THE REGULATION OF CD11B INTEGRIN LEVELS ON HUMAN BLOOD LEUKOCYTES ANDLEUKOTRIENE B4-STIMULATED SKIN BY A SPECIFIC LEUKOTRIENE B4 RECEPTOR ANTAGONIST (LY293111)

CD11b is part of the beta 2-integrin Mac-1 and plays an important role in neutrophil adhesion. Leukotriene B-4 (LTB4) is an active upregulat or of neutrophil CD11b-expression, acts as a potent chemoattractant to neutrophils and is also known to upmodulate epidermal proliferation. We performed a placebo-controlled study on LY293111, an oral LTB4 rece ptor antagonist. Twenty healthy male volunteers were randomised over t hree treatment groups that received placebo, 48 mg, or 200 mg drug twi ce daily for 10 days. Before and after treatment, flow cytometrical CD 11b assessment was performed on in vitro LTB4-stimulated peripheral br ood neutrophils. Additionally, skin biopsies were taken at 24 and 72 h after epicutaneous LTB4 application, before and after treatment. The effects on skin were assessed immunohistochemically using various mark ers. All observed effects were dose related. CD11b upregulation on blo od neutrophils was significantly suppressed in both treatment groups c ompared to placebo. In skin, a significant suppression of inflammation and hyperproliferation occurred. Pronounced inhibition was observed o n neutrophil migration into the epidermis and the inflammatory infiltr ate was decreased. A similar but weaker response was seen in the dermi s. The number of cycling cells as well as suprabasal keratin-16 expres sion were decreased in both treatment groups. LY293111 proved to be a potent inhibitor of LTB4-induced cutaneous inflammation and hyperproli feration. The potent antiinflammatory effect in vivo and the fact that in the present study the compound showed no clinically significant si de effects make it an interesting drug in the future treatment of infl ammatory conditions predominated by neutrophils. (C) 1997 Elsevier Sci ence Inc.