hydrogen sulfide and asthma

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Exp Physiol 96.9 pp 847–852 847

Symposium ReportSymposium Report

Hydrogen sulfide and asthma

Peipei Wang1, Gensheng Zhang1, Taddese Wondimu1,2, Brian Ross2 and Rui Wang1

1Department of Biology and 2Northern Ontario School of Medicine, Lakehead University, Thunder Bay, Ontario, Canada P7B 5E1

Asthma is a chronic inflammatory disease, with hyper-responsive bronchoconstrictionand airway remodelling, leading to extensive airway narrowing. The regulation of airwayresponsiveness and inflammation by endogenous hydrogen sulfide (H2S) during the pathogenicdevelopment of asthma has been suggested. Hydrogen sulfide can be produced in the lung andairway tissues via the actions of two H2S-generating enzymes, cystathionine β-synthase (CBS)and/or cystathionine γ-lyase (CSE). The abnormal metabolism and function of H2S have beenreported in experimental animals with asthma, especially ovalbumin-induced rat or mousemodels. In patients with asthma, serum H2S levels are significantly reduced. Supplementationwith exogenous H2S has been shown to mitigate the severity of asthma in experimental animals.It is hypothesized that decreased H2S production in the lung and airway tissues may be used asan early detection biomarker, and H2S-based therapy would represent a new treatment strategyfor asthma. Major challenges for establishing the diagnostic and treatment values of H2S includethe differential expression of CSE and CBS along the airway and their changes during asthma,the effects of H2S on bronchoconstriction and airway remodelling, as well as the underlyingmechanisms, and the detection of the changes in H2S levels in airway tissues and in exhaled air.

(Received 3 May 2011; accepted after revision 8 June 2011; first published online 10 June 2011)Corresponding author R. Wang: Lakehead University, 955 Oliver Road, Office of VP Research, Lakehead University,Thunder Bay, Ontario, Canada P7B 5E1. Email: [email protected]

According to Global Initiative for Asthma (GINA; 2010),asthma affects approximately 300 million people, with ahigh mortality rate of 250,000 per year worldwide. Assuch, asthma represents a major global health, economicand societal challenge. The pathogenic mechanisms ofasthma, however, are still not fully understood. Hydrogensulfide (H2S) had traditionally been known as a noxiousand toxic gas. In recent years, however, the physiologicalimportance of H2S as the third gasotransmitter, alongwith NO and CO, has gained recognition (Wang, 2002).Hydrogen sulfide is involved in different physiologicaland pathophysiological processes, including hypertension,neurodegenerative diseases, inflammation and metabolicsyndrome, to name a few. The impact of H2S metabolismon lung function and the development of asthma hasattracted significant scientific attention recently. It ishypothesized that endogenous H2S, produced in theairway and the lung, is involved in the bronchoconstrictionand airway inflammation in asthma.

Hydrogen sulfide metabolism in the lungin physiological conditions

Endogenous H2S is produced in many tissues primarilyby two H2S-generating enzymes, cystathionine β-synthase (CBS) and cystathionine γ-lyase (CSE). Workingtogether with cysteine aminotransferase (CAT), 3-mercaptopyruvate sulfur transferase (MST) may alsoproduce H2S in selective tissues (Nagahara et al. 1998).Abundant expression levels of CSE and MST have beenfound in sea lion resistance pulmonary arteries and bovinepulmonary arterial smooth muscle cells (SMCs; Olsonet al. 2010). Both human airway SMCs and humanlung primary fibroblast MRC-5 cells express CSE andCBS proteins (Baskar et al. 2007; Perry et al. 2011). Inrat lungs, CSE is expressed in peripheral lung tissuesof airway and pulmonary vessels (Chen et al. 2009a).In mouse lungs, we recently found that both CSE andCBS are mainly expressed in pulmonary blood vesselSMCs and endothelial cells and in airway SMCs (Fig. 1).

C© 2011 The Authors. Journal compilation C© 2011 The Physiological Society DOI: 10.1113/expphysiol.2011.057448

848 P. Wang and others Exp Physiol 96.9 pp 847–852

It appears that the expression patterns and extents of H2S-producing enzymes in the lung and airway tissues arevariable depending on the species and cell types.

Altered H2S metabolism and the pathogenesisof asthma

Asthma is a chronic inflammatory disorder of the airways,involving pathological changes of different types of cellsand molecules. During asthma, the activated mast cells,increased eosinophils, T-helper 2 (Th2) lymphocytes andneutrophils and the cells composing the airway walland pulmonary blood vessel walls release inflammatoryfactors to cause classic pathological changes such assubepithelial fibrosis, airway remodelling and airwayhyper-responsiveness to allergens. Inhaled corticosteroidsand long-acting β2-adrenoceptor agonists are now themainstay of asthma treatment. These agents suppressairway inflammation and decrease bronchoconstriction,but they cannot cure asthma. In addition, approximately5% of asthma patients are corticosteroid resistant (Barnes,2006). The search is ongoing to develop novel orimproved therapies for asthma, which include anti-IgE therapy, cytokine inhibitors, chemokine antagonists,phosphodiesterase 4 inhibitors and adhesion moleculeblockers (Barnes, 2006); however, many of theseexperimental treatments are limited in their therapeuticcapabilities (Barnes, 2006, 2010). For example, inhibitionof interleukin-5 with mepolizumab results in the depletionof eosinophils from the circulation and sputum of patientswith modest asthma, but has no effect on airway hyper-responsiveness and other symptoms or altered lungfunction in asthma (Flood-Page et al. 2007). For severelyasthmatic patients who have >3% eosinophils in theirsputum, in contrast, mepolizumab is much more effectivein dealing with asthma symptoms (Haldar et al. 2009;Nair et al. 2009). Novel therapeutic agents with refined

molecular and cellular targets for different types of asthmawith different severities are needed.

One of the most frequently used animal asthma modelsuses ovalbumin challenges. The animals are sensitizedby ovalbumin with an adjuvant, typically aluminumhydroxide, and then challenged with ovalbumin againby nebulization or intranasal administration. Ovalbuminchallenge induces antigen-specific Th2 cell responses.Activated Th2 cells produce Th2-associated cytokines,such as interleukin-4, interleukin-5 or interleukin-13.The ovalbumin model replicates the features of humanallergic asthma, including airway hyperesponsiveness,airway inflammation and airway remodelling. It shouldbe noted, however, that asthma is heterogeneous in originand that distinct phenotypes and different pathogenicmechanisms are probably involved. Some types of asthmaare dependent on Th2 cell activation, for example, whileothers not (Kim et al. 2010).

Wu et al. (2008) noted that the serum level ofH2S decreased from 75.2 ± 13.0 μM in healthy subjectsto 55.8 ± 13.6 μM in patients with stable asthma and31.3 ± 2.9 μM in patients with severe acute exacerbationof asthma. Serum H2S levels correlated positively withforced expiratory volume (FEV1.0) and negatively withthe count of sputum cells and the percentage of sputumneutrophils in patients with acute asthma. Whether thedrop of H2S level in asthma patient serum is the causeor the consequence of asthma development has not beenaddressed. It is also not clear in these patients whetherthe lung production of H2S was altered. In any rate, thisclinical study was mirrored by a later animal study. Chenet al. (2009a) found that serum H2S level in ovalbumin-treated asthma rats decreased by 81% and H2S productionfrom the lungs in these rats decreased by 80%. TheCSE expression level and CSE activity were decreasedsignificantly in lung tissues from ovalbumin-treated mice,which may explain the decreased endogenous levels ofH2S in lung tissues and serum in these animals. Chen et

Figure 1. Distribution of cystathionine γ-lyase (CSE) and cystathionine β-synthase (CBS) in the lungtissues of miceImmunohistochemical staining showed that the expressions of CSE (A) and CBS (B) were mainly located in airwaysmooth muscle cells (blue arrow), vascular smooth muscle cells (red arrow) and vascular endothelial cells (greenarrow).

C© 2011 The Authors. Journal compilation C© 2011 The Physiological Society

Exp Physiol 96.9 pp 847–852 Hydrogen sulfide and asthma 849

al. (2009a) also found that the peak expiratory flow was55.4% lower in ovalbumin-treated rats than that of controlrats, and the proportions of eosinophils, lymphocytesand neutrophils in bronchoalveolar lavage fluid weresignificantly increased. Administration of exogenous H2S(NaHS) improved peak expiratory flow and alleviatedairway inflammation and airway remodelling in this ratmodel.

Mitochondrial dysfunction and oxidative stress areassociated with the development and progression ofasthma (Reddy, 2011). Activated inflammatory cellsgenerate more reactive oxygen species. In contrast,antioxidants decreased mitochondrial dysfunction andoxidative stress in asthmatic mice (Mabalirajan et al.2009). Antioxidants have been used to prevent andtreat mitochondrial abnormality in asthma patients(Gvozdjakova et al. 2005). Macromolecule antioxidants,such as vitamins E and C, cannot enter mitochondriato scavenge reactive oxygen species. In contrast, thegasotransmitter H2S can freely cross the plasma memb-rane and the mitochondrial membrane. Once insidemitochondria, H2S acts as a reducing agent, which canhelp to decrease oxidative stress and enhance endogenousantioxidant defenses, leading to the preservation ofboth mitochondrial structure and function (Elrodet al. 2007). Hu et al. (2009) reported that H2Sprevented rotenone-induced mitochondrial membranedepolarization, cytochrome c release and a decreasein Bcl-2:Bax ratio in a human-derived dopaminergicneuroblastoma cell line. These protective effects ofH2S may be mediated by mitochondrial ATP-sensitivepotassium (KATP) channels. To date, whether H2S canattenuate airway inflammation and hyper-responsivenessin asthma by affecting the mitochondrial/oxidative stresspathway is not clear.

Hydrogen sulfide and airway smooth muscle cells

Hydrogen sulfide induces smooth muscle relaxation viaits actions on two different types of ion channels. One isthe KATP channel located on vascular SMCs and the otheris the small to medium conductance KCa channel locatedon vascular endothelial cells. The opening of these twochannels by H2S leads to membrane hyperpolarizationand smooth muscle relaxation. Therefore, H2S can becharacterized as an endothelium-derived relaxing factor(Wang, 2011). Although the physiological function ofH2S in the cardiovascular system is relatively clear, littleis known about its effects on the respiratory system.Perry et al. (2011) investigated the regulatory role of H2Son the proliferation of human airway SMCs. Hydrogensulfide donors, either the fast-releasing ‘donor’, NaSH, orthe slow-releasing ‘donor’, GYY4137, suppressed airwaySMC proliferation and interleukin-8 release due to theinhibited phosphorylation of ERK-1/2 and extracellular

regulated kinase1/2 p38 mitogen-activated protein kinase.These effects of H2S donors were not altered by theinhibitor of CSE, or by the manipulation of KATP channelopening or NO levels. In other studies, administration ofNaHS or the CSE blocker, D,L-propargylglycine, alleviatedor aggravated, respectively, airway hyper-responsivenessin both the cigarette smoke exposure model and theovalbumin-induced asthma model in rats (Chen et al.2009a, 2011). Isolated rat tracheal rings, which wereprecontracted with acetylcholine or potassium chloride,were relaxed by NaHS in a concentration-dependentmanner; however, this NaHS-induced relaxation was notblocked by inhibitors of the KATP channel or NOS,or by denudation of epithelium (Chen et al. 2011). Areduction in intracellular calcium level induced by H2S,due to reduced calcium influx, has been shown in airwaysmooth muscle cells, which may underlie the H2S-inducedrelaxation of airway smooth muscle (Ryu et al. 2009).

Airway SMCs contribute not only to airway narrowingin asthma, but also to bronchial inflammation throughthe secretion of inflammatory factors and recruitment andactivation of inflammatory cells (Bara et al. 2010). Giventhe high expression levels of H2S-generating enzymesin airway SMCs and the demonstrated muscle-relaxingeffect of H2S, it is rationalized that reduced endogenousH2S levels due to the downregulation of H2S-producingenzymes may constitute a pathogenic factor in thepathogenesis of asthma.

Hydrogen sulfide as a biomarker of asthma

Detecting the presence or changes of asthma biomarkersin the nasal air is an attractive approach for earlydetection of asthma symptoms, monitoring treatmentprogress of asthma and evaluating asthma prognosis. Anideal biomarker of clinical relevance should have highsensitivity and specificity for intervention effects,reliability and repeatability, and simplicity of samplingmethodology and detection techniques (Lesko &Atkinson, 2001). Biomarkers in the nasal air canbe detected non-invasively and repeatedly. A largenumber of inflammatory factors, including adenosine,ammonia, hydrogen peroxide, isoprostanes, leukotrienes,prostanoids, NO, peptides and cytokines, have beenstudied in exhaled breath condensate, and some of themcorrelate with eosinophilic airway inflammation and thetreatment schedule of corticosteroid therapy (Kharitonov& Barnes, 2006). However, these biomarkers do not alwaysreflect asthma severity and therapeutic outcomes (Kostikaset al. 2008). There is a need for new biomarkers with highspecificity and sensitivity for asthma, and H2S representsa promising biomarker for asthma.

As mentioned earlier, serum H2S was correlated withthe severity of different respiratory diseases and airwayinflammation. It appears that serum H2S may be used as a



Table 1. Analytical techniques used for the detection of H2S in biological samples

Method Sample typeSample container and

processing LOQ/LOD Drawbacks Reference

Electrochemical Rat breath Real time 50 p.p.b. Low sensitivity Insko et al. (2009)Gas chromatography Mouse tissue and

alveolar airPolypropylene

syringe/homogenization1 p.p.b. Invasive Furne et al. (2008)

Portable gaschromatography

Human oral and nasalair

Polyethylene-coatedballoon/cryotrapping

4 p.p.b. Poor repeatability Tangerman & Winkel(2008)

Selected ion flow tubemass spectrometry

Human breath Real time 300 p.p.t.v. Low sensitivity Ross (2008)

Spectrophotometry Trout plasma Chemical treatment — Invasive; prone toerror

Dombkowski et al.2004

Optical fibre sensor Mouth air Catalytic reaction;sample held inpolyvinyl fluoridebags and PTFE cell

10 p.p.b. Prone tosulfur-oxidation andnoise; lengthy

Rodrıguez-Fernandezet al. 2002

Abbreviations: LOQ/LOD, limit of quantification/limit of detection; p.p.b., parts per billion; p.p.t.v., parts per trillion by volume; PTFE,polytetrafluoroethylene.

marker for airway inflammation and lower respiratorytract infections (Wu et al. 2008; Chen et al. 2009b).However, serum H2S level can be affected by many non-respiratory diseases. To detect blood H2S level is bothnon-specific and invasive. Interestingly, H2S shares a lot ofattributes with NO and also exists in exhaled breath, whichmeans that it can be sampled non-invasively. As one of themost important breath markers of lung diseases, exhaledNO has been studied extensively in different lung diseases,such as asthma, chronic obstructive pulmonary diseaseand cystic fibrosis (Cao & Duan, 2006). Unfortunately,H2S in exhaled mouth air does not accurately reflect H2Smetabolism in the respiratory system, because it is affectedby pathophysiological conditions of oral and dental health.Hydrogen sulphide originating from bacteria also affectsthe level of H2S in exhaled breath. Although changesof exhaled H2S in different phases of asthma are stillunknown, exhaled nasal H2S may specifically reflect thehealthy or disease status of the lung and airway tissues. Itwould be desirable to develop new technologies to detectthe H2S level in nasal air as a biomarker for asthma as wellas other respiratory diseases.

Technological challenge of detecting H2S in nasal air

The detection of H2S in exhaled breath, especiallyin nasal air, is attractive because it represents betterphysiological conditions due to minimal breath moistureloss and reduced contamination by oral sources. Breathsamples contain very low concentrations of H2S andare characterized by high moisture levels; both thesefactors test the detection power and ability of analyticaltechnologies. Moreover, H2S exhibits challengingchemical and physical properties for the detectingtechnology and instruments. Technical challenges arerelated to nasal air collection, choice of storage mediaand maintenance of sample integrity. Nasal air sampling

in experimental animals requires devices that suit theanimal physiology to ensure representativeness. Themeasurement of H2S in biological materials is difficultowing to its volatility, tendency to undergo oxidation,adsorption onto containers and the sample introductionsystem, and loss during processing. Also, H2S is corrosive,and acceptable results can only be expected if inertmaterials, such as polytetrafluoroethylene (PTFE),polychlorotrifluoroethylene, vinylidene polyfluoride,polyamide, ethylene-propylene and high-quality stainless-steel, are used in sample collection, storage and sampleintroduction systems.

Instrumental challenges in nasal air analysis can berelated to moisture tolerance or to detection power.A limited number of analytical techniques have beenused for measuring H2S in breath, biological tissuesand fluids (Table 1). These include gas chromatography,electrochemical detectors, spectrophotometry, high-performance liquid chromatography (Shaji & Jadhav,2010) and an optical fibre chemical sensor (Rodrıguez-Fernandez et al. 2002), although the elevated H2S valuesreported in the latter strongly cast doubt on the accuracyof the technique in light of the low occurrence ofH2S in human breath (Ross, 2008; Snel et al. 2011).Improved technologies, such as selected ion flow tubemass spectrometry and proton transfer reaction massspectrometry, show promise for real-time analysis of H2Slevels in human breath (Miekish & Schubert, 2006; Ross,2008). Most of the techniques either fail to accommodatethe high moisture in nasal air or lack sufficient sensitivity.Nevertheless, gas chromatography is the most widely usedtechnique, perhaps due to its capability to separate anddetect traces of volatile compounds and the high sensiti-vity possible using a combination of thermal desorptionand pulsed flame photometric detection.

Overcoming technological and instrumental challengesfor detecting H2S in nasal air would help to unmask the


Exp Physiol 96.9 pp 847–852 Hydrogen sulfide and asthma 851

potential of H2S as a biomarker for respiratory-specificdiseases, such as asthma.

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Acknowledgements

This study was supported by a grant from Strategic Program ofAsthma Research, American Asthma Foundation.


hydrogen sulfide and asthma

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