ReviewThe message in the air: Hydrogen sulfide metabolism in chronic respiratory diseases☆
Highlights
► Ambient H2S intoxication can be treated with nitrite and hyperbaric oxygen. ► H2S is an important gasotransmitter in mammalian respiratory system. ► H2S biogenesis in the lungs is mostly catalyzed by CSE and CBS. ► Altered pulmonary H2S metabolism is associated with various lung diseases. ► Exhaled H2S could be a novel biomarker for various respiratory diseases.
Introduction
Hydrogen sulfide (H2S) is a colorless, flammable, water-soluble gas with the odor of rotten eggs. It is commonly encountered as an environmental contaminant in unrefined natural gas and petroleum, sulfur deposits, volcanic gases, well water, and sulfur springs. Inhalation of H2S has been reported to cause pulmonary edema, bronchiolitis, reactive airway disease, pulmonary interstitial fibrosis and death (Beauchamp et al., 1984). Growing evidence has shown that in addition to nitric oxide (NO) and carbon monoxide (CO), H2S is a third gasotransmitter (Wang, 2002). The altered metabolism of endogenously produced H2S is involved in various pathophysiological conditions of the respiratory system, such as chronic obstructive pulmonary disease (COPD), asthma, pulmonary fibrosis, hypoxia-induced pulmonary hypertension, lung ischemia–reperfusion injury, and acute lung injury.
In this article, we will first discuss respiratory intoxication caused by environmental H2S exposure and its clinical management, followed by a discussion on the endogenous biosynthesis of H2S in lung and airway tissues. We will then review the altered metabolism and functions of H2S in various subtypes of chronic respiratory diseases (CRD). Putative mechanisms for the roles of H2S in these disease states will be discussed together thereafter. The article will conclude by proposing the use of the endogenous level of H2S as a biomarker for CRD, while also providing a perspective on promising trends in this field of research.
Section snippets
Intoxication of the respiratory system by H2S
H2S intoxication is the primary chemical hazard in natural gas production in ‘sour gas’ fields. It is also a serious health and safety concern in sewage treatment and manure-containment operations, construction in wetlands, pelt processing, certain types of pulp and paper production, and any situation in which organic material decays or inorganic sulfides emerge under reducing conditions (Wang, 2010b). The clinical effects of H2S depend on its concentration and the duration of exposure.
H2S biogenesis in lung tissues
H2S is produced endogenously in mammals, including humans. It is now believed that H2S formation is mainly catalyzed by three enzymes: cystathionine-γ-lyase (CSE; EC 4.4.1.1), cystathionine-β-synthase (CBS; EC 4.2.1.22), and 3-mercaptopyruvate sulfurtransferase (MST; EC 2.8.1.2) (Wang, 2002, Shibuya et al., 2009, Wang et al., 2011). The metabolism pathway of H2S is shown in Fig. 1. CSE in the transsulfuration pathway catalyzes the conversion of cystathionine to cysteine. It also catalyzes H2S
H2S in COPD
COPD is characterized by airflow obstruction due to chronic bronchitis or emphysema. The airflow obstruction in COPD is generally progressive and may be partially reversible. Airway inflammation plays an important role in the pathogenesis of mucus hypersecretion, lung destruction, and airway obstruction, all characteristic of COPD (Rabe et al., 2007). However, the mechanisms for airway inflammation in COPD are not fully understood.
Previously, we investigated the correlation of serum H2S level
Airway smooth muscle cells proliferation
Airway smooth muscle cell (ASMC) proliferation leads to airway remodeling in COPD and asthma (Jeffery, 2004). Perry et al. (2011) found that H2S donors, either the fast-releasing ‘donor’ NaHS, or the slow-releasing ‘donor’ GYY4137, suppressed human ASMC proliferation induced by fetal calf serum and the proinflammatory cytokine, IL-1β and interleukin-8, due to the inhibited phosphorylation of ERK-1/2 and p38 mitogen-activated protein kinase. Inhibition of CBS, but not CSE, reversed the
Exhaled H2S as a biomarker
Novel biomarkers for airways disease are needed in relation to risk stratification, identification of treatment responders, identification of a clinical phenotype, monitoring of disease, and new drug development (Hillas et al., 2009). Some have proposed that the severity of various pulmonary diseases is linked to the predominant site of increased fraction of exhaled NO (FeNO). In asthma, FeNO measurement may supplement standard clinical asthma care guidelines, including spirometry, providing a
Future direction
Basic research on animal models of respiratory diseases should be strengthened to determine the metabolism of H2S in the respiratory system and its alterations in different diseases. The relationship between endogenous H2S levels and other direct inflammatory markers in sputum, and BAL and biopsy results waits to be clarified. It would be interesting also to look at the role played by H2S in different treatment regimens currently used in chronic respiratory diseases, such as
Acknowledgment
This work has been supported by a Strategic Program of Asthma Research from American Asthma Foundation.
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This paper is part of a special issue entitled “Gasotransmitters and Respiration: Consequences in Health and Disease”, guest-edited by Prem Kumar and Chris Peers.