Effects of antisense oligodeoxynucleotides targeting CCR3 on the airway response to antigen in rats.
Asthma is characterized by airway hyperresponsiveness (AHR) and inflammation, consisting predominantly of eosinophils within the airway lumen and walls. Eosinophil recruitment to the airways is mediated mainly by eotaxin and other chemokines that bind to the CC-chemokine receptor-3 (CCR3), which is highly expressed on eosinophils. This study assessed whether topical inhibition of CCR3 mRNA expression by phosphorothioate antisense oligodeoxynucleotides (AS-ODNs) modifies pulmonary eosinophilia and AHR in an antigen-induced allergic asthma model in Brown Norway (BN) rats. Results show that specific inhibition of CCR3 expression in the lungs by an AS-ODN (AS4) reduced total eosinophil infiltration and the percentage of eosinophils into the airways of ovalbumin challenged rats. Moreover, reduction in CCR3 mRNA levels was correlated with a decrease in CCR3 protein in lung tissue. In addition, AS4 treatment had no effect on circulating eosinophils or on eosinophils in the bone marrow. Finally, AHR was significantly decreased in AS4-treated rats when compared with rats treated with a mismatch AS-ODN. In conclusion, inhibition of the expression of CCR3 decreased pulmonary eosinophilia and reduced AHR after antigen challenge in rats. Topical inhibition of CCR3 expression, using an AS-ODN, could represent a novel approach for the treatment of asthma.
Fortin
Marylène
M
Topigen Pharmaceuticals, Inc., Montreal, Quebec, Canada.
Ferrari
Nicolay
N
Higgins
Marie-Eve
ME
Séguin
Serge
S
Allam
Mustapha
M
Allakhverdi
Zoulfia
Z
Piaget-Rodriguez
Carmen
C
Paquet
Luc
L
Renzi
Paolo M
PM
D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000818:Animals; D001249:Asthma / Q000188:drug therapy* / Q000378:metabolism; D004195:Disease Models, Animal; D016376:Oligonucleotides, Antisense / Q000494:pharmacology*; D010047:Ovalbumin / Q000276:immunology; D010538:Peritonitis / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011914:Rats, Inbred BN; D054397:Receptors, CCR3; D019707:Receptors, Chemokine / Q000096:biosynthesis / Q000235:genetics*
D000276:Adjuvants, Immunologic; C515352:Ccr3 protein, rat; D016376:Oligonucleotides, Antisense; D012333:RNA, Messenger; D054397:Receptors, CCR3; D019707:Receptors, Chemokine; D010047:Ovalbumin