calcimycin and Respiratory-Distress-Syndrome

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

Production of cGMP is impaired in endotoxin-induced acute lung injury. This results in dysfunction of endothelium-dependent and -independent cGMP-mediated pulmonary vasorelaxation and, therefore, pulmonary hypertension. We hypothesized that cyclic nucleotide phosphodiesterase (PDE) inhibition would attenuate endotoxin-induced impairment to cGMP-mediated mechanisms of pulmonary vasorelaxation. The purpose was to examine the effect of stimulating cGMP production with concurrent inhibition of cGMP catabolism by PDE inhibition following endotoxin-induced acute lung injury. Isolated pulmonary arterial rings from rats (n = 5) were studied 6 hrs after endotoxin (20 mg/kg ip) or saline. In a third group (n = 5), PDE inhibition was accomplished with in vitro 3-isobutyl-1-methylxanthine (IBMX, 1 microM for 30 min). Cyclic GMP-mediated relaxation was interrogated by stimulating (1) endothelium-dependent mechanisms with the receptor-dependent agonist acetylcholine and the receptor-independent agonist A23187, a calcium ionophore, and an (2) endothelium-independent mechanism with sodium nitroprusside. PDE inhibition attenuated endotoxin-induced vasomotor dysfunction. A two-pronged approach-stimulating cGMP production and preventing cGMP catabolism with PDE inhibition-may offer a therapeutically accessible mechanism to overcome vasomotor dysfunction in acute lung injury.

Topics: 1-Methyl-3-isobutylxanthine; Animals; Calcimycin; Cyclic GMP; Endothelium, Vascular; Endotoxins; Male; Muscle, Smooth, Vascular; Nitroprusside; Phosphodiesterase Inhibitors; Pulmonary Artery; Rats; Rats, Sprague-Dawley; Respiratory Distress Syndrome; Vasodilation

The aim of this study was to investigate whether the pulmonary response to inflammatory stimulation, resulting in increased vascular resistance and permeability, could be attenuated by short-term infusion of triglycerides containing omega-3 fatty acids. With the concept of altering the composition of membrane phospholipids in such a manner that stimulation resulted in the release of less vasoconstrictive and permeability-enhancing metabolites of eicosapentaenoic acid instead of those of arachidonic acid (AA), the parenteral application of a lipid emulsion prepared from fish oil (Omegavenös) was tested in comparison with a soy oil preparation (Lipovenös).. Isolated lungs from anesthetized rabbits were ventilated and recirculatingly perfused (200 ml/min) with 200 ml cell-free buffer solution to which either 2 ml saline (controls, n = 6), 2 ml Lipovenös 10% (n = 6) or 2 ml Omegavenös 10% (n = 6) were added. To study the possible metabolic alterations in states of an enhanced AA turnover, lungs of each group were stimulated with smaller doses of A23187 (10(-8) M) during the 180-min lipid perfusion period, followed by a 10 times higher calcium ionophore A23187 (10(-7) M) challenge after washing out the lipids by exchange of perfusion fluid. Pulmonary artery pressure (PAP) and the lung weight gain indicating edema formation were monitored, and eicosanoids were analyzed in samples of the perfusate.. Upon A23187 injection lung weight gain and PAP increase were significantly reduced (50%) in Omegavenös-perfused lungs in comparison with controls and Lipovenös treatment. The vascular reactions were accompanied by a shifting from LTC4 to LTC5 during and after Omegavenös perfusion.. The data demonstrate that omega-3 fatty acids seem to be incorporated into the phospholipid pool of the pulmonary tissue, even after short-term infusion (3 h) resulting in an attenuated pressure reaction and edema formation due to an altered spectrum of metabolites in the case of inflammatory stimulation.

Topics: Acute-Phase Proteins; Animals; Calcimycin; Capillary Permeability; Dose-Response Relationship, Drug; Extravascular Lung Water; Fat Emulsions, Intravenous; Fatty Acids, Omega-3; Female; Male; Perfusion; Pulmonary Circulation; Rabbits; Respiratory Distress Syndrome; Soybean Oil; Triglycerides; Vascular Resistance

Infusion of endotoxin into domestic pigs induces an acute respiratory failure that has many similarities with the adult respiratory distress syndrome. We hypothesized that mono-hydroxyeicosatetraenoic acids (HETE) and platelet-activating factor (PAF) might be involved in this model of respiratory failure. Escherichia coli endotoxin (055-B5) was infused intravenously into anesthetized young pigs at 5 micrograms/kg the first hour, followed by 2 micrograms/kg/hour for 3 hours in the presence and absence of SRI 63-675, a specific PAF receptor antagonist. SRI 63-675 (10 mg/kg before endotoxin + 3 mg/kg/hour during endotoxemia) blocked or attenuated endotoxin-induced pulmonary hypertension, bronchoconstriction, hypoxemia, thrombocytopenia, increased permeability of the alveolar-capillary membrane, and the increases in plasma (at 3 and 4 hours) and bronchoalveolar lavage fluid concentrations of 5-, 12-, and 15-HETE. In a separate group of pigs, before treatment with SRI 63-675, ex vivo stimulation of whole blood with calcium ionophore (at -25 min) caused large increases in plasma concentrations of 5-HETE and, to a lesser extent, 12-HETE. At 4 hours, these increases were not significantly modified in blood derived from pigs treated with SRI 63-675 (10 mg/kg + 3 mg/kg/hour from 0 to 4 hours), indicating no direct inhibition of 5- or 12-lipoxygenase and suggesting that the in vivo effects were PAF receptor-mediated. We conclude that PAF contributes to the release of HETEs during endotoxemia and that this phenomenon could be important in the pathophysiology associated with endotoxin-induced lung injury in anesthetized pigs.

Topics: Animals; Blood Platelets; Calcimycin; Chromatography, High Pressure Liquid; Disease Models, Animal; Endotoxins; Escherichia coli; Hydroxyeicosatetraenoic Acids; In Vitro Techniques; Neutrophils; Platelet Activating Factor; Platelet Aggregation; Quinolines; Respiratory Distress Syndrome; Swine

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