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

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.
AuthorsKristin J Carpenter, Jillian L Ewing, Jane M Schuh, Traci L Ness, Steven L Kunkel, Monica Aparici, Montserrat Miralpeix, Cory M Hogaboam
JournalBritish journal of pharmacology (Br J Pharmacol) Vol. 145 Issue 8 Pg. 1160-72 (Aug 2005) ISSN: 0007-1188 [Print] England
PMID15951834 (Publication Type: Journal Article)
Chemical References
  • Ccr1 protein, mouse
  • Phenylurea Compounds
  • Piperidines
  • Receptors, CCR1
  • Receptors, Chemokine
  • BX 471
Topics
  • 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)

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