S. Ohta et al., Inhibition of P-selectin specific cell adhesion by a low molecular weight,non-carbohydrate compound, KF38789, INFLAMM RES, 50(11), 2001, pp. 544-551
Objective and design: P-selectin is a cell adhesion molecule of the selecti
n family. This study evaluated the effects of novel, low molecular weight P
-selectin inhibitors in a cell adhesion assay and a murine model of periton
itis.
Materials: U937 or 14L60 was used for cell adhesion assay. Human polymorpho
nuclear cells were studied for the production of superoxide. BALB/c mice we
re used for the in vivo study.
Treatment: The thioglycollate (TG)-induced accumulation of leukocytes in mi
ce was measured 6 h after the treatment. KF38789 or antibody (1 mg/kg) was
injected intravenously prior to TG injection and at 3 h following initial i
njection.
Results: Low molecular weight, non-carbohydrate inhibitors against P-select
in- mediated cell adhesion were tested. One of the most potent inhibitors,
KF38789, inhibited the binding of U937 cells to immobilized P-selectin immu
noglobulin G chimeric protein (P-selectin-Ig) with an IC50 value of 1.97 mu
M. Cell adhesion to both E-selectin-Ig and L-selectin-Ig were not affected
even by 100 muM of KF38789. Moreover, Y,F38789 inhibited P-selectin-induced
superoxide production from human polymorphonuclear cells. Intravenously in
jected KF38789 significantly inhibited the TG-induced accumulation of leuko
cytes in the mouse peritoneal cavity (p < 0.01).
Conclusion: A novel low molecular weight compound, KF38789, specifically in
hibited P-selectin-dependent cell adhesion and the leukocyte recruitment in
mouse peritonitis.