Prevention of allergic rhinitis by aldose reductase inhibition in a murine model.
BACKGROUND
Allergic rhinitis, one of the most common atopic diseases, is known to be elicited by Th2 cytokine-mediated inflammatory response. We have shown earlier that a polyol pathway enzyme aldose reductase (AR) regulates airway inflammation; however its role in allergic rhinitis is not known. We have investigated the role of AR in mediating pathological symptoms associated with allergic rhinitis in mice.


METHODS
The wild-type (WT) mice treated without or with AR inhibitor and AR knock out (AR(-/-)) mice were sensitized by two intraperitoneal injections of ragweed pollen extract (RWE) with adjuvant alum on days 0 and 4 followed by challenge on day 11 and/or 18 and 25. The allergic rhinitis symptoms were assessed by monitoring the nasal scratch, mast cell degranulation and release of tryptase in nasal lavage, infiltration of inflammatory cells, production of inflammatory cytokines and nasal epithelium remodeling.


RESULTS
Sensitization and challenge of mice with RWE produced robust and reproducible pathological symptoms of allergic rhinitis as compared to control mice. AR inhibitor, fidarestat administered mice showed markedly reduced early phase response to allergen exposure such as nasal scratches, mast cells degranulation and release of tryptase in the nasal passage as well as late phase response such as inflammatory cell infiltration and release of Th2 type cytokines and nasal epithelial remodeling. Further, prevention of these events in AR(-/-)) mice suggests the role of AR in the mediation of allergic rhinitis.


CONCLUSIONS
These results indicate an important role of AR in the mediation of RWE-induced allergic rhinitis in mice and prevention by AR inhibitor, fidarestat offers a novel therapeutic approach to ameliorate allergic rhinitis.
Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX 77555-0647, USA.
Umesh C S
UC
Yadav
Rakesh
R
Mishra
Leopoldo
L
Aguilera-Aguirre
Sanjiv
S
Sur
Istvan
I
Bolodgh
Kota V
KV
Ramana
Satish K
SK
Srivatsava
D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000485:Allergens / Q000276:immunology; D031164:Ambrosia; D000818:Animals; D015550:Cell Degranulation / Q000187:drug effects; D002478:Cells, Cultured; D004195:Disease Models, Animal; D006801:Humans; D048289:Imidazolidines / Q000008:administration & dosage / Q000494:pharmacology; D008407:Mast Cells / Q000187:drug effects* / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009297:Nasal Mucosa / Q000187:drug effects* / Q000473:pathology; D011058:Pollen / Q000276:immunology; D006255:Rhinitis, Allergic, Seasonal / Q000201:enzymology / Q000517:prevention & control*; D053802:Tryptases / Q000378:metabolism
D000485:Allergens; D048289:Imidazolidines; C077139:fidarestat; D000449:Aldehyde Reductase; D053802:Tryptases