Lipid mediators, tumor necrosis factor and nitric oxide and their interactions in immune-complex-induced lung injury

• Published in: European journal of pharmacology Vol. 358; no. 1; pp. 69 - 75
• Main Authors: Tavares de Lima, Wothan, Steil, Ana A, Russo, Momtchilo, Starobinas, Nancy, Teixeira, Catarina F.P, Jancar, Sonia
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier B.V 25-09-1998; Elsevier
• Subjects: Animals; Azepines - pharmacology; Biological and medical sciences; Bronchoalveolar Lavage Fluid - chemistry; Immune complex; Immune Complex Diseases - metabolism; Leukotriene B 4; Leukotriene B4 - metabolism; Lung - immunology; Lung - metabolism; Lung - pathology; Lung inflammation; Male; Medical sciences; Neutrophils - drug effects; Neutrophils - metabolism; Neutrophils - pathology; Nitric Oxide - metabolism; NO (nitric oxide); PAF (platelet activating factor); Platelet Aggregation Inhibitors - pharmacology; Pneumology; Rats; Rats, Wistar; Respiratory system : syndromes and miscellaneous diseases; TNF (tumor necrosis factor); Triazoles - pharmacology; Tumor Necrosis Factor-alpha - metabolism; NO (nitric oxide); Leukotriene B 4; Lung inflammation; TNF (tumor necrosis factor); PAF (platelet activating factor); Immune complex; Lung disease; Pathophysiology; Rat; Respiratory disease; Arachidonic acid derivatives; Cytokine; Rodentia; Inflammation; Hemorrhage; Platelet activating factor; Vertebrata; Mammalia; Leukotriene B4; Tumor necrosis factor; Animal; Nitric oxide; Neutrophil
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/S0014-2999(98)00594-9

We investigated the contribution of eicosanoids, platelet-activating factor, tumor necrosis factor and nitric oxide to the neutrophil influx and development of pulmonary haemorrhagic lesions following immune-complex-induced pneumonitis in rats and possible interactions between these mediators. Increased levels of leukotriene B
4 and tumor necrosis factor, measured by enzyme immunoassay and L-929 cytotoxicity assay, were found in the bronchoalveolar lavage 1 and 4 h after induction of the reaction, respectively, and their release was dependent on the previous generation of platelet activating factor. Antagonism of leukotriene B
4 receptors by RO-0254094 (2-[(5-carboxypentyl])oxy]-6-[6-[3,4-dihydro-4-oxo-8-propyl-2
H-1-benzopyran-7-yl)oxy]hexyl] benzenepropanoic acid), inhibition of nitric oxide synthesis by
l-NAME (
N
W-nitro-
l-arginine methyl ester) and antagonism of PAF-receptors by WEB-2170 (5-(2-chlorphenyl)-3-4-dihydro-10-methyl-3-((4-morpholinyl)carbonyl)-2
H,7
H-cyclopenta (4,5)thieno(3,2-
f)(1,2,4)-triazolo-4,3,
a)91,4)diazepine), significantly inhibited the intensity of haemorrhage, evaluated by the increased levels of extravascular hemoglobin in homogenates of lung tissues. Little evidence support the role of tumor necrosis factor in these lesions. The infiltration of neutrophils, evaluated by measuring myeloperoxidase in homogenates of lungs, was reduced by compounds L-663,536 (3-[1-(4 chlorobenzyl)-3-
t-butyl thio-5-isopropylindol-2-yl]-2-2-dimethylpropanoic acid), WEB-2170 and
l-NAME. These results indicate that neutrophil infiltration and haemorrhagic lesions in immune-complex-induced lung inflammation are mediated by platelet activating factor, leukotriene B
4 and nitric oxide and point out to interesting interactions between these mediators.