Effects of nitric oxide on neutrophil influx depends on the tissue: role of leukotriene B4 and adhesion molecules

Br J Pharmacol. 2009 Mar;156(5):818-25. doi: 10.1111/j.1476-5381.2008.00094.x. Epub 2009 Feb 13.


Background and purpose: We investigated the effect of nitric oxide synthase (NOS) inhibition on polymorphonuclear cell (PMN) influx in zymosan or lipopolysaccharide (LPS)-induced arthritis and peritonitis.

Experimental approach: Wistar rats received intra-articular (i.art.) zymosan (30-1000 microg) or LPS (1-10 microg). Swiss C57/Bl6 mice genetically deficient in intercellular adhesion molecule-1 (ICAM-1(-/-)) or in beta(2)-integrin (beta(2)-integrin(-/-)) received zymosan either i.art. or i.p. PMN counts, leukotriene B(4) (LTB(4)), tumour necrosis factor-alpha (TNF-alpha) and interleukin-10 (IL-10) levels were measured in joint and peritoneal exudates. Groups received the NOS inhibitors N(G)-nitro-L-arginine methyl ester (LN), nitro-L-arginine, N-[3-(aminomemethyl)benzyl] acetamide or aminoguanidine, prior to zymosan or LPS, given i.p. or s.c. in the arthritis and peritonitis experiments respectively. A group of rats received LN locally (i.art. or i.p.), 30 min prior to 1 mg zymosan i.art.

Key results: Systemic or local NOS inhibition significantly prevented PMN migration in arthritis while increasing it in peritonitis, regardless of stimuli, concentration of NOS inhibitors and species. NOS inhibition did not alter TNF-alpha and IL-10 but decreased LTB(4) in zymosan-induced arthritis. LN administration significantly inhibited PMN influx into the joints of ICAM-1(-/-) and beta(2)-integrin(-/-) mice with zymosan-arthritis, while not altering PMN influx into the peritoneum of mice with zymosan-peritonitis.

Conclusions and implications: Nitric oxide has a dual modulatory role on PMN influx into joint and peritoneal cavities that is stimulus- and species-independent. Differences in local release of LTB(4) and in expression of ICAM-1 and beta(2)-integrin account for this dual role of NO on PMN migration.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute Disease
  • Animals
  • Arthritis / immunology
  • CD18 Antigens / genetics
  • CD18 Antigens / physiology*
  • Cell Movement
  • Intercellular Adhesion Molecule-1 / genetics
  • Intercellular Adhesion Molecule-1 / physiology*
  • Interleukin-10 / metabolism
  • Joints / immunology
  • Leukotriene B4 / physiology*
  • Lipopolysaccharides / pharmacology
  • Male
  • Mice
  • Mice, Knockout
  • Neutrophil Infiltration / physiology*
  • Nitric Oxide / physiology*
  • Nitric Oxide Synthase / antagonists & inhibitors
  • Peritoneal Cavity / cytology
  • Peritonitis / immunology
  • Rats
  • Rats, Wistar
  • Species Specificity
  • Tumor Necrosis Factor-alpha / metabolism
  • Zymosan


  • CD18 Antigens
  • Lipopolysaccharides
  • Tumor Necrosis Factor-alpha
  • Intercellular Adhesion Molecule-1
  • Interleukin-10
  • Leukotriene B4
  • Nitric Oxide
  • Zymosan
  • Nitric Oxide Synthase