Leukocyte-endothelial cell interactions in nitric oxide synthase-deficient mice.
Nitric oxide (NO) is known to be an important endogenous modulator of leukocyte-endothelial cell interactions within the microcirculation. We examined leukocyte rolling and adhesion under baseline conditions and following thrombin (0.25 U/ml) superfusion in the mesentery of wild-type, inducible NOS (iNOS)-deficient (-/-), neuronal NOS (nNOS) -/-, and endothelial cell NOS (ecNOS) -/- mice to further our understanding of NO and leukocyte function. Baseline leukocyte rolling (cells/min) was significantly elevated in both the 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 (cells/100 micrometers 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 rolling or adhesion in the mesentery. Baseline surface expression of P-selectin was observed in 68.0 +/- 9.0% of intestinal venules in ecNOS -/- mice compared with 10.0 +/- 2.0% in wild-type mice. Additional studies demonstrated that administration of an anti-P-selectin monoclonal antibody (RB40. 34) or the soluble P-selectin ligand, PSGL-1, completely inhibited the increased rolling and firm adhesion response in nNOS -/- and ecNOS -/- mice. Transmigration of neutrophils into the peritoneum following thioglycollate injection was also significantly augmented in nNOS -/- and ecNOS -/- mice. These studies clearly indicate the NO derived from both nNOS and ecNOS is critical in the regulation of leukocyte-endothelial cell interactions.
Lefer
D J
DJ
Department of Molecular and Cellular Physiology, Louisiana State University Medical Center, Shreveport, Louisiana 71130, USA. dlefer@mail.sh.lsumc.edu
Jones
S P
SP
Girod
W G
WG
Baines
A
A
Grisham
M B
MB
Cockrell
A S
AS
Huang
P L
PL
Scalia
R
R
D000818:Animals; D000906:Antibodies / Q000276:immunology / Q000494:pharmacology; D001772:Blood Cell Count; D001808:Blood Vessels / Q000378:metabolism; D002448:Cell Adhesion / Q000187:drug effects / Q000502:physiology; D004730:Endothelium, Vascular / Q000166:cytology / Q000502:physiology*; D018390:Gene Targeting; D006439:Hemodynamics / Q000502:physiology; D007962:Leukocytes / Q000502:physiology*; D051379:Mice; D009504:Neutrophils / Q000187:drug effects; D019001:Nitric Oxide Synthase / Q000172:deficiency* / Q000235:genetics; D052248:Nitric Oxide Synthase Type I; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D019007:P-Selectin / Q000276:immunology / Q000378:metabolism; D011994:Recombinant Proteins; D013152:Splanchnic Circulation / Q000502:physiology; D013864:Thioglycolates / Q000494:pharmacology; D013917:Thrombin / Q000494:pharmacology
D000906:Antibodies; D019007:P-Selectin; D011994:Recombinant Proteins; D013864:Thioglycolates; D019001:Nitric Oxide Synthase; D052248:Nitric Oxide Synthase Type I; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496321:Nos1 protein, mouse; C496317:Nos2 protein, mouse; C496315:Nos3 protein, mouse; D013917:Thrombin