The involvement of serotoninergic system in cigarette smoke-induced oxidative stress and inflammation: relevantto chronic obstructive pulmonary disease

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.