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(Chest. 2005;128:3205-3211.)
© 2005 American College of Chest Physicians

Endogenous Hydrogen Sulfide in Patients With COPD*

Ya-Hong Chen, MD, PhD; Wan-Zhen Yao, MD; Bin Geng, PhD; Yan-Ling Ding, MD; Ming Lu, MD; Ming-Wu Zhao, MD and Chao-Shu Tang, PhD

* From the Respiratory Department (Drs. Chen, Yao, Ding, Lu, and Zhao), Peking University, Third Hospital, Beijing; and Department of Physiology (Drs. Geng and Tang), Peking University, Health Science Center, Beijing, China.

Correspondence to: Ya-Hong Chen, MD, PhD, Respiratory Department, Peking University, Third Hospital, Beijing 100083, ROC; e-mail: chenyahong{at}vip.sina.com


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Objectives: COPD is characterized by progressive airway obstruction. Recent studies showed that besides nitric oxide (NO) and carbon monoxide (CO), endogenous hydrogen sulfide (H2S) might be the third signaling gasotransmitter. To clarify the role of endogenous H2S in the pathogenesis of COPD, we investigated the relation of serum H2S level to severity of COPD as defined by lung function and airway inflammation.

Methods: Levels of serum H2S and NO, lung function, and cell differential counts in induced sputum were studied in 27 patients with acute exacerbation of COPD (AECOPD), 37 patients with stable COPD, and 13 healthy subjects. Patients with AECOPD had arterial blood gas levels measured and underwent Doppler echocardiography. In addition, in order to clarify the effects of age and smoking status on serum H2S level, we recruited three groups who were age matched to the study group but had no airflow limitation (59 subjects).

Results: Serum H2S level (34.0 ± 0.9 to 36.4 ± 1.1 µmol/L [± SEM]) did not differ among healthy control subjects with different ages (56.6 to 75.0 years, respectively). Serum H2S level was significantly higher in patients with stable COPD than in patients with AECOPD and age-matched control subjects (p < 0.01) and correlated positively with NO level in all healthy control subjects and all patients with COPD (r = 0.352, p = 0.000). Serum H2S level was significantly lower in smokers than nonsmokers, both with AECOPD (p < 0.05) and healthy control subjects (p < 0.01). It was significantly lower in smokers with AECOPD than healthy smokers and smokers with stable COPD (p < 0.01). Serum H2S level differed and was decreased (p < 0.05) among stable COPD patients by stage of airway obstruction (p < 0.05), and it was lower in patients with stage III than stage I obstruction (p < 0.05). Serum H2S level in all patients with COPD and healthy control subjects correlated positively with the percentage of predicted FEV1 value (r = 0.300, p = 0.009). It was lower in patients with AECOPD and systolic pulmonary artery pressure (PASP) ≥ 35 mm Hg than those with PASP within the normal range (< 35 mm Hg) [p < 0.05] and was negatively correlated with PASP (r = – 0.561, p = 0.011). Serum H2S level was negatively correlated with proportion of neutrophils in sputum (r = – 0.422, p = 0.001) and positively correlated with proportion of lymphocytes (r = 0.286, p = 0.028) and macrophages (r = 0.334, p = 0.01) in all patients with COPD.

Conclusions: Endogenous H2S is involved in the pathogenesis of airway obstruction in COPD, and its alteration in level may be connected with disease activity and severity.

Key Words: airway inflammation • airway obstruction • COPD • hydrogen sulfide • nitric oxide


   Introduction
TOP
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
COPD is characterized by airflow obstruction due to chronic bronchitis or emphysema. The airflow obstruction is generally progressive and may be partially reversible.1 Airway inflammation plays an important role in the pathogenesis of mucus hypersecretion, lung destruction, and airway obstruction, all characteristic of COPD. However, the inflammatory mechanisms in COPD are less understood than those in bronchial asthma.2

There is increasing evidence that endogenous nitric oxide (NO) plays a key role in the physiologic regulation of airways and is implicated in the pathophysiologic features of airway disease.3 NO is derived endogenously from the amino acid L-arginine by three isoforms of NO synthases (NOSs): two constitutive NOSs (the neural and endothelial forms) involved in physiologic regulation of airway function, and one inducible NOS involved in inflammatory diseases of the airways and host defense against infection.4

Hydrogen sulfide (H2S) was for a long time recognized as a toxic gas with a strong odor of rotten eggs in water pollution and industrial air pollution, and its major effects were intoxication of the CNS and inhibition of the respiratory system.5 H2S has been found to be endogenously generated in various mammalian tissues and may be a functional regulator in nervous and cardiovascular systems.6 The endogenous H2S pathway is down-regulated in hypoxia pulmonary hypertension. Exogenously administered NaHS, an H2S donor, reduces pulmonary hypertension and inhibits pulmonary arterial remodeling.7 Because of its endogenous metabolism and physiologic functions, H2S is well positioned in the novel family of endogenous gaseous transmitters and, besides NO and carbon monoxide (CO), might be the third endogenous signaling gasotransmitter.8 To clarify the role of endogenous H2S in the pathogenesis of COPD, we investigated the level of serum H2S in patients with COPD and its possible relation to extent of disease, as measured by lung function and noninvasive markers of inflammation, such as proportion of inflammatory cells in sputum and NO level in serum.


   Materials and Methods
TOP
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Subjects
Patients were recruited from clinics at Peking University, Third Hospital. The study was approved by the Ethics Committee of Peking University, Third Hospital, and all patients gave their informed consent. Twenty-seven patients with acute exacerbation of COPD (AECOPD; 16 men and 11 women; mean age, 76.7 ± 1.3 years; 14 smokers [36 pack-years], 13 nonsmokers; group 1); 37 patients with stable COPD (29 men and 8 women; age, 65.6 ± 1.6 years; 28 smokers [25 pack-years], 9 nonsmokers; group 2); and 13 healthy nonsmokers (6 men and 7 women; mean age, 58.7 ± 2.3 years; group 3) participated (± SEM). Nonsmokers had never smoked and were not ex-smokers. Smokers with AECOPD stopped smoking no more than 1 month before admission to hospital. COPD was diagnosed according to the criteria recommended by the Chinese Medical Society.9 Chronic airflow limitation was defined as FEV1/FVC < 70%. Bronchodilator reversibility test revealed an increase in FEV1 < 15% above the prebronchodilator FEV1 after 400 µg of inhaled salbutamol.

AECOPD is associated with increased breathlessness, often accompanied by increased cough and sputum production. Patients with stable COPD were free from acute exacerbation of symptoms and upper respiratory tract infection in the 2 months preceding the study. They had no history of asthma or other allergic diseases (eg, rhinitis). All of the patients were receiving treatment with inhaled bronchodilators, but none received systemic or inhaled steroids. Patients with stable COPD and AECOPD were recruited simultaneously and were completely separate. Healthy volunteers did not have a history of pulmonary disease, were nonhyperresponsive, and had normal lung function. The demographic and functional characteristics of the patients are shown in Table 1 .


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  		Table 1.. Subject Characteristics*

 
In order to clarify the effects of age and smoking status on serum H2S level, we recruited three groups that age matched the study group but had no airflow limitation. Nineteen healthy control subjects matched patients with AECOPD (group 4: 10 men and 9 women; mean age, 75.0 ± 0.7 years; 9 smokers [33 pack-years] and 10 nonsmokers); 24 healthy control-matched patients with stable COPD (group 5: 12 men and 12 women; mean age, 64.6 ± 0.6 years; 12 smokers [27 pack-years] and 12 nonsmokers); and 16 normal smokers matched group 3 (group 6: 8 men and 8 women; mean age, 54.9 ± 0.7 years, [24 pack-years]).

Lung Function
Pulmonary function tests were performed with use of a spirometer (2800J Autobox; Gould Electronics; Dayton, OH). FEV1, FVC, and FEV1/FVC were measured in all patients. Arterial blood gas in patients with AECOPD was assessed during the day under resting conditions. PaO2, PaCO2, and pH values were measured by means of an automated analyzer (ABL 500; Radiometer; Copenhagen, Denmark) on blood samples obtained from the radial artery with patients in the sitting position for at least 1 h while breathing room air.

Doppler Echocardiography
Patients with AECOPD underwent real-time, phased-array, two-dimensional Doppler echocardiography (CFM 750 CV 2.5 or 3.25 MHz transducer; GE Vingmed; Milan, Italy) while breathing room air. The patients were in a semirecumbent left lateral position, and images were taken of subxiphoid, parasternal, and apical views. The mean value of three measurements was used. The systolic pulmonary artery pressure (PASP) was calculated by use of tricuspid valve regurgitation. A single examiner performed the measurements unaware of the purpose of the study.

Sputum Collection and Analysis
Sputum was collected and processed as described.10 All subjects inhaled 200 µg of salbutamol to avoid hypertonic saline solution-induced bronchoconstriction. Fifteen minutes after salbutamol inhalation, patients inhaled 4% hypertonic saline solution for 15 to 30 min by use of an ultrasonic nebulizer (MU-32; Sharp; Osaka, Japan). The nebulizer generated particles with a mean mass diameter of 5.4 µm at an output of 2.2 mL/min. Subjects were then asked to rinse their mouths and throats and expectorate sputum into a Petri dish. Sputum plugs arising from the lower respiratory tract were selected and incubated with 0.1% dithiothreitol until completely homogenized. The cell suspension was filtered through 52-µm nylon gauze and then centrifuged at 800g for 10 min. The cell pellet was resuspended in phosphate-buffered saline solution (PBS). Two slides were stained with Wright-Giemsa for differential cell counts of leukocytes.

Measurement of H2S in Serum
Serum H2S concentration was measured with use of a sulfide sensitive electrode (Model 9616; Orion Research; Beverly, MA). In brief, sulfide antioxidant buffer was added into standards or samples at a ratio of 1:1, then stirred thoroughly. Electrodes were rinsed in distilled water, blotted dry, and placed into standards and samples. When a stable reading was displayed, the millivolt value was recorded. The H2S concentration was calculated against the calibration curve of the standard H2S solution.11

Measurement of NO in Serum
The serum level of nitrite plus nitrate was measured with use of the Griess reagent as previously described.12 The assay was performed in a standard, flat-bottomed, 96-well, polystyrene microtiter plate containing 50 µL per well of standard or sample. The assay was blanked against PBS. A total of 50 µL of nitrate reductase and ß-nicotanimide adenine dinucleotide phosphate and its reduced form was added to each well for final concentrations of 300 U/L and 25 µmol/L, respectively. The plate was incubated at room temperature for 3 h. Excess ß-nicotanimide adenine dinucleotide phosphate and its reduced form was consumed by the addition of 50 µL of PBS containing L-glutamic dehydrogenase, {alpha}-ketoglutaric acid, and NH4Cl (final concentrations, 500 U/L, 4 mmol/L, and 100 mmol/L, respectively) followed by 10 min of incubation at 37°C. The nitrite concentration was then measured by the addition of 50 µL each of Griess reagents 1 and 2, and the absorbance read at 540 nm by use of a plate reader after 10 min of incubation at room temperature.

Analysis of Data
The data are expressed as mean ± SEM. Statistical analyses comparing multiple variables were performed by using analysis of variance with Bonferroni correction. For comparisons between two variables, the unpaired Student t test was used. Regression analysis was performed by use of Pearson rank correlation coefficients; p < 0.05 was considered significant.


   Results
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Subject Characteristics
The characteristics of the 77 subjects who participated in the study are in Table 1. Patients with AECOPD were significantly older than patients with stable COPD and healthy control subjects (p < 0.01). FEV1/FVC and proportion of predicted FEV1 were significantly lower in patients with AECOPD and stable COPD than in healthy control subjects (p < 0.01).

H2S and NO Levels in Serum
We investigated the effect of age on serum H2S and NO levels in normal control subjects and found no difference among group 4 (71 to 80 years), group 5 (61 to 70 years), and group 6 combined with group 3 (50 to 60 years) [H2S: 35.7 ± 1.2, 34.0 ± 0.9, and 36.4 ± 1.1 µmol/L, respectively, all p > 0.05; NO: 38.7 ± 1.6, 39.5 ± 1.2, and 50.4 ± 4.7 µmol/L, respectively, all p > 0.05]. Serum levels of H2S and NO did not differ between patients with AECOPD and age-matched healthy control subjects (group 1 vs group 4). Serum levels of H2S and NO were 49.4% and 59.5%, respectively, higher in patients with stable COPD than age-matched healthy control subjects (group 2 vs group 5, p < 0.01). However, serum levels of H2S and NO were 34.1% and 36.8% lower in patients with AECOPD than stable COPD, respectively (group 1 vs group 2, p < 0.01) [Fig 1 ].



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  		Figure 1.. Serum H2S and NO levels in patients with AECOPD, stable COPD, and healthy control subjects. Data are mean ± SEM. Group 1 represents patients with AECOPD. Group 2 represents patients with stable COPD. Groups 3 to 6 represent healthy control subjects of different ages. Group 4 was age matched with group 1. Group 5 was age matched with group 2. *p < 0.01.

 
Serum H2S level was significantly lower in smokers than nonsmokers, both with healthy control subjects (33.0 ± 0.7 µmol/L vs 37.9 ± 0.9 µmol/L, p < 0.01), and AECOPD (28.1 ± 1.3 µmol/L vs 39.4 ± 3.9 µmol/L, p < 0.05). Serum H2S level did not differ between smokers and nonsmokers with stable COPD (51.1 ± 3.0 µmol/L vs 49.8 ± 3.8 µmol/L, p > 0.05). It was significantly lower in smokers with AECOPD than healthy smokers and smokers with stable COPD (p < 0.01). Serum NO level was significantly lower in healthy smokers than nonsmokers (35.6 ± 1.0 µmol/L vs 52.2 ± 3.6 µmol/L, p < 0.01) but did not differ between smokers and nonsmokers with AECOPD (39.0 ± 3.1 µmol/L vs 40.6 ± 5.1 µmol/L, p > 0.05) and stable COPD (60.9 ± 3.4 µmol/L vs 69.5 ± 8.5 µmol/L, p > 0.05) [Fig 2 ].



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  		Figure 2.. Serum H2S (top, A) and NO (bottom, B) levels in patients with AECOPD, stable COPD, and healthy control subjects stratified by smoking status. Data are mean ± SEM. Groups 3 to 6 were combined as a control. NS = nonsmokers; S = smokers. *p < 0.05, **p < 0.01.

 
Patients with AECOPD were further classified into three groups according to Global Initiative for Chronic Obstructive Lung Disease stages of obstruction.13 Seven patients were stage I to II, 12 patients were stage III, and 8 patients were stage IV. Serum H2S level decreased with severity of disease (stage I to II, 40.5 ± 6.3 µmol/L; stage III, 33.4 ± 2.9 µmol/L; stage IV, 27.6 ± 1.6 µmol/L, p < 0.05). In patients with stable COPD, 4 patients were stage I, 17 patients were stage II, 12 patients were stage III, and 4 patients were stage IV. Serum H2S level differed significantly among stage of stable COPD (F = 3.565, p = 0.025), tending to decrease (p < 0.05). It was significantly higher in patients with stage I than healthy control subjects (p < 0.01). Serum H2S level was significantly lower in patients with stage III than stage I obstruction (p < 0.05). Serum NO level did not differ among stages of stable COPD (F = 0.596, p = 0.622) [Fig 3 ].



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  		Figure 3.. Serum H2S and NO levels in patients with stable COPD by stage of lung obstruction.13 Data are mean ± SEM. Control (group 3, n = 13); stage I, percentage of predicted FEV1≥ 80% (n = 4); stage II, percentage of predicted FEV1, 50 to 79% (n = 17); stage III, percentage of predicted FEV1, 30 to 49% (n = 12); and stage IV, percentage of predicted FEV1 < 30% (n = 4). *p < 0.01 compared with control; #p < 0.05 compared with stage I.

 
Nineteen patients with AECOPD underwent Doppler echocardiography and were classified into two groups: 8 patients with PASP ≥ 35 mm Hg (group 1) and 11 patients with PASP within the normal range (< 35 mm Hg) [group 2]. Serum H2S levels in groups 1 and 2 were 26.3 ± 2.2 µmol/L and 36.2 ± 2.5 µmol/L, respectively (p < 0.05), while serum NO levels were 42.6 ± 4.4 µmol/L and 36.2 ± 3.3 µmol/L (p > 0.05).

Arterial blood gas levels were measured in 25 patients with AECOPD. The patients were classified into two groups: 5 patients with PaO2 ≥ 80 mm Hg (high group) and 20 patients with PaO2 < 80 mm Hg (low group). Serum H2S levels in the high and low groups were 26.7 ± 3.8 µmol/L and 33.9 ± 2.2 µmol/L, respectively (p > 0.05), while serum NO levels were 32.7 ± 3.0 µmol/L and 39.6 ± 2.4 µmol/L (p > 0.05).

Cellular Parameters in Sputum
Neutrophil proportion was greater in sputum of patients with AECOPD and stable COPD than in healthy subjects (p < 0.01) and greater in patients with AECOPD than stable COPD (p < 0.01). Such patients had less proportion of macrophages than did control subjects (p < 0.01). Lymphocytes were significantly greater in proportion in patients with stable COPD than those with AECOPD (p < 0.01), as shown in Table 2 .


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  		Table 2.. Proportion of Cell Types in Sputum*

 
Correlation Between Serum H2s Level, Serum NO Level, and Clinical Parameters
Serum H2S level correlated positively with serum NO level (r = 0.352, p = 0.000) in all healthy control subjects and all patients with COPD. Serum H2S level also correlated positively with percentage of predicted FEV1 (r = 0.300, p = 0.009) in all patients with COPD and healthy subjects. Serum H2S level in patients with AECOPD correlated negatively with PASP (r = – 0.561, p = 0.011). Serum H2S level in all patients with COPD correlated negatively with proportion of neutrophils (r = – 0.422, p = 0.001) and positively with proportion of lymphocytes (r = 0.286, p = 0.028) and macrophages (r = 0.334, p = 0.01). No significant correlation was found between serum NO level and percentage of predicted FEV1 (r = 0.205, p = 0.104) and PASP (r = 0.275, p = 0.255). Serum NO level was negatively correlated with proportion of neutrophils in sputum in all patients with COPD (r = – 0.285, p = 0.026) [Fig 4 ].



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  		Figure 4.. Correlation between serum H2S level and serum NO level (top), percentage of predicted FEV1 (middle), and proportion of neutrophils in sputum (bottom). Serum H2S level correlated positively with serum NO level (r = 0.352, p = 0.000) in all healthy control subjects and all patients with COPD. Serum H2S level correlated positively with percentage of predicted FEV1 (r = 0.300, p = 0.009) in all patients with COPD and healthy control subjects (group 3). Serum H2S level in all patients with COPD correlated negatively with proportion of neutrophils (r = – 0.422, p = 0.001).

 

   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
COPD is characterized by chronic inflammation throughout the airways and parenchymal and pulmonary vasculature. Oxidative stress and imbalances in host defense mechanisms may be among the causes of COPD. NO is an endogenous gasotransmitter involved in many aspects of pulmonary function in health and disease. The increased production of NO during inflammatory immune processes involving the respiratory tract is thought to constitute a host defense mechanism, although this comes at a price, because a high level of NO can also cause respiratory tract injury and thus contribute to the pathophysiologic features of inflammatory airway diseases such as asthma.14 The increase in exhaled NO in COPD is lower and less constant.1516 Evidence exists that NO release is impaired in the pulmonary vasculature in patients with COPD. Inhalation of NO could be a promising treatment in patients with COPD and pulmonary hypertension.17

H2S has been found to be endogenous generated by 2 pyridoxal-5'-phosphate-dependent enzymes (cystathionine ß-synthase and cystathionine {gamma}-synthase [CSE]) with L-cysteine used as a main substrate. It is now considered a novel gasotransmitter.8 The physiologic function of endogenous H2S is not well known and may be multifaceted. H2S alters hippocampal long-term potentiation in the CNS, and H2S level in the brain is significantly decreased in patients with Alzheimer disease.1819 Vascular tissues are rich in CSE. H2S could be produced in various arteries and veins, including the pulmonary artery.20 Our previous work21 showed that the endogenous CSE/H2S pathway affected the pathogenesis of isoproterenol-induced rat myocardial injury. Administration of exogenous H2S effectively protected the rat myocardium against ischemic injury, at least in part by its direct scavenging of oxygen-free radicals and reducing the accumulation of lipid peroxidations.21 It was reported that the endogenous CSE/H2S pathway was altered during hypoxia pulmonary hypertension and high pulmonary blood flow-induced pulmonary hypertension in rats and that H2S relaxed pulmonary artery smooth-muscle cells and inhibited their proliferation.722 However, the changes in the endogenous CSE/H2S pathway and the role of the pathway in the pathogenesis of COPD remains to be clarified.

In our study, serum H2S level did not differ among healthy control subjects with different ages (56.6 to 75.0 years). It was significantly higher in patients with stable COPD than in age-matched control subjects, but no differences were observed between patients with AECOPD and age-matched healthy control subjects. It was significantly lower in patients with AECOPD than those with stable COPD. COPD is always associated with exacerbation of symptoms and exacerbation associated with increased airway inflammation. Increased serum H2S level in patients with stable COPD could be a compensatory mechanism. Onset of COPD or airflow limitation might up-regulate serum H2S level, playing an important role in the inhibition of airway inflammation. When the serum H2S level decreases significantly, patients may have AECOPD.

It is well known that cigarette smoking is an important risk factor for COPD. Serum H2S level was significantly lower in smokers than nonsmokers, both with AECOPD and healthy control subjects. Serum H2S level was significantly lower in smokers with AECOPD than healthy smokers and smokers with stable COPD. This observation suggests that the endogenous H2S level can be lowered by smoking and is involved in the progression of COPD. Serum NO level changed similar to that of serum H2S level. We found no obvious influence of smoking on serum NO level in patients with COPD. The lack of difference in serum NO level between smokers and nonsmokers with COPD may be due to the chronic effects of smoking, such as squamous metaplasia, or mucus hypersecretion may form a barrier against stimuli in the airway lumen, preventing airway wall cells from being stimulated to produce NO.23 Serum H2S level correlated positively with NO level in all healthy control subjects and patients with COPD. Therefore, endogenous H2S level may offer a means of monitoring disease activity that is as simple and noninvasive as endogenous NO level.

Serum H2S level in patients with AECOPD decreased with severity of disease, and the level differed significantly and was decreased among stages of stable COPD. Serum H2S level in patients with COPD correlated with percentage of predicted FEV1. When including data from healthy control subjects, the correlation coefficient is decreased. The correlation between serum H2S and COPD may be complicated. In the present study, serum H2S expresses a biphasic change in the progress of COPD. It is higher in patients with milder COPD than healthy control subjects. The mechanism is unknown. According to the biological effect of endogenous H2S, increased level of serum H2S in milder COPD may play an important role in airway protection, antagonizing the oxidative stress and airway inflammation and preventing the progress of COPD. Serum H2S level was decreased among stable COPD patients by stage of airway obstruction, suggesting that the protective effect of endogenous H2S was diminished and accelerated the progression of COPD. The severity of COPD is associated with hypoxia and loss of pulmonary vasculature. Hypoxia is reported to reduce CSE gene expression in blood vessels, resulting in decrease in serum H2S level in the COPD patients. This forms a vicious cycle. Patients with AECOPD and PASP above the normal range showed lower serum H2S level than those with a normal PASP. Serum H2S level in patients with AECOPD correlated negatively with PASP. Therefore, serum H2S level may be a useful, practical marker for monitoring disease activity in COPD.

Neutrophil inflammation is an important factor in the development of airway obstruction.24 In patients with COPD, serum H2S level was negatively correlated with proportion of neutrophils in sputum and positively correlated with proportion of lymphocytes and macrophages. Serum NO level was negatively correlated with proportion of neutrophils. Rutgers et al23 observed a positive correlation between NO level in exhaled air and proportion of eosinophils in sputum of patients with COPD, which may suggest that these cells also contribute to NO production. NO may be produced in airway epithelial cells, endothelial cells, mast cells, fibroblasts, and neurons. The source of endogenous H2S in the airway remains to be clarified.

The direct effects of endogenous H2S on airway tissue and cells are unclear. Studies show that H2S can act as an inhibitor of hypochloric acid-mediated oxidative damage in the brain,25 a scavenger of endogenous peroxynitrite in nervous tissues,26 and an antagonist of lipid peroxidation induced by oxygen-free radicals in the heart.21 More attention should be paid to the role of endogenous H2S and its mechanism in the pathogenesis of COPD and to clarify the relation of H2S to the other gasotransmitters NO and CO. It is well known that H2S has a vasorelaxant function, and the underlying mechanism of H2S is being studied. The important role of adenosine triphosphate-sensitive potassium channels in vascular smooth-muscle cells being dependent on extracellular calcium entry was reported to be involved in H2S bioactions, different from NO and CO, the cyclic guanosine monophosphate and Ca2+-dependent potassium channel pathway not included.27 Zhang et al28 investigated the relation between H2S, NO, and CO in hypoxia pulmonary hypertension and observed that H2S could play a regulatory role in the pathogenesis of hypoxia pulmonary hypertension by up-regulating the CO/heme oxygenase pathway and down-regulating the NO/NOS system. The significance of endogenous H2S in the development of airway inflammation and pulmonary hypertension in patients with COPD deserves further investigation.

In conclusion, endogenous H2S may be involved in the development of airway obstruction in COPD. Serum H2S level could be a useful, practical surrogate marker for monitoring disease activity in COPD patients. Future work should concentrate on the relation between endogenous H2S and other direct inflammatory markers in sputum, and BAL and biopsy results. It would be interesting also to look at the H2S response to different treatment regimens used in COPD, including theophylline and antioxidants, which may interfere with the neutrophil inflammatory response.


   Footnotes
 
Abbreviations: AECOPD = acute exacerbation of COPD; CSE = cystathionine {gamma}-synthase; H2S = hydrogen sulfide; NO = nitric oxide; NOS = nitric oxide synthase; PASP = systolic pulmonary artery pressure; PBS = phosphate-buffered saline solution

This work was supported by National Natural Science Foundation of China grants 30300143 and 30400151.

Received for publication January 5, 2005. Accepted for publication May 7, 2005.


   References
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

  1. . American Thoracic Society. (1995) Standards for the diagnosis and care of patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 152,78-83
  2. Barnes, PJ New therapy for chronic obstructive pulmonary disease. Thorax 1998;53,137-147[ISI][Medline]
  3. Hedenstierna, G, Hogman, M Can exhaled NO be used as a marker of airway inflammation? Eur Respir J 1998;12,1248-1249[CrossRef][ISI][Medline]
  4. Barnes, PJ Nitric oxide and airway disease. Ann Med 1995;27,91-97
  5. Beauchamp, RO, Jr, Bus, JS, Popp, JA, et al A critical review of the literature on hydrogen sulfide toxicity, C.R.C. Crit Rev Toxicol 1984;13,25-97[Medline]
  6. Geng, B, Yang, J, Qi, Y, et al H2S generated by heart in rat and its effects on cardiac function. Biochem Biophys Res Commun 2004;313,362-368[CrossRef][ISI][Medline]
  7. Zhang, CY, Du, JB, Bu, DF, et al The regulatory effect of hydrogen sulfide on hypoxic pulmonary hypertension in rats. Biochem Biophys Res Commun 2003;302,810-816[CrossRef][ISI][Medline]
  8. Wang, R Two’s company, three’s a crowd: can H2S be the third endogenous gaseous transmitter? FASEB J 2002;16,1792-1798[Abstract/Free Full Text]
  9. Chinese Medical Association.. CMA guideline for the management of chronic obstructive pulmonary disease. Chin J Tuber Respir 2002;25,453-460
  10. Pizzichini, E, Pizzichini, MMM, Elthimiadis, A, et al Indices of airway inflammation in induced sputum: reproducibility and validity of cell and fluid-phase measurements. Am J Respir Crit Care Med 1996;154,308-317[Abstract]
  11. Zhao, WM, Zhang, J, Lu, YJ, et al The vasorelaxant effect of H2S as a novel endogenous gaseous KATP channel opener. EMBO J 2001;20,6008-6016[CrossRef][ISI][Medline]
  12. Gioivannoni, G, Land, JM, Keir, G, et al Adaptation of the nitrate reductase and Griess reaction methods for the measurement of serum nitrate plus nitrite levels. Ann Clin Biochem 1997;34,193-198[Medline]
  13. Fabbri, LM, Hurd, SS, for the GOLD Scientific Committee.. Global strategy for the diagnosis, management and prevention of COPD: 2003 update. Eur Respir J 2003;22,1-2[Free Full Text]
  14. Kharitonov, SA, Yates, D, Robbins, RA, et al Increased nitric oxide in exhaled air of asthmatic patients. Lancet 1994;343,133-135[CrossRef][ISI][Medline]
  15. Corradi, M, Majori, M, Cacciani, GC, et al Increased exhaled nitric oxide in patients with stable chronic obstructive pulmonary disease. Thorax 1999;54,572-575[Abstract/Free Full Text]
  16. Maziak, W, Loukides, S, Culpitt, S, et al Exhaled nitric oxide in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1998;157,998-1002[Abstract/Free Full Text]
  17. Ashutosh, K, Phadke, K, Jackson, JF, et al Use of nitric oxide inhalation in chronic obstructive pulmonary disease. Thorax 2000;55,109-113[Abstract/Free Full Text]
  18. Eto, K, Ogasawara, M, Umemura, K, et al Hydrogen sulfide is produced in response to neuronal excitation. J Neurosci 2002;22,3386-3391[Abstract/Free Full Text]
  19. Eto, K, Asada, T, Arima, K, et al Brain hydrogen sulfide is severely decreased in Alzheimer’s disease. Biochem Biophys Res Commun 2002;293,1485-1488[CrossRef][ISI][Medline]
  20. Hosoki, R, Matsuki, N, Kimura, H The possible role of hydrogen sulfide as an endogenous smooth muscle relaxant in synergy with nitric oxide. Biochem Biophys Res Commun 1997;237,527-531[CrossRef][ISI][Medline]
  21. Geng, B, Chang, L, Pan, CS, et al Endogenous hydrogen sulfide regulation of myocardial injury induced by isoproterenol. Biochem Biophys Res Commun 2004;318,756-763[CrossRef][ISI][Medline]
  22. Du, J, Hui, Y, Cheung, Y, et al The possible role of hydrogen sulfide as a smooth muscle cell proliferation inhibitor in rat cultured cells. Heart Vessels 2004;19,75-80[CrossRef][ISI][Medline]
  23. Rutgers, SR, van der Mark, ThW, Coers, W, et al Markers of nitric oxide metabolism in sputum and exhaled air are not increased in chronic obstructive pulmonary disease. Thorax 1999;54,576-580[Abstract/Free Full Text]
  24. Stanescu, DA, Veriter, SC, Kostianev, S, et al Airway obstruction, chronic expectoration, and rapid decline of FEV1 in smokers are associated with increased levels of sputum neutrophils. Thorax 1996;51,267-271[Abstract]
  25. Whiteman, M, Cheung, NS, Zhu, YZ, et al Hydrogen sulphide: a novel inhibitor of hypochlorous acid-mediated oxidative damage in the brain? Biochem Biophys Res Commun 2005;28,326,794-798
  26. Whiteman, M, Armstrong, JS, Chu, SH, et al The novel neuromodulator hydrogen sulfide: an endogenous peroxynitrite "scavenger"? J Neurochem 2004;90,765-768[CrossRef][ISI][Medline]
  27. Zhao, W, Wang, R H2S-induced vasorelaxation and underlying cellular and molecular mechanisms. Am J Physiol Heart Circ Physiol 2002;283,H474-H480[Abstract/Free Full Text]
  28. Zhang, QY, Du, J, Zhou, W, et al Impact of hydrogen sulfide on carbon monoxide/heme oxygenase pathway in the pathogenesis of hypoxic pulmonary hypertension. Biochem Biophys Res Commun 2004;317,30-37[CrossRef][ISI][Medline]




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