bq-123 and Pleurisy

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.

Topics: Animals; Antihypertensive Agents; Atrasentan; Cell Adhesion Molecules; Chemokines; Chemotaxis, Leukocyte; Disease Models, Animal; Endothelin A Receptor Antagonists; Granulocytes; Inflammation; Lipopolysaccharides; Lung; Lymphocytes; Male; Mice; Mice, Inbred BALB C; Peptides, Cyclic; Pleurisy; Pyrrolidines

Endothelins participate in different aspects of inflammatory reactions, including edema formation and eosinophil accumulation in allergic reaction. In this study, we demonstrated a role for endogenous endothelins in eosinophil and T lymphocyte recruitment and cytokine secretion in a murine model of allergic inflammation. Intrathoracic stimulation with endothelin-1 triggered a neutrophil accumulation at 4 h, concomitant with an increase of CD4+ and CD8+ T lymphocyte populations. Antigen challenge in sensitized animals leads to an increase in eosinophil and mononuclear cell numbers at 24 h. Treatment with ETA receptor antagonist (BQ123) inhibited antigen-induced eosinophil and mononuclear cell migration, whereas the selective ETB receptor antagonist BQ-788 was ineffective. The latter effect of BQ-123 was due to inhibition of CD4+ and CD8+ T lymphocytes. Treatment with BQ-123 also inhibited interleukin-5 levels in the exudate and plasma as well as intracellular staining of interleukin-4, interleukin-5, and interferon-gamma in CD4+ lymphocytes. These findings suggest that endogenous endothelins contribute to allergic inflammation by modulating lymphocyte recruitment and cytokine production.

Topics: Animals; Bosentan; CD4-Positive T-Lymphocytes; Chemotaxis, Leukocyte; Endothelin Receptor Antagonists; Endothelin-1; Humans; Interferon-gamma; Interleukin-4; Interleukin-5; Ionomycin; Lymphocyte Subsets; Male; Mice; Mice, Inbred C57BL; Monensin; Oligopeptides; Ovalbumin; Peptides, Cyclic; Piperidines; Pleurisy; Receptor, Endothelin A; Receptor, Endothelin B; Receptors, Endothelin; Respiratory Hypersensitivity; Sulfonamides; Tetradecanoylphorbol Acetate

Investigate the role of endothelins in leukocyte recruitment in allergic and non allergic inflammation.. Pleurisy was induced in mice by intrathoracic injection of ovalbumin (OVA; in sensitized animals), E. coli LPS, carrageenan, Mycobacterium bovis (BCG) or zymosan. Animals were treated with BQ-123 or BQ-788 (1.5-150 pmol/cavity), or intravenously with bosentan (30 mg/kg).. None of the ET receptor antagonists modified early neutrophil recruitment (at 4 h) induced by OVA, LPS, carrageenan, BCG or zymosan or plasma leakage caused by carrageenan or zymosan. Mononuclear and eosinophil accumulation triggered by OVA were reduced by BQ-123 (150 pmol/cavity) or bosentan (68 and 43% inhibition of eosinophilia), but unaffected by BQ-788. BQ-123 and bosentan also inhibited LPS increases in neutrophil (by 67 and 40%) and eosinophil (by 63 and 74%) at 24 h.. Endothelins, acting via ETA receptors, play a role in late eosinophil and neutrophil accumulation (24 h), but not in the acute (4 h) neutrophilic response.

Topics: Animals; Endothelin Receptor Antagonists; Endothelins; Eosinophils; Leukocyte Count; Lipopolysaccharides; Male; Mice; Neutrophil Infiltration; Neutrophils; Oligopeptides; Ovalbumin; Peptides, Cyclic; Piperidines; Pleurisy; Proteins; Receptor, Endothelin A; Receptor, Endothelin B; Receptors, Endothelin