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. / published_or_final_version / Medicine / Doctoral / Doctor of Philosophy
| Identifer | oai:union.ndltd.org:HKU/oai:hub.hku.hk:10722/161521 |
| Date | January 2012 |
| Creators | Lau, Kwok-wai, 劉國威 |
| Contributors | Mak, JCW, Law, ACK |
| Publisher | The University of Hong Kong (Pokfulam, Hong Kong) |
| Source Sets | Hong Kong University Theses |
| Language | English |
| Detected Language | English |
| Type | PG_Thesis |
| Source | http://hub.hku.hk/bib/B47869616 |
| Rights | The author retains all proprietary rights, (such as patent rights) and the right to use in future works., Creative Commons: Attribution 3.0 Hong Kong License |
| Relation | HKU Theses Online (HKUTO) |
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