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The role of hydrogen sulphide in lung diseases

The role of hydrogen sulphide in lung diseases BioscienceHorizons Volume 6 2013 10.1093/biohorizons/hzt009 Review article Clara Hoi Ka Wu* Imperial College London, Royal Brompton Campus, Dovehouse Street, London SW3 6LY, UK *Corresponding author: Email: hkw09@ic.ac.uk Project superviser: Professor Louise E. Donnelly, National Heart and Lung Institute, Imperial College London, Royal Brompton Campus, Dovehouse Street, London SW3 6LY, UK. Hydrogen sulphide (H S) is a recently discovered gasotransmitter. It is endogenously synthesized by cystathionine β synthe- tase, cystathionine γ lyase, cysteine aminotransferase, 3-mercaptopyruvate sulphurtransferase and cysteine lyase. Its metab- 2− olism leads to the production of sulphate (SO ), methanthiol, dimethylsulphide and thiocynate. The gas interacts with ion channels, protein kinases and transcription factors. It is also involved in post-translational modification of proteins via S-sulphhydration. Although debate continues as to whether H S is pro- or anti-inflammatory, its anti-inflammatory properties seem to have beneficial effects in various lung diseases. Serum levels of H S differ between asthma, chronic obstructive pul - monary disease and pulmonary fibrosis, which makes it difficult for the gas to be used as a biomarker for lung diseases. Apart from exogenous sources of H S, targets to enhance or inhibit the gas can be found in its synthesis and metabolism pathway. H S-releasing non-steroidal anti-inflammatory drugs are currently being developed. Further research will aid to determine the precise role of H S in respiratory diseases. Key words: hydrogen sulphide, asthma, chronic obstructive pulmonary disease, pulmonary fibrosis Submitted on 18 December 2012; accepted on 21 June 2013 Hydrogen sulphide (H S) is a chemical compound made up of called gasotransmitters (Li, Rose and Moore, 2011). H S is 2 2 two hydrogen and one sulphide molecule, hence the chemical synthesized in the cytoplasm from l -cysteine by various formula H S (Hydrogen Sulfide—PubChem .). It is gaseous in enzymes—cystathionine β synthetase (CBS) (Whiteman and room temperature, has flammable properties and is toxic to Moore, 2009), cystathionine γ lyase (CSE) (Whiteman and inhale and contact (HPA - Hydrogen sulphide.). It has a dis- Moore, 2009), cysteine aminotransferase (CAT) (Li, Rose tinctive smell of rotten eggs (Hydrogen Sulfide—PubChem .). and Moore, 2011), 3-mercaptopyruvate sulphurtransferase Exogenous H S is used in industries to produce sulphur and (3-MST) (Li, Rose and Moore, 2011) and cysteine lyase (CL) analyse chemicals (Hydrogen Sulfide—PubChem .). It is also (Li, Rose and Moore, 2011)—which are the main enzymes present inside the body and involves in disease processes (Li, involved. Figure 1 shows synthesis pathways of H S. Rose and Moore, 2011). The mechanisms of H S in cell sig- Rhodanese (thiosulphate sulphurtransferase), thiol-S- nalling and cellular function alteration will be explored. methyltransferase (TSMT) and sulphite oxidase (SO) are Although H S has effects on other body systems such as the enzymes responsible for the metabolism of H S (Stipanuk cardiovascular and neurological systems (Qu et al., 2008; Li, and Ueki, 2011). Figure 2 shows three main ways in which Hsu and Moore, 2009), this paper will focus on discussing the H S can be broken down to its metabolic by-products. compound’s pathophysiological role in respiratory diseases and evaluating ways to modify its effects. H S in cell signalling Biosynthesis and metabolism of H S H S can be involved in cell signalling via its interactions with Endogenous H S, carbon monoxide (CO) and nitric oxide ion channels. Zhao et al. (2001) described that the gas acts on (NO) are gases involved in cell signalling, they can also be ATP-sensitive potassium (K ) channels (Zhao et al., 2001). ATP © The Author 2013. Published by Oxford University Press. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0 ), which per / mits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com Review article Bioscience Horizons • Volume 6 2013 ther study on mice, Kubo et al. (2007) showed that the bron- chodilatory effects of H S are possibly due to the activation of K channels (Kubo et al., 2007). Furthermore, transient ATP receptor potential vanilloid channels are also a target for H S (Trevisani et al., 2005). The gas stimulates the release of substance P (SP) and neurokinin A (NKA) at sensory nerve terminals, causing airway inflammation ( Trevisani et al., 2005). Although the exact mechanisms between the interac- tion of H S and ion channels are still unclear, the gas has definite physiological role in the lungs. Intracellular transcription factors are influenced by H S (Oh et al., 2006). Oh et al. (2006) demonstrated that H S reduces NO production by inhibiting expression of induced NO synthase (iNOS) and haem-oxygenase-1 in RAW264.7 macrophages (Oh et al., 2006). As NO is produced by iNOS and is pro-inflammatory ( Chung et al., 2001), downregulat- ing iNOS expression by H S will help decrease inflammation. Furthermore, the study found that H S also diminishes lipo- Figure 1. Synthesis of H S. Pathway 1: CBS converts cysteine to H S 2 2 polysaccharide (LPS)-induced nuclear factor kappa B (NF- and l -serine. Pathway 2: CSE converts cysteine to H S. Pathway 3: cysteine is first converted to 3-mercaptopyruvate by CAT, then to H S κB) (Chung et al., 2001). NF-κB is a protein that regulates by 3-MST. Pathway 4: CL converts cysteine and sulphate to H S and the expression of pro-inflammatory mediator genes ( Karin, l -cysteate. Pathways 1, 2 and 4 occur in the cytoplasm, whereas 1998), such as tumour necrosis factor alpha (TNFα) (Liu Pathway 3 occurs in the mitochondria. Image adapted from Li, Rose et al., 2000) and iNOS (Kleinert, Schwarz and Forstermann, and Moore (2011). 2003). Therefore, the decrease in NF-κB expression reduces inflammation. H S has regulatory effects on kinases (Du et al., 2004). Du et al. (2004) have demonstrated that H S reduces mitogen- activated protein kinase (MAPK) activity and hence suppresses VSMCs proliferation. Although the possible mechanism in pancreatic cells is the downregulation of pro-inflammatory cytokines via the phosphatidylinositol 3-kinase (Pl3K)/protein kinase B (PKB) pathway (Tamizhselvi et al., 2009), there is no current study to demonstrate that a similar process may occur in bronchial smooth muscle cells. H S can also signal through protein S-sulphhydration (Mustafa et al., 2009). S-sulphhydration is the process whereby the sulhydryl (SH)/thiol group on cysteine is con- verted to a hydropersulphide (–SSH) group by H S (Mustafa et al., 2009). –SSH group is more reactive and therefore can affect the stability and structure of a protein (Mustafa et al., Figure 2. Metabolism of H S. Pathway 1: H S is first converted to 2009). Mustafa’s group has shown that the target proteins 2 2 2− 2− thiosulphate (S O ), then to sulphite (SO ) and finally to sulphate for S-sulphhydration are glyceraldehyde-3-phosphate dehy- 2 3 3 2− (SO ) by SO. Pathway 2: TSMT converts H S to methanthiol and 4 2 drogenase, β-tubulin and actin in mouse liver (Mustafa et al., dimethylsulphide. Pathway 3: rhodanese (thiosulphate 2009). The S-sulphhydration process enhances protein activi- 2− sulphurtransferase) converts H S to thiocynate and sulphate (SO ). 2 4 ties, and is required for post-translational modification Image adapted from Li, Rose and Moore (2011). (Mustafa et al., 2009). Figure 3 shows the summary of interactions between H S In aortic vascular smooth muscle cells (VSMCs) of rats, H S and ion channels, transcription factors, protein kinases and opens K channels, causes hyperpolarization and increases ATP cellular proteins. electrical conductivity of cells (Zhao et al., 2001). In the same study, the group also measured the blood pressure and heart rate to discover endogenous effects of the gas—they Is H S all about anti-inflammation? found that there is a decrease in blood pressure after the H S injection (Zhao et al., 2001), which suggests a vascular H S has been known as an anti-inflammatory agent ( Esechie smooth muscle relaxation and hypotensive effect. In a fur- et al., 2008; Whiteman et al., 2010), whereas others view it 2 Bioscience Horizons • Volume 6 2013 Review article Figure 3. Summary of cellular targets of H S in cell signalling. H S interacts with ion channels, transcription factors and protein kinases, as well as 2 2 carry out post-translational modification of proteins. GAPDH, glyceraldehyde-3-phosphate dehydrogenase; H S, hydrogen sulphide; HO-1, heam oxygenase-1; iNOS, induced nitric oxide synthase; K , ATP-sensitive potassium channels; MAPK, mitogen-activated protein kinase; NO, nitric ATP oxide; NF-κB, nuclear factor kappa B; Pl3 K/PKB, phosphatidylinositol 3-kinase/protein kinase B pathway; TNFα, tumour necrosis factor alpha; TRPV, transient receptor potential vanilloid channels; VSMCs, vascular smooth muscle cells. Image is adapted from Li, Rose and Moore (2011). as a pro-inflammatory mediator ( Zhi et al., 2007; Bhatia 1996). Chen et al. (2009b) investigated the effects of H S on et al., 2008). Serum H S was positively correlated with the airway inflammation in rats. Ovalbumin (OVA) was used to lung function with an improved peak expiratory flow rate induce inflammation. It has been shown by the group that and peak inspiratory flow rate ( Chen et al., 2009b). H S also there is a lower level of H S in lung tissues of OVA challenged 2 2 increased anti-inflammatory cytokine (interleukin-10) and rats compared with the control; the level of CSE activity is decreased pro-inflammatory cytokine (interleukin-1-beta (IL- also lower (Chen et al., 2009b). This suggests that an abnor- 1β)) in a burn- and smoke-induced acute lung injury murine mal level of the gas is involved in the pathophysiology of model (Esechie et al., 2008). Controversially, other studies asthma. The same study compared lung histology of pre- and have showed that H S increases pro-inflammatory cytokines post-H S treatment in asthmatic rats and found that there is 2 2 (IL-1β, IL-6, TNFα) (Zhi et al., 2007), possibly via the extra- reduced airway inflammation, globlet cell hyperplasia and cellular signal-regulating kinase (ERK)-NF-κB pathway in mucus production after treatment (Chen et al., 2009b). A pos- cells (Zhi et al., 2007) or SP-neurokinin-1 receptor pathway sible mechanism is the downregulation of iNOS activity (Chen in acute pancreatitis (Bhatia et al., 2008). Some argued that et al., 2009b). This shows H S treatment seems to be benefi - the effects of inflammation produced by H S depend on the cial in diminishing airway inflammation and vascular remod - type of H S donors—slow-release H S donors are anti- elling in an animal model. Furthermore, VSMCs is responsible 2 2 inflammatory; fast-release H S donors are pro-inflammatory for airway narrowing and recruitment of inflammatory cells (Whiteman et al., 2010). Due to discrepancies in the litera- via cytokines and chemokines (Bara et al., 2010). Apart from ture, it is not possible to conclude whether the gas is pro- or targeting K channels (Zhao et al., 2001), H S also inhibits ATP 2 anti-inflammatory. However, its anti-inflammatory effects VSMCs proliferation and IL-8 production (Perry et al., 2011). seem to be beneficial in lung diseases. The suggested mechanism is the downregulation of extracel- lular signal-regulating kinases 1 and 2 (ERK-1/2) and p38 MAPK by H S (Perry et al., 2011). H S in the pathophysiology A normal whole tissue H S concentration ranges from 30 to of asthma over 100 µ M (Furne, Saeed and Levitt, 2008). Dorman et al. Symptoms of asthma include cough, wheeze and shortness of (2002) found that the H S concentration in lung tissue is breath (Barnes, 2008). It is characterized by airway inflamma - ~30 µ M (Dorman et al., 2002). Wu et al. (2008) measured tion (inflammatory cells and cytokines), vascular remodelling serum H S levels in healthy adult subjects (controls), patients (goblet cells hyperplasia) and bronchoconstriction (Barnes, with stable asthma, mild exacerbations and severe exacerbations 3 Review article Bioscience Horizons • Volume 6 2013 of asthma (Wu et al., 2008). They reported that there is a posi- it mediates anti-inflammatory effects remains unclear. Chen tive correlation between the patient’s health status and the gas et al. (2008) investigated whether H S has a role in mediating concentration in their serum (Wu et al., 2008). Another study the anti-inflammatory properties of theophylline. Although obtained a similar correlation in children (Tian et al., 2012). the study showed improved symptoms and lowered neutro- phil counts in sputum in the theophylline-treated group, there Studies have investigated the possibility of using H S as a is no significant change in the H S level (Chen et al., 2008). biomarker for the disease (Wu et al., 2008; Chen et al., H S may be involved in anti-inflammatory effects of theophyl - 2009a). Although H S is not currently used as a biomarker line via other mechanisms. Further studies are required to dis- like exhaled NO, sulphur compounds can be detected in cover the interactions between H S and COPD medications. breath, for example, in patients with chronic pancreatitis (Morselli-Labate, Fantini and Pezzilli, 2007) and cystic fibro - Since there is a positive correlation between the severity of sis (Kamboures et al., 2005). Wang et al. (2011) suggested the disease with serum H S levels (Chen et al., 2005), it has that nasal H S could be a way of accurately detecting H S been questioned whether it can be a biomarker to aid diagno- 2 2 metabolism in the respiratory system as its levels will not be sis and treatment of COPD (Chen et al., 2009a). Chen et al. affected by oral conditions (Wang et al., 2011). (2009a) reported no significant change in serum H S levels in acute exacerbation of COPD patients compared with con- trols. However, there is a significantly lower serum H S levels H S in the pathophysiology of chronic in those who required antibiotics treatment (Chen et al., 2009a). H S may not be suitable for diagnosing acute exacer- obstructive pulmonary disease bation of COPD, but its use in predicting the need for antibi- otic treatment may be considered. Chronic obstructive pulmonary disease (COPD) is a disease characterized by airflow obstruction due to airway inflamma - tion and hyper-responsiveness (Spurzem and Rennard, 2005). H S in the pathophysiology Since smoking is the main contributory factor for developing of  pulmonary fibrosis the disease, studies have been done to investigate the effects of H S on smoking-induced lung damage (Chen et al., 2011; Pulmonary fibrosis is a progressive fibrosing lung disease, Han et al., 2011). Chen et al. (2011) found a higher CSE level sometimes as a result of interstitial lung diseases and others in cigarette smoke (CS)-exposed rats compared with controls; without a known cause (idiopathic pulmonary fibrosis) and the subsequent H S administration reduced inflammatory (Raghu et al., 2011). The disease is characterized by abnor- cells and airway hyper-responsiveness in the CS-exposed mal activation of fibroblasts and myofibroblasts leading to group. In another study, similar findings were reported in excess extracellular matrix deposition and alveolar disrup- tobacco smoke-induced emphysema mice (Han et al., 2011). tion (Coward, Saini and Jenkins, 2010). The main protein Both studies suggest that H S is protective against smoking- involved is transforming growth factor beta (TGF-β). In induced lung injury. Further investigations are required to human fibroblasts, Fang et al. (2009a) reported a suppressive examine the mechanisms by which the gas reduces inflamma - effect of H S on TGF-β and hence inhibits fibroblasts migra - tory cells and cytokines. Furthermore, in humans, serum H S tion and proliferation. These findings are consistent with levels are higher in patients with COPD compared with diminished fibrotic changes in bleomycin-induced pulmonary healthy subjects (Chen et al., 2005). The group interpreted the fibrosis rats ( Fang et al., 2009b). Furthermore, measuring increase in the serum H S level as a compensatory mechanism H S levels in pulmonary fibrosis can help delineate the pos - to inhibit airway inflammation and limitation during exacer - sibility of the gas as a biomarker of the disease. bation episodes. Furthermore, the study showed that the serum H S level can be lowered by CS (Chen et al., 2005). After understanding the role of H S in the pathophysiol- 2 2 These findings indicated that H S, together with CS, affects ogy of lung diseases (Table 1), the ways to modify its effects disease progression (Chen et al., 2005). were next evaluated and its therapeutic potential assessed. Theophylline, a phosphodiesterase inhibitor, is used in the Despite the different serum H S levels found in asthma treatment of COPD (Barnes, 2005). The mechanism of which and COPD, the gas has been found to have anti- inflammatory Table 1. The role of H S in asthma, COPD and pulmonary fibrosis—similarities and differences Asthma COPD Pulmonary fibrosis Serum H S level Low High Unknown Anti-inflammation Anti-inflammation Inhibition of fibroblasts and myofibro - Role in disease Bronchodilation Bronchodilation blasts migration and proliferation H S as a biomarker? Possibly as nasal H S Possibly Possibly 2 2 4 Bioscience Horizons • Volume 6 2013 Review article and bronchodilatory effects. In pulmonary fibrosis, H S Modifying effects of H S: inhibits fibroblasts and myofibroblasts migration and prolif - sulphide-releasing derivatives eration, therefore, attenuates the disease progression. Further studies are required to investigate the possible role of H S as Scientists demonstrated that sulphide-releasing derivatives a biomarker for these diseases. accentuate anti-inflammatory effects of H S (Wallace, 2007). Non-steroidal anti-inflammatory drugs (NSAIDs), used in Modifying effects of H S: CSE and cardiovascular diseases and pain relief, have well-known side effects of gastric irritation and erosion (Bennett et al., 2005). CBS inhibitors Therefore, there is a need to discover ways to minimize these unwanted effects. Wallace et al. (2007) compared the degree Studies have looked at changes in inflammation via inhibi - of intestinal damage in the use of diclofenac and S-diclofenac tion or enhancement of H S release. As CSE and CBS are the (diclofenac linked to a H S-releasing molecule) in rats two main enzymes that produce H S (Whiteman and Moore, (Wallace et al., 2007). Figure 4 shows the structures of these 2009), decrease enzyme production in turn decreases H S two compounds. They found that S-diclofenac significantly release and vice versa. Gil, Gallego and Jimenez (2011) suc- reduced intestinal damage (Wallace et al., 2007). Furthermore, cessfully inhibited H S production by using d , l -propargylg- Li et al. (2007) have shown that S-diclofenac is effective in lycine (PAG) (a CSE inhibitor) and amino-oxyacetic acid reducing LPS-induced neutrophil infiltration in the lungs of (AOAA) (a CBS inhibitor) in rats (Gil et al., 2011). A rats (Li et al., 2007). These findings may be explained by the decrease in H S causes more leukocyte adherence and infil - ability of H S to downregulate TNFα (Liu et al., 2000) and tration through the endothelial surface (Zanardo et al., leucocyte adherence (Zanardo et al., 2006). 2006), which may promote mucosal inflammation ( Fiorucci et al., 2005). On the other hand, Sen et al. (2012) have Further studies are required to delineate ways in which shown that the increased expression of CSE and CBS via H S production can be modified and thereby allowing benefi - gene therapy increases H S levels in cell cultures (Sen et al., cial effects of the gas to be exploited. Figure 5 shows other 2012). However, whether this effect can be translated to ani- possible targets for modifying H S production. mal models and have an impact on inflammation is still yet to be discovered. Although manipulating CSE and CBS lev- Conclusion and the future els can alter H S production, it is important to recognize other functions that these enzymes have elsewhere in the H S is a recently discovered gasotransmitter (Li, Rose and body. Homocysteinaemia is a disease where CSE is deficient Moore, 2011). It has been found to be involved in cell signal- due to mutations in the human CSE gene (Miles and Kraus, ling pathways via ion channels, transcription factors, protein 2004). The condition is associated with atherosclerosis, kinases and S-sulphhydration (Li, Rose and Moore, 2011). Its endothelial dysfunction and coronary heart disease (Cheng, possible pro- and anti-inflammatory properties require fur - 1997). Inhibition of CSE may lead to detrimental conse- ther work to delineate and exploit. Although its role in inflam - quences. Therefore, it may not be suitable for long-term mation is not entirely clear, it seems to have beneficial effects therapy. in asthma, COPD and pulmonary fibrosis. Studies have shown that NO, CO and H S interact with each other (Li, Hsu and Moore, 2009) and there is possible cross talk amongst these Modifying effects of H S: H S 2 2 gases in disease processes (Chen et al., 2009a, b). Therefore, like exhaled NO, H S may be a future biomarker for pulmo- poisoning nary diseases (Barnes et al., 2010). Finally, by targeting bio- Like CO, H S has the ability to inhibit cytochrome c oxidase synthesis and metabolism pathways, therapeutic effects of (Truong et al., 2006) causing disturbance in the respiratory H S can be established. There are H S-releasing non-steroidal 2 2 drive, unconsciousness and eventually death (Almeida and Guidotti, 1999). Rhodanese, an enzyme that breaks down H S 2− into thiocynate and sulphate (SO ) (Li, Rose and Moore, 2011) may be used as an antidote for H S toxicity (Szabo, 2007). In vitro, cell damage caused by H S may be due to reac- tive oxygen species production (ROS) (Eghbal, Pennefather and O’Brien, 2004). In vivo, Almeida and Guidotti (1999) found that sodium bicarbonate (NaHCO ) infusion reversed actions of H S. However, the mechanism is unclear. Furthermore, Truong et al. (2006) reported glutathione as a possible role in reducing H S intoxication (Truong et al., Figure 4. Diclofenac (2-(2,6-dicloranilino) phenylacetic acid) and 2006). Therefore, treatment against H S poisoning should be 2 S-Diclofenac (2-[(2,6-dichlorophenyl)amino] benzeneacetic acid aimed at enhancing breakdown of the endogenous gas, reduce 4-(3H-1,2-dithiole-3-thione-5-yl)-phenyl ester) S-Diclofenac can also be ROS cell damage and reverse actions of H S. called ATB-337 or ACS 15. Image adapted from Wallace (2007). 5 Review article Bioscience Horizons • Volume 6 2013 Acknowledgements The author would like to thank Professor Louise E Donnelly, Dr Christos Rossios and Dr Charalambos Michaeloudes for their constructive feedback. Funding None. Author biography C.H.K.W. is a fourth year medical student studying respira- tory science BSc at the National Heart and Lung Institute, Imperial College London. Her mixed fields of interest include regenerative respiratory medicine and the art of surgery. She would like to become an all-rounded clinician with a back- ground of research and teaching. References Almeida, A. F. and Guidotti, T. L. (1999) Differential sensitivity of lung and brain to sulfide exposure: a peripheral mechanism for apnea. Toxicological Sciences: An Official Journal of the Society of Toxicology , 50 (2), 287–293. Bara, I., Ozier, A., Tunon de Lara, J. M. et  al. (2010) Pathophysiology of bronchial smooth muscle remodelling in asthma. 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The role of hydrogen sulphide in lung diseases

Bioscience Horizons , Volume 6 – Sep 11, 2013

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BioscienceHorizons Volume 6 2013 10.1093/biohorizons/hzt009 Review article Clara Hoi Ka Wu* Imperial College London, Royal Brompton Campus, Dovehouse Street, London SW3 6LY, UK *Corresponding author: Email: hkw09@ic.ac.uk Project superviser: Professor Louise E. Donnelly, National Heart and Lung Institute, Imperial College London, Royal Brompton Campus, Dovehouse Street, London SW3 6LY, UK. Hydrogen sulphide (H S) is a recently discovered gasotransmitter. It is endogenously synthesized by cystathionine β synthe- tase, cystathionine γ lyase, cysteine aminotransferase, 3-mercaptopyruvate sulphurtransferase and cysteine lyase. Its metab- 2− olism leads to the production of sulphate (SO ), methanthiol, dimethylsulphide and thiocynate. The gas interacts with ion channels, protein kinases and transcription factors. It is also involved in post-translational modification of proteins via S-sulphhydration. Although debate continues as to whether H S is pro- or anti-inflammatory, its anti-inflammatory properties seem to have beneficial effects in various lung diseases. Serum levels of H S differ between asthma, chronic obstructive pul - monary disease and pulmonary fibrosis, which makes it difficult for the gas to be used as a biomarker for lung diseases. Apart from exogenous sources of H S, targets to enhance or inhibit the gas can be found in its synthesis and metabolism pathway. H S-releasing non-steroidal anti-inflammatory drugs are currently being developed. Further research will aid to determine the precise role of H S in respiratory diseases. Key words: hydrogen sulphide, asthma, chronic obstructive pulmonary disease, pulmonary fibrosis Submitted on 18 December 2012; accepted on 21 June 2013 Hydrogen sulphide (H S) is a chemical compound made up of called gasotransmitters (Li, Rose and Moore, 2011). H S is 2 2 two hydrogen and one sulphide molecule, hence the chemical synthesized in the cytoplasm from l -cysteine by various formula H S (Hydrogen Sulfide—PubChem .). It is gaseous in enzymes—cystathionine β synthetase (CBS) (Whiteman and room temperature, has flammable properties and is toxic to Moore, 2009), cystathionine γ lyase (CSE) (Whiteman and inhale and contact (HPA - Hydrogen sulphide.). It has a dis- Moore, 2009), cysteine aminotransferase (CAT) (Li, Rose tinctive smell of rotten eggs (Hydrogen Sulfide—PubChem .). and Moore, 2011), 3-mercaptopyruvate sulphurtransferase Exogenous H S is used in industries to produce sulphur and (3-MST) (Li, Rose and Moore, 2011) and cysteine lyase (CL) analyse chemicals (Hydrogen Sulfide—PubChem .). It is also (Li, Rose and Moore, 2011)—which are the main enzymes present inside the body and involves in disease processes (Li, involved. Figure 1 shows synthesis pathways of H S. Rose and Moore, 2011). The mechanisms of H S in cell sig- Rhodanese (thiosulphate sulphurtransferase), thiol-S- nalling and cellular function alteration will be explored. methyltransferase (TSMT) and sulphite oxidase (SO) are Although H S has effects on other body systems such as the enzymes responsible for the metabolism of H S (Stipanuk cardiovascular and neurological systems (Qu et al., 2008; Li, and Ueki, 2011). Figure 2 shows three main ways in which Hsu and Moore, 2009), this paper will focus on discussing the H S can be broken down to its metabolic by-products. compound’s pathophysiological role in respiratory diseases and evaluating ways to modify its effects. H S in cell signalling Biosynthesis and metabolism of H S H S can be involved in cell signalling via its interactions with Endogenous H S, carbon monoxide (CO) and nitric oxide ion channels. Zhao et al. (2001) described that the gas acts on (NO) are gases involved in cell signalling, they can also be ATP-sensitive potassium (K ) channels (Zhao et al., 2001). ATP © The Author 2013. Published by Oxford University Press. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0 ), which per / mits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com Review article Bioscience Horizons • Volume 6 2013 ther study on mice, Kubo et al. (2007) showed that the bron- chodilatory effects of H S are possibly due to the activation of K channels (Kubo et al., 2007). Furthermore, transient ATP receptor potential vanilloid channels are also a target for H S (Trevisani et al., 2005). The gas stimulates the release of substance P (SP) and neurokinin A (NKA) at sensory nerve terminals, causing airway inflammation ( Trevisani et al., 2005). Although the exact mechanisms between the interac- tion of H S and ion channels are still unclear, the gas has definite physiological role in the lungs. Intracellular transcription factors are influenced by H S (Oh et al., 2006). Oh et al. (2006) demonstrated that H S reduces NO production by inhibiting expression of induced NO synthase (iNOS) and haem-oxygenase-1 in RAW264.7 macrophages (Oh et al., 2006). As NO is produced by iNOS and is pro-inflammatory ( Chung et al., 2001), downregulat- ing iNOS expression by H S will help decrease inflammation. Furthermore, the study found that H S also diminishes lipo- Figure 1. Synthesis of H S. Pathway 1: CBS converts cysteine to H S 2 2 polysaccharide (LPS)-induced nuclear factor kappa B (NF- and l -serine. Pathway 2: CSE converts cysteine to H S. Pathway 3: cysteine is first converted to 3-mercaptopyruvate by CAT, then to H S κB) (Chung et al., 2001). NF-κB is a protein that regulates by 3-MST. Pathway 4: CL converts cysteine and sulphate to H S and the expression of pro-inflammatory mediator genes ( Karin, l -cysteate. Pathways 1, 2 and 4 occur in the cytoplasm, whereas 1998), such as tumour necrosis factor alpha (TNFα) (Liu Pathway 3 occurs in the mitochondria. Image adapted from Li, Rose et al., 2000) and iNOS (Kleinert, Schwarz and Forstermann, and Moore (2011). 2003). Therefore, the decrease in NF-κB expression reduces inflammation. H S has regulatory effects on kinases (Du et al., 2004). Du et al. (2004) have demonstrated that H S reduces mitogen- activated protein kinase (MAPK) activity and hence suppresses VSMCs proliferation. Although the possible mechanism in pancreatic cells is the downregulation of pro-inflammatory cytokines via the phosphatidylinositol 3-kinase (Pl3K)/protein kinase B (PKB) pathway (Tamizhselvi et al., 2009), there is no current study to demonstrate that a similar process may occur in bronchial smooth muscle cells. H S can also signal through protein S-sulphhydration (Mustafa et al., 2009). S-sulphhydration is the process whereby the sulhydryl (SH)/thiol group on cysteine is con- verted to a hydropersulphide (–SSH) group by H S (Mustafa et al., 2009). –SSH group is more reactive and therefore can affect the stability and structure of a protein (Mustafa et al., Figure 2. Metabolism of H S. Pathway 1: H S is first converted to 2009). Mustafa’s group has shown that the target proteins 2 2 2− 2− thiosulphate (S O ), then to sulphite (SO ) and finally to sulphate for S-sulphhydration are glyceraldehyde-3-phosphate dehy- 2 3 3 2− (SO ) by SO. Pathway 2: TSMT converts H S to methanthiol and 4 2 drogenase, β-tubulin and actin in mouse liver (Mustafa et al., dimethylsulphide. Pathway 3: rhodanese (thiosulphate 2009). The S-sulphhydration process enhances protein activi- 2− sulphurtransferase) converts H S to thiocynate and sulphate (SO ). 2 4 ties, and is required for post-translational modification Image adapted from Li, Rose and Moore (2011). (Mustafa et al., 2009). Figure 3 shows the summary of interactions between H S In aortic vascular smooth muscle cells (VSMCs) of rats, H S and ion channels, transcription factors, protein kinases and opens K channels, causes hyperpolarization and increases ATP cellular proteins. electrical conductivity of cells (Zhao et al., 2001). In the same study, the group also measured the blood pressure and heart rate to discover endogenous effects of the gas—they Is H S all about anti-inflammation? found that there is a decrease in blood pressure after the H S injection (Zhao et al., 2001), which suggests a vascular H S has been known as an anti-inflammatory agent ( Esechie smooth muscle relaxation and hypotensive effect. In a fur- et al., 2008; Whiteman et al., 2010), whereas others view it 2 Bioscience Horizons • Volume 6 2013 Review article Figure 3. Summary of cellular targets of H S in cell signalling. H S interacts with ion channels, transcription factors and protein kinases, as well as 2 2 carry out post-translational modification of proteins. GAPDH, glyceraldehyde-3-phosphate dehydrogenase; H S, hydrogen sulphide; HO-1, heam oxygenase-1; iNOS, induced nitric oxide synthase; K , ATP-sensitive potassium channels; MAPK, mitogen-activated protein kinase; NO, nitric ATP oxide; NF-κB, nuclear factor kappa B; Pl3 K/PKB, phosphatidylinositol 3-kinase/protein kinase B pathway; TNFα, tumour necrosis factor alpha; TRPV, transient receptor potential vanilloid channels; VSMCs, vascular smooth muscle cells. Image is adapted from Li, Rose and Moore (2011). as a pro-inflammatory mediator ( Zhi et al., 2007; Bhatia 1996). Chen et al. (2009b) investigated the effects of H S on et al., 2008). Serum H S was positively correlated with the airway inflammation in rats. Ovalbumin (OVA) was used to lung function with an improved peak expiratory flow rate induce inflammation. It has been shown by the group that and peak inspiratory flow rate ( Chen et al., 2009b). H S also there is a lower level of H S in lung tissues of OVA challenged 2 2 increased anti-inflammatory cytokine (interleukin-10) and rats compared with the control; the level of CSE activity is decreased pro-inflammatory cytokine (interleukin-1-beta (IL- also lower (Chen et al., 2009b). This suggests that an abnor- 1β)) in a burn- and smoke-induced acute lung injury murine mal level of the gas is involved in the pathophysiology of model (Esechie et al., 2008). Controversially, other studies asthma. The same study compared lung histology of pre- and have showed that H S increases pro-inflammatory cytokines post-H S treatment in asthmatic rats and found that there is 2 2 (IL-1β, IL-6, TNFα) (Zhi et al., 2007), possibly via the extra- reduced airway inflammation, globlet cell hyperplasia and cellular signal-regulating kinase (ERK)-NF-κB pathway in mucus production after treatment (Chen et al., 2009b). A pos- cells (Zhi et al., 2007) or SP-neurokinin-1 receptor pathway sible mechanism is the downregulation of iNOS activity (Chen in acute pancreatitis (Bhatia et al., 2008). Some argued that et al., 2009b). This shows H S treatment seems to be benefi - the effects of inflammation produced by H S depend on the cial in diminishing airway inflammation and vascular remod - type of H S donors—slow-release H S donors are anti- elling in an animal model. Furthermore, VSMCs is responsible 2 2 inflammatory; fast-release H S donors are pro-inflammatory for airway narrowing and recruitment of inflammatory cells (Whiteman et al., 2010). Due to discrepancies in the litera- via cytokines and chemokines (Bara et al., 2010). Apart from ture, it is not possible to conclude whether the gas is pro- or targeting K channels (Zhao et al., 2001), H S also inhibits ATP 2 anti-inflammatory. However, its anti-inflammatory effects VSMCs proliferation and IL-8 production (Perry et al., 2011). seem to be beneficial in lung diseases. The suggested mechanism is the downregulation of extracel- lular signal-regulating kinases 1 and 2 (ERK-1/2) and p38 MAPK by H S (Perry et al., 2011). H S in the pathophysiology A normal whole tissue H S concentration ranges from 30 to of asthma over 100 µ M (Furne, Saeed and Levitt, 2008). Dorman et al. Symptoms of asthma include cough, wheeze and shortness of (2002) found that the H S concentration in lung tissue is breath (Barnes, 2008). It is characterized by airway inflamma - ~30 µ M (Dorman et al., 2002). Wu et al. (2008) measured tion (inflammatory cells and cytokines), vascular remodelling serum H S levels in healthy adult subjects (controls), patients (goblet cells hyperplasia) and bronchoconstriction (Barnes, with stable asthma, mild exacerbations and severe exacerbations 3 Review article Bioscience Horizons • Volume 6 2013 of asthma (Wu et al., 2008). They reported that there is a posi- it mediates anti-inflammatory effects remains unclear. Chen tive correlation between the patient’s health status and the gas et al. (2008) investigated whether H S has a role in mediating concentration in their serum (Wu et al., 2008). Another study the anti-inflammatory properties of theophylline. Although obtained a similar correlation in children (Tian et al., 2012). the study showed improved symptoms and lowered neutro- phil counts in sputum in the theophylline-treated group, there Studies have investigated the possibility of using H S as a is no significant change in the H S level (Chen et al., 2008). biomarker for the disease (Wu et al., 2008; Chen et al., H S may be involved in anti-inflammatory effects of theophyl - 2009a). Although H S is not currently used as a biomarker line via other mechanisms. Further studies are required to dis- like exhaled NO, sulphur compounds can be detected in cover the interactions between H S and COPD medications. breath, for example, in patients with chronic pancreatitis (Morselli-Labate, Fantini and Pezzilli, 2007) and cystic fibro - Since there is a positive correlation between the severity of sis (Kamboures et al., 2005). Wang et al. (2011) suggested the disease with serum H S levels (Chen et al., 2005), it has that nasal H S could be a way of accurately detecting H S been questioned whether it can be a biomarker to aid diagno- 2 2 metabolism in the respiratory system as its levels will not be sis and treatment of COPD (Chen et al., 2009a). Chen et al. affected by oral conditions (Wang et al., 2011). (2009a) reported no significant change in serum H S levels in acute exacerbation of COPD patients compared with con- trols. However, there is a significantly lower serum H S levels H S in the pathophysiology of chronic in those who required antibiotics treatment (Chen et al., 2009a). H S may not be suitable for diagnosing acute exacer- obstructive pulmonary disease bation of COPD, but its use in predicting the need for antibi- otic treatment may be considered. Chronic obstructive pulmonary disease (COPD) is a disease characterized by airflow obstruction due to airway inflamma - tion and hyper-responsiveness (Spurzem and Rennard, 2005). H S in the pathophysiology Since smoking is the main contributory factor for developing of  pulmonary fibrosis the disease, studies have been done to investigate the effects of H S on smoking-induced lung damage (Chen et al., 2011; Pulmonary fibrosis is a progressive fibrosing lung disease, Han et al., 2011). Chen et al. (2011) found a higher CSE level sometimes as a result of interstitial lung diseases and others in cigarette smoke (CS)-exposed rats compared with controls; without a known cause (idiopathic pulmonary fibrosis) and the subsequent H S administration reduced inflammatory (Raghu et al., 2011). The disease is characterized by abnor- cells and airway hyper-responsiveness in the CS-exposed mal activation of fibroblasts and myofibroblasts leading to group. In another study, similar findings were reported in excess extracellular matrix deposition and alveolar disrup- tobacco smoke-induced emphysema mice (Han et al., 2011). tion (Coward, Saini and Jenkins, 2010). The main protein Both studies suggest that H S is protective against smoking- involved is transforming growth factor beta (TGF-β). In induced lung injury. Further investigations are required to human fibroblasts, Fang et al. (2009a) reported a suppressive examine the mechanisms by which the gas reduces inflamma - effect of H S on TGF-β and hence inhibits fibroblasts migra - tory cells and cytokines. Furthermore, in humans, serum H S tion and proliferation. These findings are consistent with levels are higher in patients with COPD compared with diminished fibrotic changes in bleomycin-induced pulmonary healthy subjects (Chen et al., 2005). The group interpreted the fibrosis rats ( Fang et al., 2009b). Furthermore, measuring increase in the serum H S level as a compensatory mechanism H S levels in pulmonary fibrosis can help delineate the pos - to inhibit airway inflammation and limitation during exacer - sibility of the gas as a biomarker of the disease. bation episodes. Furthermore, the study showed that the serum H S level can be lowered by CS (Chen et al., 2005). After understanding the role of H S in the pathophysiol- 2 2 These findings indicated that H S, together with CS, affects ogy of lung diseases (Table 1), the ways to modify its effects disease progression (Chen et al., 2005). were next evaluated and its therapeutic potential assessed. Theophylline, a phosphodiesterase inhibitor, is used in the Despite the different serum H S levels found in asthma treatment of COPD (Barnes, 2005). The mechanism of which and COPD, the gas has been found to have anti- inflammatory Table 1. The role of H S in asthma, COPD and pulmonary fibrosis—similarities and differences Asthma COPD Pulmonary fibrosis Serum H S level Low High Unknown Anti-inflammation Anti-inflammation Inhibition of fibroblasts and myofibro - Role in disease Bronchodilation Bronchodilation blasts migration and proliferation H S as a biomarker? Possibly as nasal H S Possibly Possibly 2 2 4 Bioscience Horizons • Volume 6 2013 Review article and bronchodilatory effects. In pulmonary fibrosis, H S Modifying effects of H S: inhibits fibroblasts and myofibroblasts migration and prolif - sulphide-releasing derivatives eration, therefore, attenuates the disease progression. Further studies are required to investigate the possible role of H S as Scientists demonstrated that sulphide-releasing derivatives a biomarker for these diseases. accentuate anti-inflammatory effects of H S (Wallace, 2007). Non-steroidal anti-inflammatory drugs (NSAIDs), used in Modifying effects of H S: CSE and cardiovascular diseases and pain relief, have well-known side effects of gastric irritation and erosion (Bennett et al., 2005). CBS inhibitors Therefore, there is a need to discover ways to minimize these unwanted effects. Wallace et al. (2007) compared the degree Studies have looked at changes in inflammation via inhibi - of intestinal damage in the use of diclofenac and S-diclofenac tion or enhancement of H S release. As CSE and CBS are the (diclofenac linked to a H S-releasing molecule) in rats two main enzymes that produce H S (Whiteman and Moore, (Wallace et al., 2007). Figure 4 shows the structures of these 2009), decrease enzyme production in turn decreases H S two compounds. They found that S-diclofenac significantly release and vice versa. Gil, Gallego and Jimenez (2011) suc- reduced intestinal damage (Wallace et al., 2007). Furthermore, cessfully inhibited H S production by using d , l -propargylg- Li et al. (2007) have shown that S-diclofenac is effective in lycine (PAG) (a CSE inhibitor) and amino-oxyacetic acid reducing LPS-induced neutrophil infiltration in the lungs of (AOAA) (a CBS inhibitor) in rats (Gil et al., 2011). A rats (Li et al., 2007). These findings may be explained by the decrease in H S causes more leukocyte adherence and infil - ability of H S to downregulate TNFα (Liu et al., 2000) and tration through the endothelial surface (Zanardo et al., leucocyte adherence (Zanardo et al., 2006). 2006), which may promote mucosal inflammation ( Fiorucci et al., 2005). On the other hand, Sen et al. (2012) have Further studies are required to delineate ways in which shown that the increased expression of CSE and CBS via H S production can be modified and thereby allowing benefi - gene therapy increases H S levels in cell cultures (Sen et al., cial effects of the gas to be exploited. Figure 5 shows other 2012). However, whether this effect can be translated to ani- possible targets for modifying H S production. mal models and have an impact on inflammation is still yet to be discovered. Although manipulating CSE and CBS lev- Conclusion and the future els can alter H S production, it is important to recognize other functions that these enzymes have elsewhere in the H S is a recently discovered gasotransmitter (Li, Rose and body. Homocysteinaemia is a disease where CSE is deficient Moore, 2011). It has been found to be involved in cell signal- due to mutations in the human CSE gene (Miles and Kraus, ling pathways via ion channels, transcription factors, protein 2004). The condition is associated with atherosclerosis, kinases and S-sulphhydration (Li, Rose and Moore, 2011). Its endothelial dysfunction and coronary heart disease (Cheng, possible pro- and anti-inflammatory properties require fur - 1997). Inhibition of CSE may lead to detrimental conse- ther work to delineate and exploit. Although its role in inflam - quences. Therefore, it may not be suitable for long-term mation is not entirely clear, it seems to have beneficial effects therapy. in asthma, COPD and pulmonary fibrosis. Studies have shown that NO, CO and H S interact with each other (Li, Hsu and Moore, 2009) and there is possible cross talk amongst these Modifying effects of H S: H S 2 2 gases in disease processes (Chen et al., 2009a, b). Therefore, like exhaled NO, H S may be a future biomarker for pulmo- poisoning nary diseases (Barnes et al., 2010). Finally, by targeting bio- Like CO, H S has the ability to inhibit cytochrome c oxidase synthesis and metabolism pathways, therapeutic effects of (Truong et al., 2006) causing disturbance in the respiratory H S can be established. There are H S-releasing non-steroidal 2 2 drive, unconsciousness and eventually death (Almeida and Guidotti, 1999). Rhodanese, an enzyme that breaks down H S 2− into thiocynate and sulphate (SO ) (Li, Rose and Moore, 2011) may be used as an antidote for H S toxicity (Szabo, 2007). In vitro, cell damage caused by H S may be due to reac- tive oxygen species production (ROS) (Eghbal, Pennefather and O’Brien, 2004). In vivo, Almeida and Guidotti (1999) found that sodium bicarbonate (NaHCO ) infusion reversed actions of H S. However, the mechanism is unclear. Furthermore, Truong et al. (2006) reported glutathione as a possible role in reducing H S intoxication (Truong et al., Figure 4. Diclofenac (2-(2,6-dicloranilino) phenylacetic acid) and 2006). Therefore, treatment against H S poisoning should be 2 S-Diclofenac (2-[(2,6-dichlorophenyl)amino] benzeneacetic acid aimed at enhancing breakdown of the endogenous gas, reduce 4-(3H-1,2-dithiole-3-thione-5-yl)-phenyl ester) S-Diclofenac can also be ROS cell damage and reverse actions of H S. called ATB-337 or ACS 15. Image adapted from Wallace (2007). 5 Review article Bioscience Horizons • Volume 6 2013 Acknowledgements The author would like to thank Professor Louise E Donnelly, Dr Christos Rossios and Dr Charalambos Michaeloudes for their constructive feedback. Funding None. Author biography C.H.K.W. is a fourth year medical student studying respira- tory science BSc at the National Heart and Lung Institute, Imperial College London. Her mixed fields of interest include regenerative respiratory medicine and the art of surgery. She would like to become an all-rounded clinician with a back- ground of research and teaching. References Almeida, A. F. and Guidotti, T. L. (1999) Differential sensitivity of lung and brain to sulfide exposure: a peripheral mechanism for apnea. Toxicological Sciences: An Official Journal of the Society of Toxicology , 50 (2), 287–293. Bara, I., Ozier, A., Tunon de Lara, J. M. et  al. (2010) Pathophysiology of bronchial smooth muscle remodelling in asthma. 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Bioscience HorizonsOxford University Press

Published: Sep 11, 2013

Keywords: hydrogen sulphide asthma chronic obstructive pulmonary disease pulmonary fibrosis

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