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PMID: 15951834 Published · ppublish English Journal Article

Therapeutic targeting of CCR1 attenuates established chronic fungal asthma in mice.

British journal of pharmacology ·Vol. 145 ·No. 8 ·2005-08-00 ·Pages 1160-72

Carpenter KJ, Ewing JL, Schuh JM, Ness TL, Kunkel SL, Aparici M, Miralpeix M, Hogaboam CM

Abstract

CC chemokine receptor 1 (CCR1) represents a promising target in chronic airway inflammation and remodeling due to fungus-associated allergic asthma. The present study addressed the therapeutic effect of a nonpeptide CCR1 antagonist, BX-471, in a model of chronic fungal asthma induced by Aspergillus fumigatus conidia. BX-471 treatment of isolated macrophages inhibited CCL22 and TNF-alpha and promoted IL-10 release. BX-471 also increased toll like receptor-9 (TLR9) and decreased TLR2 and TLR6 expression in these cells. When administered daily by intraperitoneal injection, from days 15 to 30 after the initiation of chronic fungal asthma, BX-471 (3, 10, or 30 mg kg(-1)) dose-dependently reduced airway inflammation, hyper-responsiveness, and remodeling at day 30 after conidia challenge. The maximal therapeutic effect was observed at the 10 mg kg(-1) dose. In summary, the therapeutic administration of BX-471 significantly attenuated experimental fungal asthma via its effects on both innate and adaptive immune processes.

MeSH Terms
Animals Aspergillosis/drug therapy,immunology,microbiology Aspergillus fumigatus/immunology Asthma/drug therapy,immunology,microbiology Chronic Disease Disease Models, Animal Dose-Response Relationship, Drug Female Immunity, Innate/drug effects Macrophages, Peritoneal/drug effects,metabolism Mice Mice, Inbred BALB C Mice, Inbred CBA Phenylurea Compounds/therapeutic use Piperidines/therapeutic use Receptors, CCR1 Receptors, Chemokine/antagonists & inhibitors
Chemicals
Ccr1 protein, mouse Phenylurea Compounds Piperidines Receptors, CCR1 Receptors, Chemokine BX 471
Authors & Affiliations
8 authors, click to expand affiliations / ORCID
Carpenter Kristin J
Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
Ewing Jillian L
Schuh Jane M
Ness Traci L
Kunkel Steven L
Aparici Monica
Miralpeix Montserrat
Hogaboam Cory M
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Article Info
Journal
British journal of pharmacology
Abbr.
Br J Pharmacol
ISSN
0007-1188
DOI
10.1038/sj.bjp.0706243
Published
2005-08-00
Pages
1160-72
Language
English
Region
England
NLM ID
7502536
PMCID
PMC1576221
Subset
IM
External Links
PubMed source DOI: 10.1038/sj.bjp.0706243 PMC Full Text View journal details
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