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

Endothelin peptides play active roles in different aspects of inflammation. This study inves- tigates the contribution of endogenous endothelins to lipopolysaccharide (LPS) pulmonary inflamma- tion by assessing the influence of ETA receptor antagonism on leukocyte accumulation, granulo- cyte adhesion molecule expression, and chemo- kine/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 ac- cumulation in LPS-induced pleurisy at 24 h but not neutrophil migration at 4 h. The effect of endothe- lin 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 T lymphocytes, cells that are important for granulocyte recruitment in this model. Blockade of ETA receptors did not influ- ence 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 keratino- cyte-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 pro- duction and on granulocyte and lymphocyte mobi- lization in LPS-induced pleurisy. J. Leukoc. Biol. 76: 210-216; 2004.