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Effects of LTB4 receptor antagonism on pulmonary inflammation in rodents and non-human primates.

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.
AuthorsAlexandra Hicks, Robert Goodnow Jr, Gary Cavallo, Shahid A Tannu, Jessica D Ventre, Danielle Lavelle, Jose M Lora, John Satjawatcharaphong, Martin Brovarney, Karim Dabbagh, Nadine S Tare, Hyesun Oh, Martin Lamb, Achyutharao Sidduri, Romyr Dominique, Qi Qiao, Jian Ping Lou, Paul Gillespie, Nader Fotouhi, Agnieszka Kowalczyk, Grazyna Kurylko, Rachid Hamid, Matthew B Wright, Anjula Pamidimukkala, Thomas Egan, Ueli Gubler, Ann F Hoffman, Xin Wei, Ying L Li, John O'Neil, Ruben Marcano, Karen Pozzani, Tina Molinaro, Jennifer Santiago, Laura Singer, Maureen Hargaden, David Moore, A Robert Catala, Lisa C F Chao, Janet Benson, Thomas March, Radhika Venkat, Helena Mancebo, Louis M Renzetti
JournalProstaglandins & other lipid mediators (Prostaglandins Other Lipid Mediat) Vol. 92 Issue 1-4 Pg. 33-43 (Jun 2010) ISSN: 1098-8823 [Print] United States
PMID20214997 (Publication Type: Journal Article)
CopyrightCopyright 2010 Elsevier Inc. All rights reserved.
Chemical References
  • 4-(3-(6-(3-benzo(1,3)dioxol-5-yl-5-thiophen-3-ylphenoxy)hexyl)-2-(2-carboxyethyl)phenoxy)butyric acid
  • Benzodioxoles
  • Lipopolysaccharides
  • Phenylpropionates
  • Receptors, Leukotriene B4
  • Ozone
Topics
  • Animals
  • Benzodioxoles (pharmacology, therapeutic use, 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 (pharmacology, therapeutic use, toxicity)
  • Pneumonia (chemically induced, complications, drug therapy, metabolism)
  • Primates
  • Rats
  • Receptors, Leukotriene B4 (antagonists & inhibitors, metabolism)
  • Smoking (adverse effects)
  • Toxicity Tests

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