Estudo da participação do óxido nítrico na migração celular aguda na artrite e peritonite induzidas por zymosan ou lipopolissacarídeo em modelos experimentais

Abstract

Cell influx (CI) to synovium participates in physiopathology of rheumatoid arthritis (RA). There are controversies about the nitric oxide (NO) action in modulation of neutrophil influx to inflammatory sites, with NO decreasing or increasing it. This study investigated the effect of nitric oxide synthase (NOS) inhibitors on acute CI in animals submitted to arthritis or peritonitis induced by zymosan (ZyA or ZyP) or lipopolysaccharide (LPSA or LPSP), and the participation of leukotriene B4 (LTB4) and intercellular adhesion molecule -1 (ICAM-1). Rats Wistar received Zy (10-1000 micrograme) or LPS (1-10 micrograme) intraarticular (i.a.). Other groups received Zy (1 mg) or LPS (10 µg) intraperitoneal (i.p.). Wild or ICAM-1-deficient (ICAM-1-/-) mice received Zy (100 µg) i.a. or i.p. Animals were pre-treated (30 minutes before arthritis or peritonitis): in ZyA, rats received L-NAME (1-30 mg/kg; i.p. or 0.3-1 micromol; i.a), 1400W (1 mg/kg; i.p.) or Aminoguanidine (Amino) (50 mg/kg; i.p.). Mice received L-NAME (3-10 mg/kg;i.p.) or NG-nitro-L-arginine (Nitro) (50 mg/kg; i.p.). In ZyP, L-NAME (10-30 mg/kg; s.c. or i.p.) or 1400W (1 mg/kg; s.c.) was administrated in rats and mice received L-NAME (30 mg/kg; s.c.) or Nitro (50 mg/kg; s.c.). In LPSA, rats received L-NAME (10-30 mg/kg; i.p) and, in LPSP, they received L-NAME (30 mg/kg; s.c.). Controls received vehicle (NT groups). After sacrifice, CI was counted and LTB4 was measured in articular and peritoneal exudates. In ZyA (10-100 µg), L-NAME (1-3 mg) reduced CI (47.4 – 76.6%) as compared to NT animals (p<0.05). In ZyA (1mg), L-NAME (30 mg), 1400W (1mg) and Amino (50 mg) reduced CI (57.4%, 74.8% and 76.6%, respectively) (p<0.05). L-NAME (0.3 µmol) i.a. also reduced CI (85.3%) (p<0.05). Similarly, L-NAME (3-10 mg) or Nitro (50 mg) pre-treated mice showed a CI reduction (67.6%, 53.8% and 39.5%) (p<0.05). In contrast, in ZyP, L-NAME (10-30 mg) and 1400W (1 mg) increased CI (566.7%, 495.1% and 470.7%, respectively) in rats and L-NAME (30 mg) in mice (155.8%) (p<0.05). In mice, Nitro increased CI, but not significantly (p>0.05). L-NAME (10 mg) i.p. also increased CI (747.6%) (p<0.05). In LPSA, L-NAME (30 mg) decreased CI in two LPS doses (50.3% and 52.3%) (p<0.05). In LPSP, L-NAME (30 mg) increased the influx (53.4%) (p<0.05). NOS inhibitors didn’t change LTB4 levels. Arthritic pre-treated or not with Nitro ICAM-1-/- animals showed a CI reduction (57.8% or 32.1%)(p<0.05). In peritonitis, pre-treated or not with Nitro ICAM-1-/- showed a CI reduction (9.5% and 22.3%), but not significantly (p>0.05). NO, especially that produced by iNOS, reduces the acute CI in articulation while increases it in the peritoneum. This effect is independent of stimulus, species, route of administration and LTB4 liberation. Beyond, it involves resident and/or migrated cells. ICAM-1 appears to participate in CI in these models, especially in arthritis. Besides, NO modulates the expression of ICAM-1 in peritonitis.