|Title||The effect of a selective CXCR2 antagonist (AZD5069) on human blood neutrophil count and innate immune functions.|
|Authors||Jurcevic, S., Humfrey, C., Uddin, M., Warrington, S., Larsson, B. and Keen, C.|
The aim of the present study was to investigate whether selective antagonism of the cysteine-X-cysteine chemokine receptor-2 (CXCR2) receptor has any adverse effects on the key innate effector functions of human neutrophils for defence against microbial pathogens.
In a double-blind, crossover study, 30 healthy volunteers were randomized to treatment with the CXCR2 antagonist AZD5069 (100 mg) or placebo, twice daily orally for 6 days. The peripheral blood neutrophil count was assessed at baseline, daily during treatment and in response to exercise challenge and subcutaneous injection of granulocyte-colony stimulating factor (G-CSF). Neutrophil function was evaluated by phagocytosis of Escherichia coli and by the oxidative burst response to E. coli.
AZD5069 treatment reversibly reduced circulating neutrophil count from baseline by a mean [standard deviation (SD)] of -1.67 (0.67) ×10(9) l(-1) vs. 0.19 (0.78) ×10(9) l(-1) for placebo on day 2, returning to baseline by day 7 after the last dose. Despite low counts on day 4, a 10-min exercise challenge increased absolute blood neutrophil count, but the effect with AZD5069 was smaller and not sustained, compared with placebo treatment. Subcutaneous G-CSF on day 5 caused a substantial increase in blood neutrophil count in both placebo- and AZD5069-treated subjects. Superoxide anion production in E. coli-stimulated neutrophils and phagocytosis of E. coli were unaffected by AZD5069 (P = 0.375, P = 0.721, respectively vs. baseline, Day 4). AZD5069 was well tolerated.
CXCR2 antagonism did not appear adversely to affect the mobilization of neutrophils from bone marrow into the peripheral circulation, phagocytosis or the oxidative burst response to bacterial pathogens. This supports the potential of CXCR2 antagonists as a treatment option for diseases in which neutrophils play a pathological role.
|Keywords||COPD; CXCR2 antagonist; asthma; neutrophil recruitment; oxidative burst; phagocytosis|
|Journal||Br J Clin Pharmacol.|
|Journal citation||80 (6), pp. 1324-36|
|Accepted author manuscript||BJCP_CXCR2 antagonist_Accepted.pdf|
|Supplementary data or files||bjcp12724-sup-0001-SI.pdf|
|Digital Object Identifier (DOI)||doi:10.1111/bcp.12724|
|Published||02 Oct 2015|