Therapeutic targeting of CCR1 attenuates established chronic fungal asthma in mice.
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.
Carpenter
Kristin J
KJ
Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
Ewing
Jillian L
JL
Schuh
Jane M
JM
Ness
Traci L
TL
Kunkel
Steven L
SL
Aparici
Monica
M
Miralpeix
Montserrat
M
Hogaboam
Cory M
CM
D000818:Animals; D001228:Aspergillosis / Q000188:drug therapy* / Q000276:immunology / Q000382:microbiology; D001232:Aspergillus fumigatus / Q000276:immunology; D001249:Asthma / Q000188:drug therapy* / Q000276:immunology / Q000382:microbiology; D002908:Chronic Disease; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D007113:Immunity, Innate / Q000187:drug effects; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008808:Mice, Inbred CBA; D010671:Phenylurea Compounds / Q000627:therapeutic use*; D010880:Piperidines / Q000627:therapeutic use*; D054389:Receptors, CCR1; D019707:Receptors, Chemokine / Q000037:antagonists & inhibitors*
C515301:Ccr1 protein, mouse; D010671:Phenylurea Compounds; D010880:Piperidines; D054389:Receptors, CCR1; D019707:Receptors, Chemokine; C411885:BX 471