title: 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.
authors.affiliation: Department of RNA Therapeutics, Roche, 340 Kingsland Street, Nutley, NJ 07110, USA. alexandra.hicks@roche.com
authors.forename: Alexandra
authors.initials: A
authors.lastname: Hicks
authors.forename: Robert
authors.initials: R
authors.lastname: Goodnow
authors.forename: Gary
authors.initials: G
authors.lastname: Cavallo
authors.forename: Shahid A
authors.initials: SA
authors.lastname: Tannu
authors.forename: Jessica D
authors.initials: JD
authors.lastname: Ventre
authors.forename: Danielle
authors.initials: D
authors.lastname: Lavelle
authors.forename: Jose M
authors.initials: JM
authors.lastname: Lora
authors.forename: John
authors.initials: J
authors.lastname: Satjawatcharaphong
authors.forename: Martin
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authors.lastname: Brovarney
authors.forename: Karim
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authors.lastname: Dabbagh
authors.forename: Nadine S
authors.initials: NS
authors.lastname: Tare
authors.forename: Hyesun
authors.initials: H
authors.lastname: Oh
authors.forename: Martin
authors.initials: M
authors.lastname: Lamb
authors.forename: Achyutharao
authors.initials: A
authors.lastname: Sidduri
authors.forename: Romyr
authors.initials: R
authors.lastname: Dominique
authors.forename: Qi
authors.initials: Q
authors.lastname: Qiao
authors.forename: Jian Ping
authors.initials: JP
authors.lastname: Lou
authors.forename: Paul
authors.initials: P
authors.lastname: Gillespie
authors.forename: Nader
authors.initials: N
authors.lastname: Fotouhi
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Kowalczyk
authors.forename: Grazyna
authors.initials: G
authors.lastname: Kurylko
authors.forename: Rachid
authors.initials: R
authors.lastname: Hamid
authors.forename: Matthew B
authors.initials: MB
authors.lastname: Wright
authors.forename: Anjula
authors.initials: A
authors.lastname: Pamidimukkala
authors.forename: Thomas
authors.initials: T
authors.lastname: Egan
authors.forename: Ueli
authors.initials: U
authors.lastname: Gubler
authors.forename: Ann F
authors.initials: AF
authors.lastname: Hoffman
authors.forename: Xin
authors.initials: X
authors.lastname: Wei
authors.forename: Ying L
authors.initials: YL
authors.lastname: Li
authors.forename: John
authors.initials: J
authors.lastname: O'Neil
authors.forename: Ruben
authors.initials: R
authors.lastname: Marcano
authors.forename: Karen
authors.initials: K
authors.lastname: Pozzani
authors.forename: Tina
authors.initials: T
authors.lastname: Molinaro
authors.forename: Jennifer
authors.initials: J
authors.lastname: Santiago
authors.forename: Laura
authors.initials: L
authors.lastname: Singer
authors.forename: Maureen
authors.initials: M
authors.lastname: Hargaden
authors.forename: David
authors.initials: D
authors.lastname: Moore
authors.forename: A Robert
authors.initials: AR
authors.lastname: Catala
authors.forename: Lisa C F
authors.initials: LC
authors.lastname: Chao
authors.forename: Janet
authors.initials: J
authors.lastname: Benson
authors.forename: Thomas
authors.initials: T
authors.lastname: March
authors.forename: Radhika
authors.initials: R
authors.lastname: Venkat
authors.forename: Helena
authors.initials: H
authors.lastname: Mancebo
authors.forename: Louis M
authors.initials: LM
authors.lastname: Renzetti
mesh_terms: D000818:Animals; D052117:Benzodioxoles / Q000494:pharmacology* / Q000627:therapeutic use / Q000633:toxicity; D004285:Dogs; D064420:Drug-Related Side Effects and Adverse Reactions; D005260:Female; D006168:Guinea Pigs; D018922:HL-60 Cells; D006801:Humans; D006967:Hypersensitivity / Q000150:complications; D008070:Lipopolysaccharides / Q000494:pharmacology; D008168:Lung / Q000187:drug effects; D008297:Male; D051379:Mice; D010126:Ozone / Q000494:pharmacology; D010666:Phenylpropionates / Q000494:pharmacology* / Q000627:therapeutic use / Q000633:toxicity; D011014:Pneumonia / Q000139:chemically induced / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism; D011323:Primates; D051381:Rats; D018102:Receptors, Leukotriene B4 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012907:Smoking / Q000009:adverse effects; D018675:Toxicity Tests
chemical_list: C551588:4-(3-(6-(3-benzo(1,3)dioxol-5-yl-5-thiophen-3-ylphenoxy)hexyl)-2-(2-carboxyethyl)phenoxy)butyric acid; D052117:Benzodioxoles; D008070:Lipopolysaccharides; D010666:Phenylpropionates; D018102:Receptors, Leukotriene B4; D010126:Ozone