050 ng/mg creatinine sulphate; n = 7) compared with a non-ARDS postoperative group (0.254 +/- 0.114 ng/mg; n = 5) and normal control subjects (0.035 +/- 0.010 ng/mg; n = 12). LTE4 excretion in the first 24 h was estimated to be 6.9 micrograms, representing a release of 0.1 micrograms/kg/h of peptido leukotrienes into the bloodstream. These values were physiologically important based on a comparison with the increased urinary LTE4 excretion observed after antigen-induced bronchoconstriction in allergic asthmatics (baseline LTE4, 0.06 +/- 0.04 ng/mg; postantigen, 0.56 +/- 0.14 ng/mg; 0.17 micrograms LTE4/24 h; n = 8). In subjects with ARDS, this pathologic LTE4 excretion persisted during a subsequent 5-day study period. Leukotriene E4 excretion was associated with persistent abnormalities in gas exchange, pulmonary edema, and lung compliance, suggesting an important role for peptido leukotrienes in the pathophysiology of ARDS.

Topics: Adult; Aged; Asthma; Female; Humans; Leukotriene E4; Leukotrienes; Lung Compliance; Male; Middle Aged; Pulmonary Gas Exchange; Respiratory Distress Syndrome; SRS-A; Time Factors

Increased synthesis of peptidoleukotrienes may occur in a variety of inflammatory diseases. To test this theory, hospitalized patients with a variety of diseases were studied and urine LTE4 quantitated as an index of total body peptidoleukotriene synthesis. 10 patients with ARDS, 7 of which had additional organ involvement, and 5 patients suffering from severe burn injuries were studied. Patients with uncomplicated ARDS excreted approximately 6-fold higher amounts of LTE4 in urine compared to healthy subjects. When ARDS was complicated by multiple organ failure (MOF), urine LTE4 levels were 2- to 150-fold higher than in healthy volunteers. Patients with severe burn injuries had peak urine LTE4 levels which were approximately 20-fold higher than in healthy volunteers. As additional controls, patients with cardiac arrhythmias (absence of inflammatory disease) and patients with uncomplicated pneumonia (localized inflammation) showed normal or mildly elevated urinary LTE4 levels. The urinary LTE4 levels in ARDS patients did not correlate with serum creatinine, bilirubin, or LDH levels, or with the WBC, nor did renal or liver failure by itself predict extremely elevated urinary LTE4 levels. In conclusion, patients with ARDS or ARDS/MOF and patients with severe injuries and sepsis syndrome excrete higher levels of urinary LTE4 than patients healthy volunteers or patients with limited inflammatory disease. In certain situations, urinary LTE4 levels may be useful as a marker of the degree of inflammation.

Topics: Burns; Chromatography, High Pressure Liquid; Humans; Inflammation; Intensive Care Units; Leukotriene E4; Multiple Organ Failure; Respiratory Distress Syndrome; SRS-A; Tritium

1. The aim of the present study was to evaluate the systemic synthesis of cysteinyl leukotrienes in patients with multiple trauma. In order to do this, the urinary excretion of leukotriene E4 was assessed in the first 10 days after trauma. 2. Leukotriene E4 was unequivocally identified by g.c.-m.s. in the urine of healthy subjects and patients with multiple trauma after its conversion to 5-hydroxyeicosanoic acid. Leukotriene E4 was routinely isolated from 24 h urine samples by solid-phase extraction followed by reverse-phase h.p.l.c. and was subsequently quantified by r.i.a. 3. Healthy subjects excreted daily 10 +/- 3 nmol of leukotriene E4/mol of creatinine (mean +/- SEM, n = 16) into urine. 4. Patients with multiple trauma who did not develop adult respiratory distress syndrome (n = 7) excreted 76.8 +/- 6.7 nmol of leukotriene E4/mol of creatinine (mean +/- SEM) daily during the first 10 days after trauma, which was significantly (P less than 0.01) more than did healthy subjects. 5. Excretion of leukotriene E4 was even more enhanced in three patients with multiple trauma who developed adult respiratory distress syndrome. Maximal amounts of 593 +/- 185 nmol of leukotriene E4/mol of creatinine (mean +/- SEM) were excreted on day 9 after trauma by these three patients, which corresponds to a 7.7- and a 59-fold increase in excretion of leukotriene E4 compared with patients with multiple trauma who did not develop adult respiratory distress syndrome and healthy subjects, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adolescent; Adult; Gas Chromatography-Mass Spectrometry; Humans; Hydroxyeicosatetraenoic Acids; Leukotriene E4; Male; Multiple Trauma; Respiratory Distress Syndrome; SRS-A; Time Factors

Topics: Animals; Capillary Permeability; Complement C5; Complement C5a; Guinea Pigs; Histamine Release; In Vitro Techniques; Leukotriene E4; Mast Cells; Muscle Contraction; Muscle, Smooth; Platelet Activating Factor; Rats; Rats, Inbred Strains; Respiratory Distress Syndrome; SRS-A

Topics: Calcimycin; Chromatography, High Pressure Liquid; Granulocytes; Humans; Leukotriene B4; Leukotriene E4; Pulmonary Alveoli; Radioimmunoassay; Respiratory Distress Syndrome; SRS-A; Therapeutic Irrigation