Abstract
Neutrophil recruitment and activation in the lungs is implicated in the pathophysiology of a number of inflammatory lung diseases. We investigated the ability of the selective CXCR2 receptor antagonist SB-656933 to modulate ex vivo rat CXCL2-induced CD11b expression on the surface of neutrophils and to inhibit LPS-induced neutrophil recruitment into the lungs. Rats were dosed orally with SB-656933 and 1 h later whole blood was removed and treated with CXCL2 and analysed for neutrophil CD11b expression by FACS. A separate group of rats were dosed with SB-656933 1 h before exposure to LPS aerosol and neutrophil recruitment in BAL fluid was assessed 4 h post-challenge. Treatment with SB-656933 inhibited ex vivo CXCL2 induced neutrophil CD11b expression in a dose-dependent manner exhibiting a maximum shift in agonist response curves at a 30 mg/kg dose with an EC50 of 22.2 nM ± 3.5 compared to 3.4 nM ± 0.1 in vehicle-treated rats (p<0.001). SB-656933 inhibited LPS-induced neutrophil recruitment in BAL fluid in a dose-dependent manner with 92.2% ± 2.6 inhibition at 30 mg/kg compared to vehicle-treated rats (p<0.001), (ED50: 6.6 mg/kg). Inhibition of neutrophil CD11b by SB-656933 was correlated with decreases in LPS-induced neutrophil recruitment (dose range: 0.3-30 mg/kg). Ex vivo CD11b expression may be a pharmacokinetic marker of CXCR2 antagonist activity in humans and is a potential indicator of lung neutrophil recruitment.