Leukocyte-endothelial cell interactions in nitric oxide synthase-deficientmice

Nitric oxide (NO) is known to be an important endogenous modulator of leuko cyte-endothelial cell interactions within the microcirculation. We examined leukocyte rolling and adhesion under baseline conditions and following thr ombin (0.25 U/ml) superfusion in the mesentery of wildtype, inducible NOS ( iNOS)-deficient (-/-), neuronal NOS (nNOS) -/-, and endothelial cell NOS (e cNOS) -/- mice to further our understanding of NO and leukocyte function. B aseline leukocyte rolling (cells/min) was significantly elevated in both th e nNOS -/- (30.0 +/- 4.0) and ecNOS -/- mice (67.0 +/- 12.0) compared with wild-type mice (11.0 +/- 1.4). In addition, baseline leukocyte adherence (c ells/100 mu m of vessel). was also significantly elevated in the nNOS -/- ( 5.2 +/- 1.0) and ecNOS -/- (13.0 +/- 1.3) compared with wild-type animals ( 1.3 +/- 0.5). Deficiency of iNOS had no effect on baseline leukocyte rollin g or adhesion in the mesentery. Baseline surface expression of P-selectin w as observed in 68.0 +/- 9.0% of intestinal venules in ecNOS -/- mice compar ed with 10.0 +/- 2.0% in wild-type mice. Additional studies demonstrated th at administration of an anti-P-selectin monoclonal antibody (RB40.34) or th e soluble P-selectin ligand, PSGL-1, completely inhibited the increased rol ling and firm adhesion response in nNOS -/- and ecNOS -/- mice. Transmigrat ion of neutrophils into the peritoneum following thioglycollate injection w as also significantly augmented in nNOS -/- and ecNOS -/- mice. These studi es clearly indicate the NO derived from both nNOS and ecNOS is critical in the regulation of leukocyte-endothelial cell interactions.