Search tips
Search criteria 


Logo of aairAllergy, Asthma & Immunology ResearchThis ArticleThis JournalAboutFor Contributorse-Submission
Allergy Asthma Immunol Res. 2010 July; 2(3): 183–187.
Published online 2010 April 29. doi:  10.4168/aair.2010.2.3.183
PMCID: PMC2892050

The Role of Oxidative Stress in the Pathogenesis of Asthma


Oxidative stress plays a critical role in the pathogenesis of asthma. To effectively control oxidative stress in asthmatics, it is important to investigate the precise intracellular mechanism by which the development of immunity, rather than immune tolerance and progression of airway inflammation, is induced. In this article, we suggest that protein tyrosine phosphatases, as intracellular negative regulators, and intracellular antioxidant enzymes such as peroxiredoxins can be regulated by oxidative stress during intracellular signaling.

Keywords: Oxidative stress, asthma, protein tyrosine phosphatases, antioxidants, immune tolerance, airway inflammation, allergy


Oxidative stress is believed to play a role in the development of human diseases such as cancer, cardiovascular disorders, and immunologic diseases. Asthma is a chronic inflammatory airway disease, and oxidative stress may be involved in its pathogenesis.1,2 Despite an inconclusive debate about whether the enhanced oxidative stress observed in asthma subjects is caused by inflammation or is a causative factor in the pathogenesis of the disease, many recent reports have supported the critical role of oxidative stress in the development of various chronic immunologic diseases. Reactive oxygen species (ROS) such as hydrogen peroxide (H2O2) transfer stimulating signals as a critical intracellular second messenger, resulting in the modulation of immune responses.3

In bronchial asthma, oxidative stress aggravates airway inflammation by inducing diverse proinflammatory mediators, enhancing bronchial hyperresponsiveness, stimulating bronchospasm, and increasing mucin secretion.4-8 Although many studies have discussed the pivotal role of enhanced oxidative stress in the development and maintenance of airway inflammation, the therapeutic effects of many antioxidant agents on allergic airway inflammation are moderate at best.4,5 These observations, however, do not necessarily imply a negligible role of oxidative stress in the pathogenesis of asthma. Rather, they reflect the need to investigate the proper antioxidants for each type of immunologic disease and the ideal situations for their use. Therefore, it is necessary to clarify the precise role of oxidative stress in the development of asthma.


Oxidative stress has traditionally been considered to be a toxic byproduct of aerobic metabolism and a factor involved in tissue damage. The results of many recent studies, however, have shown that compounds involved in oxidative stress, such as H2O2, act as key molecules in signal transduction.3 In fact, many types of cellular stimuli, including antigens, infections, various chemical mediators, and growth factors, induce a transient increase in intracellular ROS-in particular H2O2-mainly through activation of NADPH oxidase immediately after the exposure of the stimuli to cells.6 Furthermore, a broad field of antioxidant activity must be present within the cytosol to confine oxidative effects to the proximity of their origin and to maintain intracellular ROS levels within a narrow range.3 The physiologic intracellular concentration of H2O2 is 0.002-0.2 µM at steady state, reaching up to 0.5-0.7 µM when intracellular signaling is generated. What is interesting is that this physiologic concentration range appears to be consistent throughout forms of life as diverse as plants and mammals, which is unlikely to be a coincidence.3 Many functions of intracellular negative regulators, such as various types of phosphatases and the molecules involved in the ubiquitylation process, are inhibited after exposure to ROS.7

Taken together, these observations indicate that ROS are closely involved in the initiation and activation of intracellular signaling. In other words, intracellular ROS provide not only intracellular activating signals, which may have a detrimental effect on cells, but also essential surviving signals, which are critically involved in the appropriate functioning of the cells. Dynamic changes in intracellular levels of H2O2 from diverse microenvironments may lead to various intracellular signaling events. A recent concept involving cellular response to ROS involves a hierarchical oxidative stress response.2,8 In brief, under lower levels of oxidative stress, appropriate antioxidant defense systems begin to operate through the activation of Nrf2, which is a critical transcription factor that induces more than 200 intracellular antioxidant molecules. If a higher level of oxidative stress occurs, inflammatory cellular responses caused by the activation of AP-1 and NF-kB can be expected. This results in the secretion of various types of proinflammatory cytokines and chemokines. The highest level of oxidative stress causes serious cytotoxic effects, including apoptosis and necrosis. Thus, the maintenance of intracellular ROS in a proper range should be considered an important factor in the management of various inflammatory diseases.

In summary, it is speculated that levels of ROS must be maintained within appropriate ranges and times as opposed to simply removing oxidative stress to manage certain pathologic conditions.


Losing control of intracellular oxidants through inappropriate responses to environmental cellular stress may lead to degenerative diseases by inducing unscheduled death and cell cycle arrests, neoplasia (triggered by insensitivity to stress), and allergic or autoimmune disorders (caused by immune cell overstimulation and a break in immune tolerance).9-11 In the airway, losing control of oxidants may bring about initiation of Th2-dominant immunity instead of inducing immune tolerance in the initial phase of development of airway allergic inflammation. Some researchers have reported that increased ROS in antigen-presenting cells can derive immunity instead of a Th2 response.12-14 Furthermore, enhanced oxidative stress may contribute to the progression or perpetuation of existing airway inflammation through enhanced airway hyperresponsiveness, stimulation of mucin secretion, and induction of various proinflammatory chemical mediators,15-19 all of which are believed to be related to severe asthma.20-22

A large amount of epidemiological and clinical evidence exists to support the relationship between increased ROS and the pathogenesis of bronchial asthma. Higher levels of the molecules involved in enhanced oxidative stress were found in biological samples taken from asthmatic patients compared with normal control subjects.23-28 Higher incidences of bronchial asthma have been reported in areas with air pollution, which is a representative stimulus among exogenous oxidants.20,29,30 Reduced intake of foods containing antioxidants is also related to the increased incidence of asthma.4,5,31 Moreover, air pollution was suggested to cause more severe asthma and more frequent asthma attacks.30 Increased oxidative stress in asthmatic patients is also related to suppressed pulmonary function.

Despite these findings, it is still unclear whether increased oxidative stress in the asthmatic airway is simply a consequence of chronic airway inflammation or a principal contributor to the development of allergic inflammation. Recently, an elegant study concluded that increased oxidative stress plays a critical role in mounting an immune response in a murine model of asthma using a ragweed pollen extract.32 In the study, removal of ROS generated by intrinsic pollen NADPH oxidase prevented an immune response and airway inflammation, demonstrating that ROS provide an essential signal in the initiation and augmentation of antigen-induced allergic airway inflammation. We used the mouse model of asthma to analyze the kinetics of various aspects of allergic asthma.33 The results showed that increased oxidative stress in the airway precedes the development of allergic inflammation, airway hyperresponsiveness, and other pivotal features of asthma such as enhanced mucus secretion. Therefore, it is strongly suggested that an increased level of ROS acts as a critical contributor to the induction of allergic airway inflammation. Controlling intracellular oxidative stress with appropriate timing, as opposed to simply focusing on the reduction of oxidative stress, is important for effectively managing bronchial asthma.


Epidemiological studies have shown that the incidence of allergic asthma has surged in recent decades. Changes in the external environmental can reasonably explain this change. An increase in air pollution, an increased use of oxidant medication, and a decreased intake of antioxidants account for increased airway oxidative stress, which can cause immunity and airway inflammation.

Another explanation for the recent increase in the development of asthma may be associated with individual variations in the cellular machineries that handle intracellular antioxidants. A partial deficiency in the intracellular antioxidant defense system may critically affect oxidants when the level of increased oxidative stress goes beyond the capability of the system.34-37 Increased oxidative stress in the environment may contribute to allergic airway inflammation by inducing a break in immune tolerance in genetically predisposed individuals whose antioxidant systems are unable to handle the oxidative stress burden imposed on immune cells. The association between oxidative stress and the development of airway inflammation is depicted in Figure. It is assumed that a higher severity of asthma is also closely related to a lower ability to control oxidative stress in genetically predisposed patients.34

Results of properly controlled oxidative stress and consequences of inadequately controlled intracellular oxidative stress in the pathogenesis of asthma.

Therefore, intrinsic defects in certain intracellular molecules involved in the processes of intracellular oxidative stress signaling may be a plausible molecular mechanism explaining the crucial and direct role of oxidative stress in the pathogenesis of bronchial asthma, especially the chronic, severe asthma phenotype.


A variety of intracellular molecules are directly or indirectly involved in signal transduction in oxidative stress. These molecules, which include protein tyrosine phosphatases (PTPs), have cysteine residues, which are highly reactive to oxidative stress, at their active catalytic sites. In general, PTP enzymes behave as important negative regulators by inhibiting the function of protein tyrosine kinases. Oxidative stress leads to conformational changes in the PTPs, which then lose functionality. It is speculated that overactivation of protein tyrosine kinases would occur if the activities of PTPs were not properly controlled by inappropriately enhanced intracellular oxidative stress.3,7

SHP-1, a critical negative regulator in intracellular signaling, is expressed predominantly in hematopoietic and epithelial cells.38 SHP-1 had an inhibitory role in the development of allergic airway inflammation in a mouse model of asthma using heterozygous SHP-1-deficient mutant mice (mev/+).39 SHP-1-deficient homozygous mice (mev/mev) also developed spontaneous allergic lung inflammation without an identified allergen.40 We have also demonstrated that oxidative stress contributes to the development of lung inflammation in SHP-1-deficient mice through a break in immune tolerance to aeroallergens.39 In summary, because SHP-1 plays a role in regulating oxidative stress, increased intracellular oxidative stress with a lack of SHP-1 may lead to the development of allergic airway inflammation in the presence of Th2-prone cellular activation.

SHIP-1, another type of PTP, may also play a role in the development of Th2-dominant inflammation, as demonstrated in an experiment using genetically engineered mice.41 The precise role of SHIP-1 in increased oxidative stress, however, has not been clearly determined.42 It is assumed that other types of phosphatases may play roles in regulating intracellular oxidative stress and may also be involved in signaling processes. Therefore, further studies of other phosphatases are needed to clarify the precise role of PTPs in the pathogenesis of allergic airway inflammation in an environment of increased oxidative stress.


Myriad intracellular molecules play roles as antioxidants in increased oxidative stress. The intracellular concentration of glutathione is critically important in keeping the intracellular oxidant level within the proper range.43 Genetic polymorphisms of glutathione-S-transferase, which helps to maintain intracellular glutathione levels, are associated with the development of asthma.44-46 Nrf2 is an essential transcription factor that is able to induce many antioxidant enzymes and molecules when oxidative stress occurs in cells.8,47 Nrf2 knockout mice developed exaggerated allergic airway inflammation in a mouse model of asthma.47 A defect in peroxiredoxin 2 was also recently reported to be involved in the pathogenesis of asthma in the murine model of asthma using peroxiredoxin knockout mice.48

All of these results strongly support the idea that defects in the intracellular antioxidant defense system may be critical contributors to the development of asthma under increased oxidative stress. There is an urgent need to investigate the exact role of intracellular antioxidant molecules and to discover a way to regulate the molecules to achieve effective management of asthma.


Oxidative stress is increased in the asthmatic airway, and this increased oxidative stress may play a role in the pathogenesis of asthma. We have summarized studies supporting the viewpoint that oxidative stress can be a critical contributor to asthma development and can initiate various intracellular signaling pathways that lead to a break in immune tolerance and exaggerated allergic inflammation. Recent increases in the incidence of asthma may be attributed not only to increased oxidative stress in the environment but also to intrinsic functional variability in intracellular antioxidant molecules such as protein phosphatases, Nrf2, glutathione and peroxidase system. Controlling oxidative stress at the appropriate times and with the proper methods is critical for effectively managing asthma.


This study was supported by grants to H.B.M. (A040153) from Korea Health 21 R&D Project, Ministry of Health, Welfare and Family Affairs and to Y.S.C. (20090086092) from Ministry of Education, Science and Technology, Republic of Korea.


There are no financial or other issues that might lead to conflict of interest.


1. Sugiura H, Ichinose M. Oxidative and nitrative stress in bronchial asthma. Antioxid Redox Signal. 2008;10:785–797. [PubMed]
2. Riedl MA, Nel AE. Importance of oxidative stress in the pathogenesis and treatment of asthma. Curr Opin Allergy Clin Immunol. 2008;8:49–56. [PubMed]
3. Stone JR, Yang S. Hydrogen peroxide: a signaling messenger. Antioxid Redox Signal. 2006;8:243–270. [PubMed]
4. Omenaas E, Fluge O, Buist AS, Vollmer WM, Gulsvik A. Dietary vitamin C intake is inversely related to cough and wheeze in young smokers. Respir Med. 2003;97:134–142. [PubMed]
5. Grievink L, Smit HA, Ocke MC, van't Veer P, Kromhout D. Dietary intake of antioxidant (pro)-vitamins, respiratory symptoms and pulmonary function: the MORGEN study. Thorax. 1998;53:166–171. [PMC free article] [PubMed]
6. Brown DI, Griendling KK. Nox proteins in signal transduction. Free Radic Biol Med. 2009;47:1239–1253. [PMC free article] [PubMed]
7. Terada LS. Specificity in reactive oxidant signaling: think globally, act locally. J Cell Biol. 2006;174:615–623. [PMC free article] [PubMed]
8. Li N, Nel AE. Role of the Nrf2-mediated signaling pathway as a negative regulator of inflammation: implications for the impact of particulate pollutants on asthma. Antioxid Redox Signal. 2006;8:88–98. [PubMed]
9. Chaudhri G, Clark IA, Hunt NH, Cowden WB, Ceredig R. Effect of antioxidants on primary alloantigen-induced T cell activation and proliferation. J Immunol. 1986;137:2646–2652. [PubMed]
10. Matsue H, Edelbaum D, Shalhevet D, Mizumoto N, Yang C, Mummert ME, Oeda J, Masayasu H, Takashima A. Generation and function of reactive oxygen species in dendritic cells during antigen presentation. J Immunol. 2003;171:3010–3018. [PubMed]
11. Williams MS, Kwon J. T cell receptor stimulation, reactive oxygen species, and cell signaling. Free Radic Biol Med. 2004;37:1144–1151. [PubMed]
12. Peterson JD, Herzenberg LA, Vasquez K, Waltenbaugh C. Glutathione levels in antigen-presenting cells modulate Th1 versus Th2 response patterns. Proc Natl Acad Sci U S A. 1998;95:3071–3076. [PubMed]
13. Kim HJ, Barajas B, Chan RC, Nel AE. Glutathione depletion inhibits dendritic cell maturation and delayed-type hypersensitivity: implications for systemic disease and immunosenescence. J Allergy Clin Immunol. 2007;119:1225–1233. [PubMed]
14. Murata Y, Shimamura T, Hamuro J. The polarization of T(h)1/T(h)2 balance is dependent on the intracellular thiol redox status of macrophages due to the distinctive cytokine production. Int Immunol. 2002;14:201–212. [PubMed]
15. Rahman I. Oxidative stress, chromatin remodeling and gene transcription in inflammation and chronic lung diseases. J Biochem Mol Biol. 2003;36:95–109. [PubMed]
16. Henderson WR, Chi EY, Teo JL, Nguyen C, Kahn M. A small molecule inhibitor of redox-regulated NF-kappa B and activator protein-1 transcription blocks allergic airway inflammation in a mouse asthma model. J Immunol. 2002;169:5294–5299. [PubMed]
17. Rahman I, Yang SR, Biswas SK. Current concepts of redox signaling in the lungs. Antioxid Redox Signal. 2006;8:681–689. [PubMed]
18. Barnes PJ. Reactive oxygen species and airway inflammation. Free Radic Biol Med. 1990;9:235–243. [PubMed]
19. Bowler RP, Crapo JD. Oxidative stress in airways: is there a role for extracellular superoxide dismutase? Am J Respir Crit Care Med. 2002;166:S38–S43. [PubMed]
20. Comhair SA, Ricci KS, Arroliga M, Lara AR, Dweik RA, Song W, Hazen SL, Bleecker ER, Busse WW, Chung KF, Gaston B, Hastie A, Hew M, Jarjour N, Moore W, Peters S, Teague WG, Wenzel SE, Erzurum SC. Correlation of systemic superoxide dismutase deficiency to airflow obstruction in asthma. Am J Respir Crit Care Med. 2005;172:306–313. [PMC free article] [PubMed]
21. Fitzpatrick AM, Teague WG, Holguin F, Yeh M, Brown LAS. Airway glutathione homeostasis is altered in children with severe asthma: Evidence for oxidant stress. J Allergy Clin Immunol. 2009;123:146–152. [PMC free article] [PubMed]
22. Fitzpatrick AM, Brown LAS, Holguin F, Teague WG. Levels of nitric oxide oxidation products are increased in the epithelial lining fluid of children with persistent asthma. J Allergy Clin Immunol. 2009;124:990–996. [PMC free article] [PubMed]
23. Loukides S, Bouros D, Papatheodorou G, Panagou P, Siafakas NM. The relationships among hydrogen peroxide in expired breath condensate, airway inflammation, and asthma severity. Chest. 2002;121:338–346. [PubMed]
24. Montuschi P, Corradi M, Ciabattoni G, Nightingale J, Kharitonov SA, Barnes PJ. Increased 8-isoprostane, a marker of oxidative stress, in exhaled condensate of asthma patients. Am J Respir Crit Care Med. 1999;160:216–220. [PubMed]
25. Kharitonov SA, Barnes PJ. Exhaled markers of pulmonary disease. Am J Respir Crit Care Med. 2001;163:1693–1722. [PubMed]
26. Nadeem A, Raj HG, Chhabra SK. Increased oxidative stress in acute exacerbations of asthma. J Asthma. 2005;42:45–50. [PubMed]
27. Suzuki S, Matsukura S, Takeuchi H, Kawaguchi M, Ieki K, Odaka M, Watanabe S, Homma T, Dohi K, Aruga T, Sato M, Kurokawa M, Kokubu F, Adachi M. Increase in reactive oxygen metabolite level in acute exacerbations of asthma. Int Arch Allergy Immunol. 2008;146(Suppl 1):67–72. [PubMed]
28. Kongerud J, Crissman K, Hatch G, Alexis N. Ascorbic acid is decreased in induced sputum of mild asthmatics. Inhal Toxicol. 2003;15:101–109. [PubMed]
29. Battaglia S, den Hertog H, Timmers MC, Lazeroms SP, Vignola AM, Rabe KF, Bellia V, Hiemstra PS, Sterk PJ. Small airways function and molecular markers in exhaled air in mild asthma. Thorax. 2005;60:639–644. [PMC free article] [PubMed]
30. Ercan H, Birben E, Dizdar EA, Keskin O, Karaaslan C, Soyer OU, Dut R, Sackesen C, Besler T, Kalayci O. Oxidative stress and genetic and epidemiologic determinants of oxidant injury in childhood asthma. J Allergy Clin Immunol. 2006;118:1097–1104. [PubMed]
31. Fogarty A, Lewis S, Weiss S, Britton J. Dietary vitamin E, IgE concentrations, and atopy. Lancet. 2000;356:1573–1574. [PubMed]
32. Boldogh I, Bacsi A, Choudhury BK, Dharajiya N, Alam R, Hazra TK, Mitra S, Goldblum RM, Sur S. ROS generated by pollen NADPH oxidase provide a signal that augments antigen-induced allergic airway inflammation. J Clin Invest. 2005;115:2169–2179. [PMC free article] [PubMed]
33. Park CS, Kim TB, Lee KY, Moon KA, Bae YJ, Jang MK, Cho YS, Moon HB. Increased oxidative stress in the airway and development of allergic inflammation in a mouse model of asthma. Ann Allergy Asthma Immunol. 2009;103:238–247. [PubMed]
34. Yang IA, Fong KM, Zimmerman PV, Holgate ST, Holloway JW. Genetic susceptibility to the respiratory effects of air pollution. Thorax. 2008;63:555–563. [PubMed]
35. Romieu I, Sienra-Monge JJ, Ramirez-Aguilar M, Moreno-Macias H, Reyes-Ruiz NI, Estela del Rio-Navarro B, Hernandez-Avila M, London SJ. Genetic polymorphism of GSTM1 and antioxidant supplementation influence lung function in relation to ozone exposure in asthmatic children in Mexico City. Thorax. 2004;59:8–10. [PMC free article] [PubMed]
36. Li YF, Gauderman WJ, Avol E, Dubeau L, Gilliland FD. Associations of tumor necrosis factor G-308A with childhood asthma and wheezing. Am J Respir Crit Care Med. 2006;173:970–976. [PMC free article] [PubMed]
37. Tamer L, Calikoğlu M, Ates NA, Yildirim H, Ercan B, Saritas E, Unlü A, Atik U. Glutathione-S-transferase gene polymorphisms (GSTT1, GSTM1, GSTP1) as increased risk factors for asthma. Respirology. 2004;9:493–498. [PubMed]
38. Chong ZZ, Maiese K. The Src homology 2 domain tyrosine phosphatases SHP-1 and SHP-2: diversified control of cell growth, inflammation, and injury. Histol Histopathol. 2007;22:1251–1267. [PMC free article] [PubMed]
39. Cho YS, Oh SY, Zhu Z. Tyrosine phosphatase SHP-1 in oxidative stress and development of allergic airway inflammation. Am J Respir Cell Mol Biol. 2008;39:412–419. [PMC free article] [PubMed]
40. Oh SY, Zheng T, Kim YK, Cohn L, Homer RJ, McKenzie AN, Zhu Z. A critical role of SHP-1 in regulation of type 2 inflammation in the lung. Am J Respir Cell Mol Biol. 2009;40:568–574. [PMC free article] [PubMed]
41. Oh SY, Zheng T, Bailey ML, Barber DL, Schroeder JT, Kim YK, Zhu Z. Src homology 2 domain-containing inositol 5-phosphatase 1 deficiency leads to a spontaneous allergic inflammation in the murine lung. J Allergy Clin Immunol. 2007;119:123–131. [PubMed]
42. Rivera J, Olivera A. Src family kinases and lipid mediators in control of allergic inflammation. Immunol Rev. 2007;217:255–268. [PubMed]
43. Rahman I, MacNee W. Oxidative stress and regulation of glutathione in lung inflammation. Eur Respir J. 2000;16:534–554. [PubMed]
44. Saadat M, Ansari-Lari M. Genetic polymorphism of glutathione S-transferase T1, M1 and asthma, a meta-analysis of the literature. Pak J Biol Sci. 2007;10:4183–4189. [PubMed]
45. Vavilin VA, Chasovnikova OB, Liakhovich VV, Gavalov SM, Riabova OA. [Genetic polymorphism in glutathione S-transferase M1 and T1 in children with bronchial asthma] Vopr Med Khim. 2000;46:388–397. Russian. [PubMed]
46. Lee YL, Hsiue TR, Lee YC, Lin YC, Guo YL. The association between glutathione S-transferase P1, M1 polymorphisms and asthma in Taiwanese schoolchildren. Chest. 2005;128:1156–1162. [PubMed]
47. Li N, Alam J, Venkatesan MI, Eiguren-Fernandez A, Schmitz D, Di Stefano E, Slaughter N, Killeen E, Wang X, Huang A, Wang M, Miguel AH, Cho A, Sioutas C, Nel AE. Nrf2 is a key transcription factor that regulates antioxidant defense in macrophages and epithelial cells: protecting against the proinflammatory and oxidizing effects of diesel exhaust chemicals. J Immunol. 2004;173:3467–3481. [PubMed]
48. Moon EY, Kang JS, Han SH, Yang KH, Pyo S, Lee MY, Lee HK, Yu DY. Differential role of peroxiredoxin II (PrxII) on the expression of toll-like receptor 4 (TLR4) and B-cell activating factor (BAFF) in ovalbumin (OVA)-induced mouse asthma. Int Immunopharmacol. 2008;8:935–944. [PubMed]

Articles from Allergy, Asthma & Immunology Research are provided here courtesy of Korean Academy of Asthma, Allergy and Clinical Immunology and Korean Academy of Pediatric Allergy and Respiratory Disease