leukotriene-e4 and Lung-Diseases

The history, biosynthetic pathways and biological activities of the leukotrienes have been reviewed. These extremely potent substances probably play a major role in the manifestations of reversible obstructive airways disease and possibly in other diseases of the lung. Their relative contribution remains to be determined and awaits the development of an antagonist or 5-lipoxygenase inhibitor which can be safely administered to man. Perhaps in man in vivo, as has been shown in vitro with human airways tissues [100], the combination of an antihistamine and a leukotriene antagonist will prevent antigen-induced and possibly other forms of airways smooth muscle constriction.

Topics: Animals; Bronchi; Hemodynamics; Humans; In Vitro Techniques; Leukotriene E4; Lung; Lung Diseases; Mucus; Respiratory Function Tests; SRS-A

Transfusion-related acute lung injury (TRALI) is a serious complication of hemotherapy. During blood storage, lipids are generated and released into the plasma. In this study, the role of these lipids in TRALI was investigated using an isolated, perfused rat lung model. Rats were pretreated with endotoxin (LPS) or saline in vivo and the lungs were isolated, ventilated, and perfused with saline, or (a) 5% (vol/ vol) fresh human plasma, (b) plasma from stored blood from the day of isolation (D.0) or from the day of outdate (D.42), (c) lipid extracts from D.42 plasma, or (d) purified lysophosphatidylcholines. Lungs from saline or LPS-pretreated rats perfused with fresh (D.0) plasma showed no pulmonary damage as compared with saline perfused controls. LPS pretreatment/D.42 plasma perfusion caused acute lung injury (ALI) manifested by dramatic changes in both pulmonary artery pressure and edema. Incubation of LPS pre-tx rats with mibefradil, a Ca2+ channel blocker, or WEB 2170, a platelet-activating factor (PAF) receptor antagonist, inhibited ALI caused by D.42 plasma. Lung histology showed neutrophil sequestration without ALI with LPS pretreatment/saline or D.0 plasma perfusion, but ALI with LPS pretreatment/D.42 plasma perfusion, and inhibition of D.42 plasma induced ALI with WEB 2170 or mibefradil. A significant increase in leukotriene E4 was present in LPS-pretreated/D.42 plasma-perfused lungs that was inhibited by WEB 2170. Lastly, significant pulmonary edema was produced when lipid extracts of D.42 plasma or lysophosphatidylcholines were perfused into LPS-pretreated lungs. Lipids caused ALI without vasoconstriction, except at the highest dose employed. In conclusion, both plasma and lipids from stored blood produced pulmonary damage in a model of acute lung injury. TRALI, like the adult respiratory distress syndrome, may be the result of two insults: one derived from stored blood and the other from the clinical condition of the patient.

Topics: Acute Disease; Adult; Animals; Azepines; Benzimidazoles; Blood Preservation; Blood Pressure; Calcium; Calcium Channel Blockers; Humans; Leukotriene E4; Lipids; Lung Diseases; Lysophosphatidylcholines; Male; Mibefradil; Neutrophil Activation; Neutrophils; Platelet Aggregation Inhibitors; Pulmonary Artery; Pulmonary Edema; Rats; Rats, Sprague-Dawley; Tetrahydronaphthalenes; Transfusion Reaction; Triazoles

The pathophysiology of chronic lung disease (CLD) in premature infants who require mechanical ventilation and prolonged oxygen supplementation has been well-described but the underlying mechanisms are not understood. Our aim was to test the hypothesis that excess cysteinyl leukotriene (LT) production was a contributing factor in CLD. We compared LT production and lung function, at 7 months of age, in nine premature infants with CLD and in eight control infants without CLD. None of the control infants developed any neonatal respiratory problems, but two subsequently required bronchodilator therapy. Respiratory function was assessed by the measurement of thoracic gas volume (TGV), airways resistance (Raw) and functional residual capacity (FRC). Total cysteinyl LT production was quantified by measurement of leukotriene E4 (LTE4) in a spot urine sample. Although all patients were asymptomatic at follow-up, there was evidence of significant lung function abnormalities in infants with CLD. The CLD infants had significantly elevated TGV, Raw and FRC values reflecting airway obstruction when compared to the controls. Urinary LTE4 levels were significantly higher in the CLD infants when compared to the controls (geometric mean: 741 and 337 pmol.mmol-1 creatinine, respectively). There was no direct correlation between urinary LTE4 levels in the CLD group and TGV, Raw or FRC values. Although this study is small and a direct correlation between lung function and urinary leukotriene E4 was not demonstrated, pathological lung function and an enhanced urinary leukotriene E4 production in infants with chronic lung disease would tend to suggest that the cysteinyl leukotrienes were involved in the sequelae of this disease.

Topics: Airway Obstruction; Airway Resistance; Bronchodilator Agents; Chronic Disease; Cohort Studies; Creatinine; Follow-Up Studies; Functional Residual Capacity; Humans; Infant; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Leukotriene E4; Lung; Lung Diseases; Oxygen Inhalation Therapy; Prospective Studies; Respiration, Artificial; Tidal Volume

Lipoxins are biologically active trihydroxytetraene containing products derived from arachidonic acid that are formed by interactions between lipoxygenases. Although the lipoxins have been generated from mixed cell suspensions in vitro, it has not been established whether these products are synthesized in vivo. We have performed bronchoalveolar lavage (BAL) in 12 patients with lung disease (sarcoid, six; pneumonia, two; asthma, two; carcinoma, one; alveolitis of unknown cause, one) and in six normal control subjects. The BAL fluid was analyzed for lipoxin A4 (LXA4) using gas chromatography mass spectrometry with selective ion monitoring, and the levels of the sulfidopeptide leukotrienes were determined using reverse-phase high-performance liquid chromatography and radioimmunoassay. LXA4 was detected in BAL fluid from nine of the 12 patients studied. The levels of LXA4 ranged from 0.4 to 2.8 ng/ml. LXA4 was not detected in any of the six normal subjects. Sulfidopeptide leukotrienes were detected in all the BAL samples, ranging from 0.04 to 0.7 ng/ml, and there was no significant difference between the patients and the normal subjects. In patients with detectable LXA4 in BAL fluid, the ratio of the concentrations of LXA4 to those of the sulfidopeptide leukotrienes ranged from 1.9 to 62 (mean, 19.0). This is the first demonstration of the presence of LXA4 in disease.

Topics: Adult; Bronchoalveolar Lavage Fluid; Chromatography, High Pressure Liquid; Female; Gas Chromatography-Mass Spectrometry; Humans; Hydroxyeicosatetraenoic Acids; Leukotriene B4; Leukotriene E4; Lipoxins; Lung Diseases; Male; Middle Aged; Radioimmunoassay; Sarcoidosis; SRS-A