Background The bronchial asthma, a clinical complication of persistent inflammation of the airway and subsequent airway hyper-responsiveness, is a leading cause of morbidity and mortality in critically ill patients. Several studies have shown that oxidative stress plays a key role in initiation as well as amplification of inflammation in airways. However, still there are no good anti-oxidant strategies available for therapeutic intervention in asthma pathogenesis. Most recent studies suggest that polyol pathway enzyme, aldose reductase (AR), contributes to the pathogenesis of oxidative stress–induced inflammation by affecting the NF-κB-dependent expression of cytokines and chemokines and therefore inhibitors of AR could be anti-inflammatory. Since inhibitors of AR have already gone through phase-III clinical studies for diabetic complications and found to be safe, our hypothesis is that AR inhibitors could be novel therapeutic drugs for the prevention and treatment of asthma. Hence, we investigated the efficacy of AR inhibition in the prevention of allergic responses to a common natural airborne allergen, ragweed pollen that leads to airway inflammation and hyper-responsiveness in a murine model of asthma. Methods and Findings Primary Human Small Airway Epithelial Cells (SAEC) were used to investigate the in vitro effects of AR inhibition on ragweed pollen extract (RWE)-induced cytotoxic and inflammatory signals. Our results indicate that inhibition of AR prevents RWE -induced apoptotic cell death as measured by annexin-v staining, increase in the activation of NF-κB and expression of inflammatory markers such as inducible nitric oxide synthase (iNOS), cycloxygenase (COX)-2, Prostaglandin (PG) E2, IL-6 and IL-8. Further, BALB/c mice were sensitized with endotoxin-free RWE in the absence and presence of AR inhibitor and followed by evaluation of perivascular and peribronchial inflammation, mucin production, eosinophils infiltration and airway hyperresponsiveness. Our results indicate that inhibition of AR prevents airway inflammation and production of inflammatory cytokines, accumulation of eosinophils in airways and sub-epithelial regions, mucin production in the bronchoalveolar lavage fluid and airway hyperresponsiveness in mice. Conclusions These results suggest that airway inflammation due to allergic response to RWE, which subsequently activates oxidative stress-induced expression of inflammatory cytokines via NF-κB-dependent mechanism, could be prevented by AR inhibitors. Therefore, inhibition of AR could have clinical implications, especially for
Pearce N, Aοt-Khaled N, Beasley R, Mallol J, Keil U, et al. (2007) Worldwide trends in the prevalence of asthma symptoms: Phase III of the International Study of Asthma and Allergies in Childhood (ISAAC). Thorax 62: 758–766.
Wang CC, Lin WN, Lee CW, Lin CC, Luo SF, et al. (2005) Involvement of p42/p44 MAPK, p38 MAPK, JNK, and NF-kappaB in IL-1beta-induced VCAM-1 expression in human tracheal smooth muscle cells. Am J Physiol Lung Cell Mol Physiol 288: L227–237.
Ramana KV, Friedrich B, Srivastava S, Bhatnagar A, Srivastava SK (2004) Activation of nuclear factor-kappaB by hyperglycemia in vascular smooth muscle cells is regulated by aldose reductase. Diabetes 53: 2910–2920.
Tammali R, Ramana KV, Singhal SS, Awasthi S, Srivastava SK (2006) Aldose reductase regulates growth factor-induced cyclooxygenase-2 expression and prostaglandin e2 production in human colon cancer cells. Cancer Res 66: 9705–9713.
Bacsi A, Dharajiya N, Choudhury BK, Sur S, Boldogh I (2005) Effect of pollen-mediated oxidative stress on immediate hypersensitivity reactions and late-phase inflammation in allergic conjunctivitis. J Allergy Clin Immunol 116: 836–843.
Boldogh I, Bacsi A, Choudhury BK, Dharajiya N, et al. (2005) ROS generated by pollen NADPH oxidase provide a signal that augments antigen-induced allergic airway inflammation. J Clin Invest 115: 2169–2179.
Lordan JL, Bucchieri F, Richter A, Konstantinidis A, Holloway JW, et al. (2002) Cooperative effects of Th2 cytokines and allergen on normal and asthmatic bronchial epithelial cells. J Immunol 169: 407–414.
Robinson D, Hamid Q, Bentley A, Ying S, Kay AB, et al. (1993) Activation of CD4+ T cells, increased TH2-type cytokine mRNA expression, and eosinophil recruitment in bronchoalveolar lavage after allergen inhalation challenge in patients with atopic asthma. J Allergy Clin Immunol 92: 313–324.
Kierstein S, Krytska K, Sharma S, Amrani Y, Salmon M, et al. (2008) Ozone inhalation induces exacerbation of eosinophilic airway inflammation and hyperresponsiveness in allergen-sensitized mice. Allergy 63: 438–446.
Rahman I, Mulier B, Gilmour PS, Watchorn T, Donaldson K, et al. (2001) Oxidant-mediated lung epithelial cell tolerance: the role of intracellular glutathione and nuclear factor-kappaB. Biochem Pharmacol 62: 787–794.
Pourazar J, Mudway IS, Samet JM, Helleday R, Blomberg A, et al. (2005) Diesel exhaust activates redox-sensitive transcription factors and kinases in human airways. Am J Physiol Lung Cell Mol Physiol 289: L724–730.
Profita M, Sala A, Bonanno A, Riccobono L, Siena L, Melis MR, et al. (2003) Increased prostaglandin E2 concentrations and cyclooxygenase-2 expression in asthmatic subjects with sputum eosinophilia. J Allergy Clin Immunol 112: 709–716.
Gonzalo JA, Lloyd CM, Kremer L, Finger E, Martinez-A C, et al. (1996) Eosinophil recruitment to the lung in a murine model of allergic inflammation. The role of T cells, chemokines, and adhesion receptors. J Clin Invest 98: 2332–2345.
Pantano C, Ather JL, Alcorn JF, Poynter ME, Brown AL, et al. (2008) Nuclear factor-kappaB activation in airway epithelium induces inflammation and hyperresponsiveness. Am J Respir Crit Care Med 177: 959–969.
Ramana KV, Bhatnagar A, Srivastava S, Yadav UC, et al. (2006) Mitogenic responses of vascular smooth muscle cells to lipid peroxidationderived aldehyde 4-hydroxy-trans-2-nonenal (HNE): role of aldose reductase-catalyzed reduction of the HNE-glutathione conjugates in regulating cell growth. J Biol Chem 281: 17652–17660.
Dharajiya N, Choudhury BK, Bacsi A, Boldogh I, et al. (2007) Inhibiting pollen reduced nicotinamide adenine dinucleotide phosphate oxidase-induced signal by intrapulmonary administration of antioxidants blocks allergic airway inflammation. J Allergy Clin Immunol 119: 646–653.
Sadowska AM, van Overveld FJ, Górecka D, Zdral A, et al. (2005) The interrelationship between markers of inflammation and oxidative stress in chronic obstructive pulmonary disease: modulation by inhaled steroids and antioxidant. Respir Med 99: 241–249.
Shardonofsky FR, Venzor J 3rd, Barrios R, Leong KP, Huston DP (1999) Therapeutic efficacy of an anti-IL-5 monoclonal antibody delivered into the respiratory tract in a murine model of asthma. J Allergy Clin Immunol 104: 215–221.
Leckie MJ, ten Brinke A, Khan J, Diamant Z, O'Connor BJ, et al. (2000) Effects of an interleukin-5 blocking monoclonal antibody on eosinophils, airway hyper-responsiveness, and the late asthmatic response. Lancet 356: 2144–2148.
Cheng G, Arima M, Honda K, Hirata H, Eda F, et al. (2002) Anti-interleukin-9 antibody treatment inhibits airway inflammation and hyperreactivity in mouse asthma model. Am J Respir Crit Care Med 166: 409–416.
Redington AE, Meng QH, Springall DR, Evans TJ, Créminon C, et al. (2001) Increased expression of inducible nitric oxide synthase and cyclo-oxygenase-2 in the airway epithelium of asthmatic subjects and regulation by corticosteroid treatment. Thorax 56: 351–357.
Rogers CA, Wayne PM, Macklin EA, Muilenberg ML, et al. (2006) Interaction of the onset of spring and elevated atmospheric CO2 on ragweed (Ambrosia artemisiifolia L.) pollen production. Environ Health Perspect 114: 865–869.