AMD3100, a CxCR4 antagonist, attenuates allergic lung inflammation and airway hyperreactivity.
The role of specific chemokine receptors during allergic asthmatic responses has been relatively undefined. A number of receptors are preferentially expressed on Th2 cells, including CCR4, CCR8, and CxCR4. In the present study, we have examined the role of CxCR4 in the development of cockroach allergen-induced inflammation and airway hyperreactivity in a mouse model of asthma. Using a specific inhibitor of CxCR4, AMD3100, our results indicate that blocking this receptor has a significant effect in down-regulating the inflammation and pathophysiology of the allergen-induced response. Treatment of allergic mice with AMD3100 significantly reduced airway hyperreactivity, peribronchial eosinophilia, and the overall inflammatory responses. In addition, there was a shift in the cytokine profile that was observed in the AMD3100-treated animals. Specifically, there was a significant reduction in interleukin-4 and interleukin-5 levels and a significant increase in interleukin-12 and interferon-gamma levels within the lungs of treated allergic mice. Furthermore, there was a significant alteration in the local chemokine production of CCL22 (MDC) and CCL17 (TARC), two chemokines previously shown to be important in Th2-type allergen responses. Overall, specifically blocking CxCR4 using AMD3100 reduced a number of pathological parameters related to asthmatic-type inflammation.
Lukacs
Nicholas W
NW
Department of Pathology, University of Michigan Medical School, Ann Arbor 48109-0602, USA. nlukacs@umich.edu
Berlin
Aaron
A
Schols
Dominique
D
Skerlj
Renato T
RT
Bridger
Gary J
GJ
D000485:Allergens / Q000276:immunology; D000818:Animals; D001596:Benzylamines; D016535:Bronchial Hyperreactivity / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects; D018925:Chemokines / Q000378:metabolism; D000080027:Cyclams; D016207:Cytokines / Q000378:metabolism; D005260:Female; D006571:Heterocyclic Compounds / Q000627:therapeutic use*; D006967:Hypersensitivity / Q000188:drug therapy* / Q000503:physiopathology; D007962:Leukocytes / Q000502:physiology; D051379:Mice; D008808:Mice, Inbred CBA; D011014:Pneumonia / Q000188:drug therapy* / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors*
D000485:Allergens; D001596:Benzylamines; D018925:Chemokines; D000080027:Cyclams; D016207:Cytokines; D006571:Heterocyclic Compounds; D019718:Receptors, CXCR4; C088327:plerixafor