Leukocyte adherence in rat mesenteric venules: effects of adenosine and methotrexate.

BACKGROUND Methotrexate (MTX) reduces neutrophil adhesion to endothelial cell monolayers, possibly via stimulation of adenosine production. However, it remains unclear whether adenosine participates in the anti-inflammatory actions of MTX in postcapillary venules. METHODS Leukocyte-endothelial cell adhesive interactions were measured in rat mesenteric venules (25-35 microns diameter) during superfusion with either bicarbonate-buffered saline (BBS) alone, BBS combined with platelet-activating factor (PAF), or BBS combined with leukotriene B4 (LTB4). In some experiments, either MTX or adenosine was added to a superfusate containing either PAF or LTB4. In other experiments, either adenosine deaminase (ADA), an adenosine A1-receptor antagonist, or an A2-receptor antagonist was added to a superfusate containing PAF and either MTX or adenosine. RESULTS Both MTX and adenosine were effective in preventing the leukocyte-endothelial cell adhesive interactions elicited by PAF, but not by LTB4. These actions of adenosine and MTX against PAF-induced leukocyte adhesion were blunted by ADA and the A2-(but not the A1-) receptor antagonist. CONCLUSIONS These results indicate that both adenosine and methotrexate attenuate PAF-induced leukocyte-endothelial cell adhesion in postcapillary venules via activation of A2-receptors on the leukocyte.

[1]  H. Granger,et al.  Superoxide mediates reperfusion-induced leukocyte-endothelial cell interactions. , 1989, The American journal of physiology.

[2]  J. Daly,et al.  3,7-Dimethyl-1-propargylxanthine: a potent and selective in vivo antagonist of adenosine analogs. , 1988, Life sciences.

[3]  G. Weissmann,et al.  Adenosine: an endogenous inhibitor of neutrophil-mediated injury to endothelial cells. , 1986, The Journal of clinical investigation.

[4]  H. W. Hamilton,et al.  PD 116,948, a highly selective A1 adenosine receptor antagonist. , 1987, Life sciences.

[5]  G. Zimmerman,et al.  Hydrogen peroxide stimulates the synthesis of platelet-activating factor by endothelium and induces endothelial cell-dependent neutrophil adhesion. , 1988, The Journal of clinical investigation.

[6]  R. Kozarek,et al.  Methotrexate induces clinical and histologic remission in patients with refractory inflammatory bowel disease. , 1989, Annals of internal medicine.

[7]  G. Weissmann,et al.  Engagement of adenosine receptors inhibits hydrogen peroxide (H2O2-) release by activated human neutrophils. , 1987, Clinical immunology and immunopathology.

[8]  Michael J. Davis,et al.  Determination of volumetric flow in capillary tubes using an optical Doppler velocimeter. , 1987, Microvascular research.

[9]  C. Nathan,et al.  Adenosine regulates the respiratory burst of cytokine-triggered human neutrophils adherent to biologic surfaces. , 1989, Journal of immunology.

[10]  S. D. House,et al.  Leukocyte-endothelium adhesion: microhemodynamics in mesentery of the cat. , 1987, Microvascular research.

[11]  Y. Miyachi,et al.  Dissociation of the inhibitory effect of dapsone on the generation of oxygen intermediates--in comparison with that of colchicine and various scavengers. , 1984, Biochemical pharmacology.

[12]  S. Charleson,et al.  Leukotriene B4, polymorphonuclear leukocytes and inflammatory exudates in the rat. , 1984, Prostaglandins.

[13]  M. Grisham,et al.  Leukocyte adherence to venular endothelium during ischemia-reperfusion. , 1989, The American journal of physiology.

[14]  B. Cronstein,et al.  The adenosine/neutrophil paradox resolved: human neutrophils possess both A1 and A2 receptors that promote chemotaxis and inhibit O2 generation, respectively. , 1990, The Journal of clinical investigation.

[15]  M. Entman,et al.  Mac-1 (CD11b/CD18) mediates adherence-dependent hydrogen peroxide production by human and canine neutrophils. , 1990, Journal of immunology.

[16]  R. D. del Maestro,et al.  Evidence for the participation of superoxide anion radical in altering the adhesive interaction between granulocytes and endothelium, in vivo. , 1982, International journal of microcirculation, clinical and experimental.

[17]  M. Grisham,et al.  Adenosine inhibits ischemia-reperfusion-induced leukocyte adherence and extravasation. , 1989, The American journal of physiology.

[18]  S. B. Kramer,et al.  Adenosine; a physiologic modulator of superoxide anion generation by human neutrophils. Adenosine acts via an A2 receptor on human neutrophils. , 1985, Journal of immunology.

[19]  S. Abramson,et al.  Neutrophil adherence to endothelium is enhanced via adenosine A1 receptors and inhibited via adenosine A2 receptors. , 1992, Journal of immunology.

[20]  P. Kubes,et al.  Neutrophil-derived oxidants promote leukocyte adherence in postcapillary venules. , 1991, Microvascular research.

[21]  S. B. Kramer,et al.  Adenosine: a physiological modulator of superoxide anion generation by human neutrophils , 1983, The Journal of experimental medicine.

[22]  M. Weinblatt,et al.  Efficacy of low-dose methotrexate in rheumatoid arthritis. , 1985, The New England journal of medicine.

[23]  M. McCormick,et al.  Leukocyte recruitment in the subcutaneous sponge implant model of acute inflammation in the rat is not mediated by leukotriene B1. , 1986, Biochemical pharmacology.

[24]  M. Weinblatt,et al.  Long-term prospective trial of low-dose methotrexate in rheumatoid arthritis. , 1988, Arthritis and rheumatism.

[25]  K. Halprin,et al.  Blood levels of methotreate and the treatment of psoriasis. , 1971, Archives of dermatology.

[26]  G. Olaison,et al.  Novel aspect of Crohn's disease: increased content of platelet-activating factor in ileal and colonic mucosa. , 1990, Digestion.

[27]  B. Cronstein,et al.  Methotrexate inhibits neutrophil function by stimulating adenosine release from connective tissue cells. , 1991, Proceedings of the National Academy of Sciences of the United States of America.