1. Effects of LTB4 receptor antagonism on pulmonary inflammation in rodents and non-human primates.
- Author
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Hicks A, Goodnow R Jr, Cavallo G, Tannu SA, Ventre JD, Lavelle D, Lora JM, Satjawatcharaphong J, Brovarney M, Dabbagh K, Tare NS, Oh H, Lamb M, Sidduri A, Dominique R, Qiao Q, Lou JP, Gillespie P, Fotouhi N, Kowalczyk A, Kurylko G, Hamid R, Wright MB, Pamidimukkala A, Egan T, Gubler U, Hoffman AF, Wei X, Li YL, O'Neil J, Marcano R, Pozzani K, Molinaro T, Santiago J, Singer L, Hargaden M, Moore D, Catala AR, Chao LC, Benson J, March T, Venkat R, Mancebo H, and Renzetti LM
- Subjects
- Animals, Benzodioxoles therapeutic use, Benzodioxoles toxicity, Dogs, Drug-Related Side Effects and Adverse Reactions, Female, Guinea Pigs, HL-60 Cells, Humans, Hypersensitivity complications, Lipopolysaccharides pharmacology, Lung drug effects, Male, Mice, Ozone pharmacology, Phenylpropionates therapeutic use, Phenylpropionates toxicity, Pneumonia chemically induced, Pneumonia complications, Pneumonia metabolism, Rats, Receptors, Leukotriene B4 metabolism, Smoking adverse effects, Toxicity Tests, Benzodioxoles pharmacology, Phenylpropionates pharmacology, Pneumonia drug therapy, Primates, Receptors, Leukotriene B4 antagonists & inhibitors
- Abstract
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., (Copyright 2010 Elsevier Inc. All rights reserved.)
- Published
- 2010
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