Postgraduate Thesis: The involvement of serotoninergic system in cigarette smoke-induced oxidative stress and inflammation

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Title	The involvement of serotoninergic system in cigarette smoke-induced oxidative stress and inflammation
Authors	Lau, Kwok-wai 劉國威
Issue Date	2012
Publisher	The University of Hong Kong (Pokfulam, Hong Kong)
Abstract	Cigarette smoking is a major risk factor in the development of age-related chronic obstructive pulmonary disease (COPD) with chronic airway inflammation as a key feature. Currently, no effective treatment can reduce the protracted inflammation in the lung of COPD. Further research on the inflammatory mechanisms would therefore be important in determining new potential therapeutic targets in COPD. Serotonin (5-hydroxytryptamine, 5-HT) is a neurotransmitter that plays an important role in pulmonary functions and inflammatory responses. The serotoninergic system including serotonin transporter (SERT), serotonin receptors (5-HTR) and its metabolic enzyme monoamine oxidase (MAO) have been reported to associate with cigarette smoking and/or COPD. Blockade of serotonin receptor 2A (5-HTR2A) with its selective antagonist ketanserin has been shown to improve lung function in COPD patients. In this study, we hypothesize that the serotoninergic system is involved in cigarette smoke-induced oxidative stress, inflammation and COPD. Exposure to cigarette smoke medium (CSM) caused the elevation of interleukin (IL)-8 levels in primary normal human bronchial epithelial (NHBE) cells and a human bronchial epithelial cell line (BEAS-2B) in vitro via activation of p38 and extracellular signal-regulated kinases 1 and 2 (ERK1/2) signaling pathway. Besides, CSM was found to disrupt the glutathione (GSH) system, resulting in the translocation of nuclear factor-erythroid 2 related factor 2 (Nrf2) to the nucleus. Knock-down of Nrf2 by small interference RNA (siRNA) blocked CSM-induced IL-8 release. Pretreatment with ketanserin was found to attenuate CSM-induced IL-8 release by inhibiting the p38, ERK1/2, and Nrf2 signaling pathways, and by partially restoring the GSH system. On the other hand, CSM reduced MAO activity in BEAS-2B, indicating a reduced catabolism of 5-HT. Furthermore, 5-HT was found to share the common p38 and ERK1/2 signaling pathway with CSM in IL-8 release. In the cigarette smoke-exposed rat model, the GSH system in the lung was found to be disrupted compared to the sham-air control, supporting our in vitro findings. Interestingly, we found an increased MAO-A activity in the lung of cigarette smoke-exposed rats in comparison to sham air-exposed rats. The increased MAO-A activity in the lung was associated with the reduction of 5-HT levels in bronchoalveolar lavage (BAL) and lung homogenates, while the increased metabolism of 5-HT may be involved in cigarette smoke-induced superoxide anion levels. On the other hand, serum, but not plasma level of 5-HT was elevated in cigarette smoke-exposed group, which may be due to platelet activation caused by cigarette smoke. In the clinical study, the elevated plasma 5-HT levels were found to be associated with an increased odds ratio for COPD and positively correlated with age in COPD patients. Furthermore, plasma 5-HT was also demonstrated to be a significant mediator on the relation between cigarette smoking and COPD. In summary, our study supports the hypothesis that the serotoninergic system contributes to cigarette smoke-induced oxidative stress, inflammation and COPD. The serotoninergic system (e.g. 5-HTR2A) may constitute potential therapeutic targets for the treatment of COPD, which is worthy for further investigation.
Advisors	Law, ACK Mak, JCW
Degree	Doctor of Philosophy
Subject	Serotoninergic mechanisms. Oxidative stress. Lungs - Diseases, Obstructive.
Dept/Program	Medicine

DC Field	Value
dc.contributor.advisor	Law, ACK
dc.contributor.advisor	Mak, JCW
dc.contributor.author	Lau, Kwok-wai
dc.contributor.author	劉國威
dc.date.hkucongregation	2012
dc.date.issued	2012
dc.description.abstract	Cigarette smoking is a major risk factor in the development of age-related chronic obstructive pulmonary disease (COPD) with chronic airway inflammation as a key feature. Currently, no effective treatment can reduce the protracted inflammation in the lung of COPD. Further research on the inflammatory mechanisms would therefore be important in determining new potential therapeutic targets in COPD. Serotonin (5-hydroxytryptamine, 5-HT) is a neurotransmitter that plays an important role in pulmonary functions and inflammatory responses. The serotoninergic system including serotonin transporter (SERT), serotonin receptors (5-HTR) and its metabolic enzyme monoamine oxidase (MAO) have been reported to associate with cigarette smoking and/or COPD. Blockade of serotonin receptor 2A (5-HTR2A) with its selective antagonist ketanserin has been shown to improve lung function in COPD patients. In this study, we hypothesize that the serotoninergic system is involved in cigarette smoke-induced oxidative stress, inflammation and COPD. Exposure to cigarette smoke medium (CSM) caused the elevation of interleukin (IL)-8 levels in primary normal human bronchial epithelial (NHBE) cells and a human bronchial epithelial cell line (BEAS-2B) in vitro via activation of p38 and extracellular signal-regulated kinases 1 and 2 (ERK1/2) signaling pathway. Besides, CSM was found to disrupt the glutathione (GSH) system, resulting in the translocation of nuclear factor-erythroid 2 related factor 2 (Nrf2) to the nucleus. Knock-down of Nrf2 by small interference RNA (siRNA) blocked CSM-induced IL-8 release. Pretreatment with ketanserin was found to attenuate CSM-induced IL-8 release by inhibiting the p38, ERK1/2, and Nrf2 signaling pathways, and by partially restoring the GSH system. On the other hand, CSM reduced MAO activity in BEAS-2B, indicating a reduced catabolism of 5-HT. Furthermore, 5-HT was found to share the common p38 and ERK1/2 signaling pathway with CSM in IL-8 release. In the cigarette smoke-exposed rat model, the GSH system in the lung was found to be disrupted compared to the sham-air control, supporting our in vitro findings. Interestingly, we found an increased MAO-A activity in the lung of cigarette smoke-exposed rats in comparison to sham air-exposed rats. The increased MAO-A activity in the lung was associated with the reduction of 5-HT levels in bronchoalveolar lavage (BAL) and lung homogenates, while the increased metabolism of 5-HT may be involved in cigarette smoke-induced superoxide anion levels. On the other hand, serum, but not plasma level of 5-HT was elevated in cigarette smoke-exposed group, which may be due to platelet activation caused by cigarette smoke. In the clinical study, the elevated plasma 5-HT levels were found to be associated with an increased odds ratio for COPD and positively correlated with age in COPD patients. Furthermore, plasma 5-HT was also demonstrated to be a significant mediator on the relation between cigarette smoking and COPD. In summary, our study supports the hypothesis that the serotoninergic system contributes to cigarette smoke-induced oxidative stress, inflammation and COPD. The serotoninergic system (e.g. 5-HTR2A) may constitute potential therapeutic targets for the treatment of COPD, which is worthy for further investigation.
dc.description.nature	published_or_final_version
dc.description.thesisdiscipline	Medicine
dc.description.thesislevel	doctoral
dc.description.thesisname	Doctor of Philosophy
dc.identifier.hkul	b4786961
dc.language	eng
dc.publisher	The University of Hong Kong (Pokfulam, Hong Kong)
dc.relation.ispartof	HKU Theses Online (HKUTO)
dc.rights	The author retains all proprietary rights, (such as patent rights) and the right to use in future works.
dc.rights	Creative Commons: Attribution 3.0 Hong Kong License
dc.source.uri	http://hub.hku.hk/bib/B47869616
dc.subject.lcsh	Serotoninergic mechanisms.
dc.subject.lcsh	Oxidative stress.
dc.subject.lcsh	Lungs - Diseases, Obstructive.
dc.title	The involvement of serotoninergic system in cigarette smoke-induced oxidative stress and inflammation
dc.type	PG_Thesis

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chronic obstructive pulmonary disease (COPD) with chronic airway inflammation

as a key feature. Currently, no effective treatment can reduce the protracted

inflammation in the lung of COPD. Further research on the inflammatory

mechanisms would therefore be important in determining new potential

therapeutic targets in COPD. Serotonin (5-hydroxytryptamine, 5-HT) is a

neurotransmitter that plays an important role in pulmonary functions and

inflammatory responses. The serotoninergic system including serotonin

transporter (SERT), serotonin receptors (5-HTR) and its metabolic enzyme

monoamine oxidase (MAO) have been reported to associate with cigarette

smoking and/or COPD. Blockade of serotonin receptor 2A (5-HTR2A) with its

selective antagonist ketanserin has been shown to improve lung function in COPD

patients. In this study, we hypothesize that the serotoninergic system is involved

in cigarette smoke-induced oxidative stress, inflammation and COPD.

Exposure to cigarette smoke medium (CSM) caused the elevation of

interleukin (IL)-8 levels in primary normal human bronchial epithelial (NHBE)

cells and a human bronchial epithelial cell line (BEAS-2B) in vitro via activation

of p38 and extracellular signal-regulated kinases 1 and 2 (ERK1/2) signaling

pathway. Besides, CSM was found to disrupt the glutathione (GSH) system,

resulting in the translocation of nuclear factor-erythroid 2 related factor 2 (Nrf2)

to the nucleus. Knock-down of Nrf2 by small interference RNA (siRNA) blocked

CSM-induced IL-8 release. Pretreatment with ketanserin was found to attenuate

CSM-induced IL-8 release by inhibiting the p38, ERK1/2, and Nrf2 signaling

pathways, and by partially restoring the GSH system. On the other hand, CSM

reduced MAO activity in BEAS-2B, indicating a reduced catabolism of 5-HT.

Furthermore, 5-HT was found to share the common p38 and ERK1/2 signaling

pathway with CSM in IL-8 release.

In the cigarette smoke-exposed rat model, the GSH system in the lung was

found to be disrupted compared to the sham-air control, supporting our in vitro

findings. Interestingly, we found an increased MAO-A activity in the lung of

cigarette smoke-exposed rats in comparison to sham air-exposed rats. The

increased MAO-A activity in the lung was associated with the reduction of 5-HT

levels in bronchoalveolar lavage (BAL) and lung homogenates, while the

increased metabolism of 5-HT may be involved in cigarette smoke-induced

superoxide anion levels. On the other hand, serum, but not plasma level of 5-HT

was elevated in cigarette smoke-exposed group, which may be due to platelet

activation caused by cigarette smoke.

In the clinical study, the elevated plasma 5-HT levels were found to be

associated with an increased odds ratio for COPD and positively correlated with

age in COPD patients. Furthermore, plasma 5-HT was also demonstrated to be a

significant mediator on the relation between cigarette smoking and COPD.

In summary, our study supports the hypothesis that the serotoninergic

system contributes to cigarette smoke-induced oxidative stress, inflammation and

COPD. The serotoninergic system (e.g. 5-HTR2A) may constitute potential

therapeutic targets for the treatment of COPD, which is worthy for further

investigation.</description.abstract><language>eng</language><publisher>The University of Hong Kong (Pokfulam, Hong Kong)</publisher><relation.ispartof>HKU Theses Online (HKUTO)</relation.ispartof><rights>The author retains all proprietary rights, (such as patent rights) and the right to use in future works.</rights><rights>Creative Commons: Attribution 3.0 Hong Kong License</rights><source.uri>http://hub.hku.hk/bib/B47869616</source.uri><subject.lcsh>Serotoninergic mechanisms.</subject.lcsh><subject.lcsh>Oxidative stress.</subject.lcsh><subject.lcsh>Lungs - Diseases, Obstructive.</subject.lcsh><title>The involvement of serotoninergic system in cigarette smoke-induced oxidative stress and inflammation</title><type>PG_Thesis</type><identifier.hkul>b4786961</identifier.hkul><description.thesisname>Doctor of Philosophy</description.thesisname><description.thesislevel>doctoral</description.thesislevel><description.thesisdiscipline>Medicine</description.thesisdiscipline><description.nature>published_or_final_version</description.nature><date.hkucongregation>2012</date.hkucongregation><bitstream.url>http://hub.hku.hk/bitstream/10722/161521/1/FullText.pdf</bitstream.url></item>