全部 标题 作者
关键词 摘要

PLOS ONE  2009 

Inhibition of Aldose Reductase Prevents Experimental Allergic Airway Inflammation in Mice

DOI: 10.1371/journal.pone.0006535

Full-Text   Cite this paper   Add to My Lib

Abstract:

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

References

[1]  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.
[2]  Holgate ST (1999) The epidemic of allergy and asthma. Nature 402: B2–4.
[3]  Ciencewicki J, Trivedi S, Kleeberger SR (2008) Oxidants and the pathogenesis of lung diseases. J Allergy Clin Immunol 122: 456–468.
[4]  Hensley K, Robinson KA, Gabbita SP, Salsman S, Floyd RA (2000) Reactive oxygen species, cell signaling, and cell injury. Free Radic Biol Med 28: 1456–1462.
[5]  Dworski R (2000) Oxidant stress in asthma. Thorax 55: S51–S53.
[6]  Kay AB, Corrigan CJ (1992) Asthma. Eosinophils and neutrophils. Br Med Bull 48: 51–64.
[7]  Schünemann HJ, Muti P, Freudenheim JL, Armstrong D, Browne R, et al. (1997) Oxidative stress and lung function. Am J Epidemiol 146: 939–948.
[8]  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.
[9]  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.
[10]  Ramana KV, Fadl AA, Tammali R, Reddy AB, Chopra AK, et al. (2006) Aldose reductase mediates the lipopolysaccharide-induced release of inflammatory mediators in RAW264.7 murine macrophages. J Biol Chem 281: 33019–33029.
[11]  Srivastava SK, Ramana KV, Bhatnagar A (2005) Role of aldose reductase and oxidative damage in diabetes and the consequent potential for therapeutic options. Endocr Rev 26: 380–392.
[12]  Ramana KV, Chandra D, Srivastava S, Bhatnagar A, Aggarwal BB, et al. (2002) Aldose reductase mediates mitogenic signaling in vascular smooth muscle cells. J Biol Chem 277: 32063–32070.
[13]  Ramana KV, Bhatnagar A, Srivastava SK (2004) Aldose reductase regulates TNF-alpha-induced cell signaling and apoptosis in vascular endothelial cells. FEBS Lett 570: 189–194.
[14]  Ramana KV, Friedrich B, Bhatnagar A, Srivastava SK (2003) Aldose reductase mediates cytotoxic signals of hyperglycemia and TNF-alpha in human lens epithelial cells. FASEB J 17: 315–317.
[15]  Yadav UC, Ighani-Hosseinabad F, van Kuijk FJ, Srivastava SK, Ramana KV (2009) Prevention of posterior capsular opacification through aldose reductase inhibition. Invest Ophthalmol Vis Sci 50: 752–759.
[16]  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.
[17]  Yadav UC, Srivastava SK, Ramana KV (2007) Aldose reductase inhibition prevents endotoxin-induced uveitis in rats. Invest Ophthalmol Vis Sci 48: 4634–4642.
[18]  Hamada Y, Nakamura J (2004) Clinical potential of aldose reductase inhibitors in diabetic neuropathy. Treat Endocrinol 3: 245–255.
[19]  King TP (1976) Chemical and biological properties of some atopic allergens. Adv Immunol 23: 77–105.
[20]  Rafnar T, Griffith IJ, Kuo MC, Bond JF, et al. (1991) Cloning of Amb a I (antigen E), the major allergen family of short ragweed pollen. J Biol Chem 266: 1229–1236.
[21]  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.
[22]  Holgate ST (2007) Epithelium dysfunction in asthma. J Allergy Clin Immunol 120: 1233–1244.
[23]  Holgate ST (2008) The airway epithelium is central to the pathogenesis of asthma. Allergol Int 57: 1–10.
[24]  Puchelle E, Zahm JM, Tournier JM, Coraux C (2006) Airway epithelial repair, regeneration, and remodeling after injury in chronic obstructive pulmonary disease. Proc Am Thorac Soc 3: 726–733.
[25]  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.
[26]  Hauber HP, Zabel P (2008) Emerging mucus regulating drugs in inflammatory and allergic lung disease. Inflamm Allergy Drug Targets 7: 30–34.
[27]  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.
[28]  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.
[29]  Bacsi A, Choudhury BK, Dharajiya N, Sur S, Boldogh I (2006) Subpollen particles: carriers of allergenic proteins and oxidases. J Allergy Clin Immunol 118: 844–850.
[30]  Casillas AM, Hiura T, Li N, Nel AE (1999) Enhancement of allergic inflammation by diesel exhaust particles: permissive role of reactive oxygen species. Ann Allergy Asthma Immunol 83: 624–629.
[31]  Cho HY, Zhang LY, Kleeberger SR (2001) Ozone-induced lung inflammation and hyperreactivity are mediated via tumor necrosis factor-alpha receptors. Am J Physiol Lung Cell Mol Physiol 280: L537–546.
[32]  Ebtekar M (2006) Air pollution induced asthma and alterations in cytokine patterns. Iran J Allergy Asthma Immunol 5: 47–56.
[33]  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.
[34]  Kato A, Schleimer RP (2007) Beyond inflammation: airway epithelial cells are at the interface of innate and adaptive immunity. Curr Opin Immunol 19: 711–720.
[35]  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.
[36]  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.
[37]  Janssen-Heininger YM, Poynter ME, Baeuerle PA (2000) Recent advances towards understanding redox mechanisms in the activation of nuclear factor kappaB. Free Radic Biol Med 28: 1317–1327.
[38]  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.
[39]  Ramis I, Bioque G, Lorente J, Jares P, Quesada P, et al. (2000) Constitutive nuclear factor-kappaB activity in human upper airway tissues and nasal epithelial cells. Eur Respir J 15: 582–589.
[40]  Zhao Y, Usatyuk PV, Gorshkova IA, He D, Wang T, et al. (2009) Regulation of COX-2 expression and IL-6 release by particulate matter in airway epithelial cells. Am J Respir Cell Mol Biol 40: 19–30.
[41]  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.
[42]  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.
[43]  Yang L, Cohn L, Zhang DH, Homer R, Ray A, Ray P (1998) Essential role of nuclear factor kappaB in the induction of eosinophilia in allergic airway inflammation. J Exp Med 188: 1739–1750.
[44]  Liu T, Castro S, Brasier AR, Jamaluddin M, Garofalo RP, et al. (2004) Reactive oxygen species mediate virus-induced STAT activation: role of tyrosine phosphatases. J Biol Chem 279: 2461–2469.
[45]  Awasthi YC, Sharma R, Cheng JZ, Yang Y, Sharma A, et al. (2003) Role of 4-hydroxynonenal in stress-mediated apoptosis signaling. Mol Aspects Med 24: 219–230.
[46]  Awasthi YC, Sharma R, Sharma A, Yadav S, Singhal SS, et al. (2008) Self-regulatory role of 4-hydroxynonenal in signaling for stress-induced programmed cell death. Free Radic Biol Med 45: 111–118.
[47]  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.
[48]  Kirkham P, Rahman I (2006) Oxidative stress in asthma and COPD: antioxidants as a therapeutic strategy. Pharmacol Ther 111: 476–494.
[49]  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.
[50]  Schwartz J, Weiss ST (1994) Relationship between dietary vitamin C intake and pulmonary function in the First National Health and Nutrition Examination Survey (NHANES I). Am J Clin Nutr 59: 110–114.
[51]  Dekhuijzen PN (2004) Antioxidant properties of N-acetylcysteine: their relevance in relation to chronic obstructive pulmonary disease. Eur Respir J 23: 629–636.
[52]  De Benedetto F, Aceto A, Dragani B, Spacone A, Formisano S, et al. (2005) Long-term oral N-acetylcysteine reduces exhaled hydrogen peroxide in stable COPD. Pulm Pharmacol Ther 18: 41–47.
[53]  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.
[54]  Yamashita M, Onodera A, Nakayama T (2007) Immune mechanisms of allergic airway disease: regulation by transcription factors. Crit Rev Immunol 27: 539–546.
[55]  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.
[56]  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.
[57]  Yang G, Li L, Volk A, Emmell E, Petley T, et al. (2005) Therapeutic dosing with anti-interleukin-13 monoclonal antibody inhibits asthma progression in mice. J Pharmacol Exp Ther 313: 8–15.
[58]  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.
[59]  Hamid Q, Springall DR, Riveros-Moreno V, Chanez P, Howarth P, et al. (1993) Induction of nitric oxide synthase in asthma. Lancet 342: 1510–1513.
[60]  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.
[61]  Humbles AA, Lloyd CM, McMillan SJ, Friend DS, Xanthou G, et al. (2004) A critical role for eosinophils in allergic airways remodeling. Science 305: 1776–1779.
[62]  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.
[63]  Pladzyk A, Reddy AB, Yadav UC, Tammali R, Ramana KV, et al. (2006) Inhibition of aldose reductase prevents lipopolysaccharide-induced inflammatory response in human lens epithelial cells. Invest Ophthalmol Vis Sci 47: 5395–5403.
[64]  Chaturvedi MM, Mukhopadhyay A, Aggarwal BB (2000) Assay for redox-sensitive transcription factor. Methods Enzymol 319: 585–602.

Full-Text

comments powered by Disqus