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This Article Full Text Full Text (PDF) All Versions of this Article: jimmunol.0901177v1 183/7/4723    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Google Scholar Articles by Yadav, U. C. S. Articles by Srivastava, S. K. PubMed PubMed Citation Articles by Yadav, U. C. S. Articles by Srivastava, S. K.

Aldose Reductase Inhibition Suppresses the Expression of Th2 Cytokines and Airway Inflammation in Ovalbumin-Induced Asthma in Mice¹

Umesh C. S. Yadav^*, Amarjit S. Naura, Leopoldo Aguilera-Aguirre, Kota V. Ramana^*, Istvan Boldogh, Sanjiv Sur^,, Hamid A. Boulares and Satish K. Srivastava^2,*

Departments of ^* Biochemistry and Molecular Biology, and Microbiology and Immunology, Internal Medicine-Allergy, University of Texas Medical Branch, Galveston, TX 77555; and Department of Pharmacology and Experimental Therapeutics, Louisiana State University Health Sciences Center, New Orleans, LA 70112

Airway inflammation induced by reactive oxygen species-mediated activation of redox-sensitive transcription factors is the hallmark of asthma, a prevalent chronic respiratory disease. In various cellular and animal models, we have recently demonstrated that, in response to multiple stimuli, aldose reductase (AR) regulates the inflammatory signals mediated by NF-B. Because NF-B-mediated inflammation is a major characteristic of asthma pathogenesis, we have investigated the effect of AR inhibition on NF-B and various inflammatory markers in cellular and animal models of asthma using primary human small airway epithelial cells and OVA-sensitized/challenged C57BL/6 mice, respectively. We observed that pharmacological inhibition or genetic ablation of AR by small interfering RNA prevented TNF-- as well as LPS-induced apoptosis; reactive oxygen species generation; synthesis of inflammatory markers IL-6, IL-8, and PGE₂; and activation of NF-B and AP-1 in small airway epithelial cells. In OVA-challenged mice, we observed that administration of an AR inhibitor markedly reduced airway hyperresponsiveness, IgE levels, eisonophils infiltration, and release of Th2 type cytokines in the airway. Our results indicate that AR inhibitors may offer a novel therapeutic approach to treat inflammatory airway diseases such as asthma.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This study was supported by funds made available from American Asthma Foundation Grant (AAF 08-0219; to S.K.S.), National Institute of Environmental Health Sciences Core facility Grant (ES-006676), and National Institutes of Health Grant (HL072889; to H.A.B.).

² Address correspondence and reprint requests to Dr. Satish K. Srivastava, Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX 77555-0647. E-mail address: ssrivast{at}utmb.edu

³ Abbreviations used in this paper: ROS, reactive oxygen species; AR, aldose reductase; GS-HNE, glutathione-4-hydroxynonenal; SAEC, small airway epithelial cell; SABM, small airway epithelial basal medium; E2F2, E2F transcription factor-2; DHE, dihydroethidium; PI, propidium iodide; H₂DCF-DA, 5- (and –6)-carboxy-2',7'-dichlorodihydrofluorescin diacetate; SEAP, pNF-B-secretory alkaline phosphatase; BAL, brochoalveolar lavage; KC, keratinocyte-derived chemokine; iNOS, inducible nitric oxide synthase; siRNA, small interfering RNA.