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 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 gammadelta 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 alpha 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.
Sampaio
André L F
AL
Instituto de Tecnologia em Fármacos, FarManguinhos-Fundação Oswaldo Cruz, Rua Sizenando Nabuco, 100, Rio de Janeiro cep 21041-250, Brasil.
Rae
Giles A
GA
Henriques
Maria das Graças M O
Md
D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D000077868:Atrasentan; D015815:Cell Adhesion Molecules / Q000187:drug effects / Q000276:immunology; D018925:Chemokines / Q000378:metabolism; D002634:Chemotaxis, Leukocyte / Q000187:drug effects* / Q000276:immunology; D004195:Disease Models, Animal; D065130:Endothelin A Receptor Antagonists; D006098:Granulocytes / Q000187:drug effects / Q000276:immunology*; D007249:Inflammation / Q000276:immunology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008168:Lung / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D008214:Lymphocytes / Q000187:drug effects / Q000276:immunology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D010456:Peptides, Cyclic / Q000494:pharmacology; D010998:Pleurisy / Q000276:immunology*; D011759:Pyrrolidines / Q000494:pharmacology
D000959:Antihypertensive Agents; D015815:Cell Adhesion Molecules; D018925:Chemokines; D065130:Endothelin A Receptor Antagonists; D008070:Lipopolysaccharides; D010456:Peptides, Cyclic; D011759:Pyrrolidines; C072247:cyclo(Trp-Asp-Pro-Val-Leu); D000077868:Atrasentan