作者: Robert Goodnow ; Helena Mancebo ; Thomas Egan ; Ying L. Li ; Alexandra Hicks ; Danielle Lavelle ; Xin Wei ; Agnieszka Kowalczyk ; Karen Pozzani ; Paul Gillespie ; Grazyna Kurylko ; Nader Fotouhi ; Karim Dabbagh ; Martin Lamb ; Ruben Marcano ; Janet Benson ; Jennifer Santiago ; John O’Neil ; David Moore ; Lisa C.F. Chao ; Shahid A. Tannu ; Matthew B. Wright ; A. Robert Catala ; Ueli Gubler ; Jose M. Lora ; Rachid Hamid ; Jessica D. Ventre ; Romyr Dominique ; Tina Molinaro ; Laura Singer ; John Satjawatcharaphong ; Ann F. Hoffman ; Achyutharao Sidduri ; Anjula Pamidimukkala ; Hyesun Oh ; Radhika Venkat ; Martin Brovarney ; Jian Ping Lou ; Louis M. Renzetti ; Thomas March ; Maureen Hargaden ; Gary Cavallo ; Nadine S. Tare ; Qi Qiao

Asthma, chronic obstructive pulmonary disease (COPD) and acute lung injury/acute respiratory distress syndrome (ALI/ARDS) are characterized by neutrophilic inflammation and elevated levels of leukotriene B4 (LTB4). However, the exact role of LTB4 pathways in mediating pulmonary neutrophilia and the potential therapeutic application of LTB4 receptor antagonists in these diseases remains controversial. Here we show that a novel dual BLT1 and BLT2 receptor antagonist, RO5101576, potently inhibited LTB4-evoked calcium mobilization in HL-60 cells and chemotaxis of human neutrophils. RO5101576 significantly attenuated LTB4-evoked pulmonary eosinophilia in guinea pigs. In non-human primates, RO5101576 inhibited allergen and ozone-evoked pulmonary neutrophilia, with comparable efficacy to budesonide (allergic responses). RO5101576 had no effects on LPS-evoked neutrophilia in guinea pigs and cigarette smoke-evoked neutrophilia in mice and rats. In toxicology studies RO5101576 was well-tolerated. Theses studies show differential effects of LTB4 receptor antagonism on neutrophil responses in vivo and suggest RO5101576 may represent a potential new treatment for pulmonary neutrophilia in asthma.

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