The regulation of CD11b integrin levels on human blood leukocytes and leukotriene B4-stimulated skin by a specific leukotriene B4 receptor antagonist (LY293111).
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.
van Pelt
J P
JP
Department of Dermatology, University Hospital Nijmegen, The Netherlands.
de Jong
E M
EM
van Erp
P E
PE
Mitchell
M I
MI
Marder
P
P
Spaethe
S M
SM
van Hooijdonk
C A
CA
Kuijpers
A L
AL
van de Kerkhof
P C
PC
D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001565:Benzoates / Q000494:pharmacology*; D018845:CD11 Antigens / Q000032:analysis; D005434:Flow Cytometry; D006801:Humans; D007150:Immunohistochemistry; D007962:Leukocytes / Q000187:drug effects* / Q000276:immunology; D007975:Leukotriene B4 / Q000494:pharmacology*; D008297:Male; D016028:Receptors, Leukocyte-Adhesion / Q000032:analysis*; D018102:Receptors, Leukotriene B4 / Q000037:antagonists & inhibitors*; D012867:Skin / Q000187:drug effects* / Q000276:immunology; D015854:Up-Regulation
D000894:Anti-Inflammatory Agents, Non-Steroidal; D001565:Benzoates; D018845:CD11 Antigens; C094099:LY 293111; D016028:Receptors, Leukocyte-Adhesion; D018102:Receptors, Leukotriene B4; D007975:Leukotriene B4