CD11b is part of the beta2-integrin Mac-1 and plays an important role in neutrophil adhesion.
Leukotriene B4 (
LTB4) is an active upregulator 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 receptor antagonist. Twenty healthy male volunteers were randomised over three treatment groups that received placebo, 48 mg, or 200 mg
drug twice daily for 10 days. Before and
after treatment, flow cytometrical CD11b assessment was performed on in vitro LTB4-stimulated peripheral blood 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 markers. All observed effects were dose related. CD11b upregulation on blood neutrophils was significantly suppressed in both treatment groups compared to placebo. In skin, a significant suppression of
inflammation and hyperproliferation occurred. Pronounced inhibition was observed on neutrophil migration into the epidermis and the inflammatory infiltrate was decreased. A similar but weaker response was seen in the dermis. The number of cycling cells as well as suprabasal
keratin-16 expression were decreased in both treatment groups.
LY293111 proved to be a potent inhibitor of LTB4-induced cutaneous
inflammation and hyperproliferation. The potent antiinflammatory effect in vivo and the fact that in the present study the compound showed no clinically significant side effects make it an interesting
drug in the future treatment of inflammatory conditions predominated by neutrophils.