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Published online before print April 23, 2004

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(Journal of Leukocyte Biology. 2004;76:210-216.)
© 2004 by Society for Leukocyte Biology

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

André L. F. Sampaio^*, Giles A. Rae and Maria das Graças M. O. Henriques^*,1

^* Department of Applied Pharmacology, FarManguinhos, Fundação Oswaldo Cruz (FIOCRUZ), Rio de Janeiro, Brazil; and
Department of Pharmacology, CCB, Universidade Federal de Santa Catarina, Florianópolis, Brazil

¹Correspondence: Departamento de Farmacologia Aplicada, Instituto de Tecnologia em Fármacos, Farmanguinhos–Fundação Oswaldo Cruz, Rua Sizenando Nabuco, 100, Rio de Janeiro cep 21041-250, Brasil. E-mail: gracahen{at}far.fiocruz.br

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 ET_A 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 ET_A 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 ET_A receptor blockade did not inhibit the accumulation of T lymphocytes, cells that are important for granulocyte recruitment in this model. Blockade of ET_A receptors did not influence the expression of adhesion molecules (CD11b, CD49d) on granulocytes but abrogated the increase in tumor necrosis factor 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 ET_A receptors, endogenous endothelins play an important role in early cytokine/chemokine production and on granulocyte and lymphocyte mobilization in LPS-induced pleurisy.

Key Words: eosinophil • neutrophil • lung inflammation • T cell • cytokine • chemokine

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