Inhibition of SCF attenuates peribronchial remodeling in chronic cockroach allergen-induced asthma.
The progression and severity of chronic asthma likely depends upon the intensity of the damage and remodeling of the tissue. We have developed a chronic model of allergic asthma using multiple cockroach allergen challenges. Using this clinically relevant allergen we have established significant peribronchial fibrosis and mucus overproduction. These remodeling events are accompanied by intense peribronchial inflammation, including lymphocytes and eosinophils. A cytokine that has been identified as having a prominent role in short-term allergic events, stem cell factor (SCF), appears to have a significant role in this late-stage process. Using our polyclonal antibody specific for SCF administered into the airways of mice during the final allergen challenges, we find a significant effect on the chronic peribronchial allergen-induced fibrotic remodeling. This was characterized by reduced inflammation, especially eosinophils, as well as reduced hydroxyproline levels in anti-SCF compared to control antibody-treated animals. In addition, when we examined chemokines associated with the chronic disease and neutralized SCF in vivo we observed a corresponding decrease in CCL6 and CCL17. Using an inhibitor, imatinib mesylate, that blocks SCF/c-kit-associated RTK, we find similar results as with anti-SCF for attenuating AHR and fibrotic changes, suggesting that a potential clinical treatment for chronic asthma already exists related to this pathway. These results further support the potential use of SCF/c-kit inhibition for targeting chronic severe asthmatic responses.
Berlin
Aaron A
AA
Department of Pathology, University of Michigan Medical School, 1301 Catherine St., Ann Arbor, 48109-0602, USA.
Hogaboam
Cory M
CM
Lukacs
Nicholas W
NW
D000281:Administration, Intranasal; D000485:Allergens / Q000276:immunology / Q000494:pharmacology*; D000818:Animals; D001249:Asthma / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000628:therapy; D001549:Benzamides; D001980:Bronchi / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D016535:Bronchial Hyperreactivity; D054414:Chemokine CCL17; D019742:Chemokines, CC / Q000032:analysis; D002908:Chronic Disease; D003058:Cockroaches; D004804:Eosinophils / Q000473:pathology; D005355:Fibrosis / Q000473:pathology; D006909:Hydroxyproline / Q000032:analysis; D000068877:Imatinib Mesylate; D008168:Lung / Q000737:chemistry / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D009500:Neutralization Tests; D010879:Piperazines / Q000627:therapeutic use; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011743:Pyrimidines / Q000627:therapeutic use; D019089:Stem Cell Factor / Q000037:antagonists & inhibitors*
D000485:Allergens; D001549:Benzamides; C499538:Ccl17 protein, mouse; D054414:Chemokine CCL17; D019742:Chemokines, CC; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D019089:Stem Cell Factor; C070959:Ccl6 protein, mouse; D000068877:Imatinib Mesylate; D006909:Hydroxyproline