Effects of LTB4 receptor antagonism on pulmonary inflammation in rodents and non-human primates.
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.
Hicks
Alexandra
A
Department of RNA Therapeutics, Roche, 340 Kingsland Street, Nutley, NJ 07110, USA. alexandra.hicks@roche.com
Goodnow
Robert
R
Cavallo
Gary
G
Tannu
Shahid A
SA
Ventre
Jessica D
JD
Lavelle
Danielle
D
Lora
Jose M
JM
Satjawatcharaphong
John
J
Brovarney
Martin
M
Dabbagh
Karim
K
Tare
Nadine S
NS
Oh
Hyesun
H
Lamb
Martin
M
Sidduri
Achyutharao
A
Dominique
Romyr
R
Qiao
Qi
Q
Lou
Jian Ping
JP
Gillespie
Paul
P
Fotouhi
Nader
N
Kowalczyk
Agnieszka
A
Kurylko
Grazyna
G
Hamid
Rachid
R
Wright
Matthew B
MB
Pamidimukkala
Anjula
A
Egan
Thomas
T
Gubler
Ueli
U
Hoffman
Ann F
AF
Wei
Xin
X
Li
Ying L
YL
O'Neil
John
J
Marcano
Ruben
R
Pozzani
Karen
K
Molinaro
Tina
T
Santiago
Jennifer
J
Singer
Laura
L
Hargaden
Maureen
M
Moore
David
D
Catala
A Robert
AR
Chao
Lisa C F
LC
Benson
Janet
J
March
Thomas
T
Venkat
Radhika
R
Mancebo
Helena
H
Renzetti
Louis M
LM
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
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