Feng Li, PhD
Department of Respiratory Medicine Shanghai First People’s Hospital Shanghai Jiao Tong University No.100, Haining Road, Shanghai 200080 PR, China; Tel. 0086 21 63071428; Fax: 0086 21 63071428; E-mail: lifeng741@aliyun.com
Hydrogen Sulfide (H2 S) is a colorless, water-soluble gas with the odor of rotten eggs. H2 S can be produced via non-enzymatic pathways, but is mainly synthesized from L-cysteine as the substrate by Cystathionine-γ-lyase (CSE), Cystathionine-β-synthetase (CBS) and 3-mercaptopyruvate sulfur transferase (3MTS).1 H2 S is now recognized as the third signaling gasotransmitter after Carbon monoxide (CO) and Nitric Oxide (NO), and it plays an important role in the pathophysiology of airway disease, such as asthma and Chronic Obstructive Pulmonary Disease (COPD).1
Asthma is a chronic airway disorder characterized as airway inflammation, airway hyper responsiveness (AHR), and airway remodeling, which is caused by inflammatory cells such as eosinophils, mast cells, T-helper 2 (Th2) lymphocytes, neutrophils, and structural cells such as airway epithelial cells and airway smooth muscle cells (ASMCs). The levels of H2 S in serum were decreased in patients with stable asthma or acute exacerbation asthma.2 The changes in serum H2 S levels or exhaled air were positively correlated with FEV1 % and negatively with the total count of sputum cells and neutrophils percentage.2,3 Similar findings were observed in pediatric asthmatics. The serum levels of H2 S were significantly decreased in asthmatic children compared to healthy children and the levels were positively correlated with lung function.4 Therefore, it was proposed that H2 S level could be used as a biomarker for asthma.5
Animal studies showed that the serum H2 S level, the production rate of H2 S in lung tissue, and the expression of CSE were decreased in an Ovalbumin (OVA)-induced rat model of asthma.6,7
Exogenous supplementation with Sodium Hydrogen Sulfide (NaHS, an exogenous donor of H2 S) improved the airway flow and attenuated airway inflammation and remodeling in the model,6 while inhibition in the synthesis of H2 S aggravated the development of airway inflammation and AHR.7
Chronic Obstructive Pulmonary Disease (COPD) is a chronic airway disease characterized by chronic inflammation and parenchymal destruction (emphysema), which ultimately contributes to irreversible airflow obstruction. Cigarette Smoke (CS) or other noxious particles are the main etiologic factors for the development of COPD. A clinical study investigating the relation of serum H2 S levels to the severity of COPD showed that serum H2 S levels were significantly higher in patients with stable COPD than in patients with Acute Exacerbation of COPD (AECOPD) and control subjects. Serum H2 S levels were positively correlated with the percentage of predicted FEV1 value, and negatively correlated with the proportion of neutrophils in sputum in all patients.8This study indicated that H2 S may be involved in the pathogenesis of airflow obstruction in COPD and may be connected with disease activity and severity. Moreover, sputum H2 S levels were higher in AECOPD patients than those in stable COPD patients. Thus, the high sputum-to-serum ratio of H2 S may indicate an ongoing neutrophilic inflammation.9
The important role of H2 S in COPD was further confirmed through animal studies. Han, et al. showed that chronic CS could down-regulate the expression of CSE and CBS in the rat lung, while treatment with NaHS could inhibit both airway inflammation and airway remodeling as well as attenuate the development of emphysema and pulmonary artery hypertension.10 Another study showed that the treatment with NaHS reduced the airway inflammation and AHR caused by Cigarette Smoke (CS) while treatment with PPG (the inhibitor of CSE) further aggravated the development of airway inflammation and AHR due to the inhibition of the production of endogenous H2 S.11
Anti-inflammatory
Presently, most studies demonstrate that H2 S possesses an anti-inflammatory function in many models of respiratory disease, including asthma,6,7 COPD.10,11 Although the anti-inflammatory mechanism of H2 S is not clear, the exogenous addition of H2 S could inhibit Th2-cytokines like IL-5 and IL-13 in addition toeotaxin-1 in the BAL fluid in an OVA-induced murine asthma model.7 Treatment with NaHS could decrease the production of pro-inflammatory cytokines such as IL-6 and IL-8 and increase the production of anti-inflammatory cytokines such as IL-10 in the plasma and lung tissues.12
Anti-oxidative
H2 S can freely cross the plasma membrane and the mitochondrial membrane to scavenge Reactive Oxygen Species (ROS) and Reactive Nitrogen Species (RNS).13 Moreover, H2 S enhances the production of reduced Glutathione (GSH) by enhancing cystine/cysteine transporters and redistributes GSH to mitochondria.14 NaHS increased the ratio of reduced/oxidized glutathione (GSH/GSSG) and decreased the content of 8-hydroxy-deoxyguanosine (8-OHdG) in the lungs of CS-exposed mice,10 which was similar to our findings that NaHS inhibited ozone-induced oxidative stress in a murine model.15 Benetti, et al. confirmed that NaHS treatment abolished the increased lipid peroxidation in the allergic mouse lungs and increased Superoxide dismutase (SOD), Glutathione peroxidase (GPx) and Glutathione Reductase (GR) enzyme activities.16 Nuclear factor (erythroid-derived 2)-like 2, also known as Nrf2, is a key transcription factor that regulates the expression of many important antioxidant proteins that protect against oxidative damage triggered by injury and inflammation.
Regulation of Cell Proliferation and Apoptosis
H2 S can inhibit cell proliferation; however, the effects of H2 S on cellular apoptosis are complex. An in vitro study showed that both NaHS (the fast-releasing H2 S donor) and GYY4137 (the slow-releasing H2 S donor) suppressed human Airway Smooth Muscle Cell (ASMC) proliferation induced by Fetal Bovine Serum (FBS) and the proinflammatory cytokines IL-1β and IL-8.17 H2 S decreased the migration and proliferation of a human lung fibroblast cell line (MRC5) stimulated by FBS and basic Fibroblast Growth Factor (bFGF), which is probably related to the fact that H2 S inhibits ERK-1/2 phosphorylation in MRC5 cells.18
Inhibitory Effect on AHR
Animal experiments showed that NaHS reduced the AHR caused by OVA,7 ozone,19 and cigarette smoke,11 while treatment with PPG aggravated the development of AHR. The underlying mechanism may be related to the direct relaxant effect on bronchial smooth muscle as well as anti-inflammatory and anti-oxidative effects of NaHS. Kube, et al. found that NaHS relaxed the carbachol-precontracted mouse bronchial rings, and this relaxant effect was not affected.20 The mechanism may be due to that NaHS activates large conductance Calcium activated potassium channels (BKCa) or activates K (ATP) channels in airway smooth muscle cells.21,22
Inhibitory Effect on Airway Remodeling
NaHS inhibited goblet cell hyperplasia, airway mucus secretion, collagen deposition, and subepithelial fibrosis in an OVA-induced rat asthma model.6 NaHS also inhibited increases in bronchial thickness in a CS-induced mouse emphysema model.10 NaHS reduces increases in right ventricular systolic pressure, the thickness of pulmonary vascular walls, and the ratio of right ventricle/left ventricle+septum in a CS-induced mouse emphysema model.10 The inhibitory effect on vascular remodeling by H2 S may be related to the roles of H2 S in promoting the apoptosis of pulmonary artery SMC, 18and in reducing collagen deposition in the pulmonary vasculature.23
H2 S is a novel gas molecule with many biological effects. More research is needed to clarify the metabolism and mechanism of H2 S in airway diseases. Clinical studies have shown that the level of H2 S in plasma, sputum, and exhaled breath could reflect the disease condition and severity of asthma or COPD. Since H2 S plays many roles in airway disease, more focused studies about the effects of H2 S on respiratory protection is urgently needed. Currently, some pharmaceutical companies are developing slow-releasing, controllable H2 S donors and H2 S-releasing hybrid drugs. These drugs may pave new way for the treatment of airway diseases.
This work was supported by grants No. 81100024 from the National Natural Science Foundation of China and No. 2011274 from the Shanghai Health Bureau.
None.
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