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The involvement of serotoninergic system in cigarette smoke-induced oxidative stress and inflammation: relevantto chronic obstructive pulmonary diseaseLau, Kwok-wai, 劉國威 January 2012 (has links)
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
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Plasma inflammatory biomarkers in stable COPD patientsChu, Ling-fung., 朱凌峯. January 2012 (has links)
Chronic obstructive pulmonary disease (COPD) is one of the world’s most common chronic diseases, and consists of chronic bronchitis that involves chronic inflammation of the bronchi, or emphysema that involves destruction of lung alveoli. In COPD patients, the airways become narrowed, and the airflow is irreversibly obstructed. This leads to a limitation of the flow of air to and from the lungs, causing shortness of breath (dyspnea), as well as abnormal inflammatory response in the lung. Nowadays, COPD is often under-diagnosed, as spirometry was not performed until patient has significant symptoms of dyspnea, cough and sputum production. At that stage, the COPD patients may have reached an advanced stage with considerable loss of lung function. Thus, biomarkers are of great interest for research and clinical purposes in COPD, especially for early diagnosis of COPD.
In this study, the relationship between plasma levels of different biomarkers, including monocyte chemoattractant protein-1 (MCP)-1 (a primary chemoattractant biomarker), matrix metalloproteinase nine (MMP)-9, vascular endothelial growth factor (VEGF), and hepatocyte growth factor (HGF) (injury and repair biomarkers), and growth differentiation factor 15 (GDF)-15 (a novel biomarker), in 29 healthy ever-smokers and 116 COPD patients was investigated using commercially available enzyme-linked immunosorbent assay (ELISA) kits. We also investigated the correlations between these biomarkers and lung function. There were significant increases in plasma MCP-1, MMP-9, HGF and GDF-15 in COPD patients compared to healthy smokers. Among ever-smokers with or without COPD, plasma MCP-1, MMP-9 and HGF levels were inversely correlated with force expiratory volume in one second![FEV1 (% predicted)] after adjustment for age, smoking status and packyears smoked. Correlation was also found between plasma MCP-1 and HGF, plasma MMP-9 and HGF or GDF-15, plasma HGF and GDF-15 after adjustment for age, smoking status and pack-years smoked. Further multiple linear regression analyses demonstrated that plasma MMP-9 level increased with the COPD GOLD stages.
In conclusion, our findings suggest that MMP-9 might be as an important biomarker for COPD initiation and progression. As this study provides only evidence of association rather than of causation, prospective studies are required to assess biological significance of these associations between the plasma biomarkers. / published_or_final_version / Medicine / Master / Master of Medical Sciences
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Mutations of epidermal growth factor receptor (EGFR) pathway genes andMET in primary lung adenocarcinomaHo, Ka-yan, Rebecca Lucinda., 何嘉茵. January 2012 (has links)
This study completed the analysis of mutational frequencies and clinicopathological patterns of six EGFR pathway-related genes (EGFR, HER2, HER4, KRAS, BRAF and MET) in 212 resected lung adenocarcinomas (AD) from 98 male and 114 female Chinese patients without prior chemotherapy or tyrosine kinase inhibitor (TKI) therapy. Genomic DNA and cDNA sequencing, quantitative PCR and fluorescence in-situ hybridization (FISH) were employed to investigate mutation and amplification status of the relevant genes. Overall, more than 75% of tumours were detected to harbour mutations or amplification in one of these six genes. The commonest mutation was found to involve EGFR, comprising 60.38% of cases, followed by KRAS (9.43%), HER2 (2.36%), MET (2.36%), BRAF (1.42%) and HER4 (0.47%). Four somatic mutations in MET exon 14 splicing region were found, leading to alternative splicing and a transcript lacking exon 14. Two of the MET mutant tumours and one MET wild-type tumour showed MET amplification of more than 3.5 fold increase in copy number. Mutations of EGFR were significantly more frequent in female (p = 0.0196), non-smokers (p < 0.001) and well differentiated tumours (p = 0.0209). KRAS mutations showed significant association with male (p = 0.0099) and smoking history (p = 0.0011). A novel HER2 D769Y mutation was found and HER2 mutations were associated with smokers (p = 0.0013) and poorly differentiated tumours (p = 0.0147). BRAF, MET mutations and MET amplification were not associated with clinicopathological factors. Mutations were mutually exclusive except for two cases with KRAS and HER4/BRAF. MET amplification was co-existent with MET mutations in two cases. MET amplification was found to negatively correlate with disease-free and cancer-specific survivals. The results suggested that MET amplification may contribute to disease progression and could be a therapeutic target in primary lung AD in Hong Kong Chinese patients. / published_or_final_version / Pathology / Master / Master of Medical Sciences
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Role of imaging in evaluation of lung involvement in severe acute respiratory syndrome (SARS)Ooi, Gaik Cheng., 黃玉清. January 2010 (has links)
Diagnostic imaging played a substantial role in the management and treatment of
patients during the Severe Acute Respiratory Syndrome (SARS) outbreak when daily
chest radiographs were performed as a measure of disease severity and respiratory
status. This thesis was performed to address several issues relating to the
radiological spectrum of SARS, its temporal pattern on chest radiograph and high
resolution computed tomography (HRCT) during the course of disease, and
relationships between severity of opacities quantified on chest radiographs and
clinical parameters including treatment response. Radiological parameters that could
discriminate SARS from non-SARS community-acquired pneumonia (CAP) were
also studied.
Unifocal unilateral ground glass opacities was the dominant radiographic abnormality
at presentation that progressed rapidly to maximal disease within 9.35 ± 4.09
(median 9, range 3-21) days after onset of symptoms with bilateral consolidation in
62.5% of patients. Complete resolution and significant residual disease was noted in
50% and 20% of cases respectively at end of assessment period. There was a
temporal pattern of lung abnormalities on HRCT with ground glass opacity and
consolidation at presentation. Reticulation developed after the first week and was
present in 50% of patients at ?four weeks. HRCT was useful in illustrating
parenchymal abnormalities in patients with normal radiographs at presentation.
Severity of lung abnormalities quantified on chest radiograph at different time points
of disease correlated with clinical and laboratory parameters such as SaO2 and liver
transaminases ALT and AST. Significant relationships were also found between
radiographic parameters, and O2 supplementation and treatment response. There
are discriminating differences in the radiographic pattern, rate of radiographic
progression, and zone of involvement between SARS and non-SARS CAP. / published_or_final_version / Medicine / Master / Doctor of Medicine
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The role of ALDH and SOX2 as tumour initiating cell markers in non-small cell lung cancerChui, Tung-yung, 崔董庸 January 2013 (has links)
The abundance of tumour initiating cells (TIC) has been suggested to be an important prognostic indicator in cancers. Both SOX2 and ALDH have been individually reported to be putative TIC markers but their combined status is unclear and their usefulness in the prognostication of non-small cell lung cancer (NSCLC)has not been reported. This study investigated the patterns of ALDH and SOX2 protein expression in NSCLC using immunohistochemistry. Expression was graded using semi-automated signal capturing and image analysis software. ALDH and SOX2 were expressed in 41% and 43% of all NSCLC, respectively. ALDH was expressed in 36% of adenocarcinomas (AD)and 65% of squamous cell carcinomas (SCC), while SOX2 was expressed in 36% of AD and 80% of SCC., respectively. Taking all cases into consideration, the expression of ALDH and SOX2 significantly correlated with each other (p=0.003). No prognostic value of the abundance of ALDH and SOX2-expressing cancer cells was found with regard to all NSCLC or in AD. In contrast, for SCC, a significantly better prognosis with longer cancer-specific survival (CSS) and disease-free survival was found in tumours with higher ALDH expression, while a longer CSS was found in those with higher SOX2 expression. Contrary to the hypothesis that a high TIC content indicated by high combined ALDH and SOX2 expression would predict poor patient outcome, amongst all NSCLC, the combined phenotype of SOX2+/ALDH-was associated with the worst prognosis compared with the SOX2+/ALDH+(p=0.026) and SOX-/ALDH-(p=0.048),while no significant difference was observed with the SOX-/ALDH+ phenotypes. In view of the tight correlation between ALDH and SOX2 protein levels, in vitro studies were performed to investigate whether ALDH could be an upstream regulator of SOX2 expression. Pharmacological inhibition of ALDH enzyme function led to down-regulation of SOX2 mRNA and nuclear protein expression in lung cancer cell lines, indicating a regulatory role of ALDH on the SOX2 stemness pathway in lung cancer. In summary, the findings implicate complex factors are likely to be involved in determining the expression levels of ALDH and SOX2 in clinical lung cancers and their mechanisms affecting patient survival remain to be clarified. Further investigations on the specificity of ALDH/SOX2 as TIC marker, TIC interaction with the tumour micro-environment, and potential complex antagonistic functions of ALDH in TIC maintenance are required. / published_or_final_version / Pathology / Master / Master of Medical Sciences
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Hypermethylation of tumor suppressor genes in non-small cell lung cancer李冬靑, Li, Tung-ching, Kathy. January 2003 (has links)
published_or_final_version / Medical Sciences / Master / Master of Medical Sciences
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The role of computed tomography volumetry in the assessment of advanced lung cancer and oesophageal cancerYip, Tsz-chung., 葉子仲. January 2002 (has links)
published_or_final_version / abstract / toc / Diagnostic Radiology / Master / Master of Philosophy
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A study of diagnostic criteria employed in the analysis of lung function of textile workers何禮明, Ho, Lai-ming. January 1991 (has links)
published_or_final_version / Community Medicine / Master / Master of Philosophy
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Nutritional assessment of individuals with chronic obstructive pulmonary diseaseTremper, Joyce Carol January 1980 (has links)
No description available.
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A rapid method for the preparation of lung cell fractions enriched in alveolar type II pneumocytesLafranconi, Walter Mark January 1981 (has links)
No description available.
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