Effects of endothelin ETA receptor antagonism on granulocyte and lymphocyte accumulation in LPS-induced inflammation

• Published in: Journal of leukocyte biology Vol. 76; no. 1; pp. 210 - 216
• Main Authors: Sampaio, André L. F., Rae, Giles A., Henriques, Maria das Graças M. O.
• Format: Journal Article
• Language: English
• Published: United States Society for Leukocyte Biology 01-07-2004
• Subjects: Animals; Antihypertensive Agents - pharmacology; Cell Adhesion Molecules - drug effects; Cell Adhesion Molecules - immunology; chemokine; Chemokines - metabolism; Chemotaxis, Leukocyte - drug effects; Chemotaxis, Leukocyte - immunology; cytokine; Disease Models, Animal; Endothelin A Receptor Antagonists; eosinophil; Granulocytes - drug effects; Granulocytes - immunology; Inflammation - immunology; Lipopolysaccharides - pharmacology; Lung - drug effects; Lung - immunology; Lung - pathology; lung inflammation; Lymphocytes - drug effects; Lymphocytes - immunology; Male; Mice; Mice, Inbred BALB C; neutrophil; Peptides, Cyclic - pharmacology; Pleurisy - immunology; Pyrrolidines - pharmacology; γδ T cell
• ISSN: 0741-5400; 1938-3673
• DOI: 10.1189/jlb.1003504

Endothelin peptides play active roles in different aspects of inflammation. This study investigates the contribution of endogenous endothelins to lipopolysaccharide (LPS) pulmonary inflammation by assessing the influence of ETA receptor antagonism on leukocyte accumulation, granulocyte adhesion molecule expression, and chemokine/cytokine modulation. Local pretreatment with BQ‐123 or A‐127722 (150 pmol), two selective and chemically unrelated endothelin ETA receptor antagonists, inhibits neutrophil and eosinophil accumulation in LPS‐induced pleurisy at 24 h but not neutrophil migration at 4 h. The effect of endothelin antagonism on neutrophil accumulation at 24 h was concomitant with inhibition of eosinophil and CD4 and CD8 T lymphocyte influx. It is surprising that the ETA receptor blockade did not inhibit the accumulation of γδ T lymphocytes, cells that are important for granulocyte recruitment in this model. Blockade of ETA receptors did not influence the expression of adhesion molecules (CD11b, CD49d) on granulocytes but abrogated the increase in tumor necrosis factor α levels 4 h after LPS stimulation and also markedly inhibited increases in levels of interleukin‐6 and keratinocyte‐derived chemokine/CXC chemokine ligand 1 but not eotaxin/chemokine ligand 11. Thus, acting via ETA receptors, endogenous endothelins play an important role in early cytokine/chemokine production and on granulocyte and lymphocyte mobilization in LPS‐induced pleurisy.