published_or_final_version / Nursing Studies / Master / Master of Nursing

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

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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Malnutrition, as evidenced by low weight for height, low triceps skinfold thickness and low midarm muscle circumference, is prevalent among COPD patients. A stepped decline in nutritional status has been postulated as a mechanism for malnutrition wherein patients progressively suffer weight loss with each COPD exacerbation. A randomized clinical trial of continuous enteral nutrition could not successfully address whether or not the stepped decline in weight can be prevented. Despite this, sixteen patients admitted for a COPD exacerbation, participated in an observational prospective study wherein anthropometric, biochemical, dynamometric, respiratory, general well-being and energy consumption measures were obtained. Twelve patients had body weights below 90% of ideal weight. The mean energy intake was 107% $ pm$ 30 of estimated resting energy expenditure. Measures were repeated to assess changes during hospitalization. Weight change was a poor indicator of nutritional status. Midarm muscle circumference and handgrip strength appear to be useful as nutritional status indicators among unstable hospitalized COPD patients. Changes in handgrip strength and midarm muscle circumference were closely linked (r =.78, p $<$ 0.0005) and tended to decrease over the course of hospitalization despite clinical improvement. In the absence of adequate nutrition, COPD patients have at least as much risk of developing iatrogenic malnutrition as are other hospitalized medical patients.

Chronic obstructive pulmonary disease (COPD) is characterized by an expiratory flow limitation, as well as an evident reduced exercise capacity compared to that of healthy age-matched individuals. Clearly, the expiratory flow limitation plays a significant role in this exercise intolerance; however, the extent of the contributions of other systemic factors remains unclear. More specifically, there is little data thus far on the role of blood flow delivery as a possible exercise limitation in COPD, especially in light of the potential interactions between cardiac output (Qc) and pulmonary hyperinflation. Thus, the purpose of this study was to compare the slope of the Qc versus oxygen uptake (VO 2) response through several submaximal cycling loads in patients with moderately severe COPD with that of age-matched healthy control subjects (CTRL). Also examined was the possibility that ventilatory constraints such as dynamic hyperinflation contribute to an abnormal Qc response. Cardiac output was measured using the CO2-rebreathing equilibrium technique during baseline conditions and cycling at 20, 40 and 65% of peak power in 17 COPD (Age: 64 +/- 8 yrs; FEV1/FVC: 37 +/- 11%; FEV1: 41 +/- 15% predicted) and 10 age-matched CTRL subjects. Inspiratory capacity (IC) was also measured for the determination of dynamic hyperinflation during the steady state exercise bouts. The results indicate that while the absolute Qc values are lower in COPD than in CTRL during moderately intense (65% peak power) cycling (11.30 +/- 2.38 vs. 15.63 +/- 2.15 L⋅min -1, p < 0.01), likely due to their lower exercise metabolic demand, the Qc/VO2 response to increasing levels of exercise intensity is normal or hyperdynamic in COPD. Indeed, the majority of patients with COPD exhibited Qc/VO2 slopes greater than 7.0, which may be indicative of a peripheral muscle bioenergetic disturbance that may drive the need for greater oxygen delivery, and thus result in an exaggerated ce

Despite the acknowledged importance of nutritional support for COPD patients, it is difficult to accomplish in acutely stressed individuals. A randomized trial of nutritional supplementation during an acute exacerbation was carried out in 16 hospitalized patients for a 2 week period. Six control patients consumed a standard diet supplying 1,951 $ pm$ 130 (mean $ pm$ SEM) kcal and 80 $ pm$ 6 g protein/d, while ten treatment patients, in addition to the usual diet received oral supplements (Ensure) or snacks, resulting in an intake of 2,516 $ pm$ 129 kcal (p = 0.012) and 99 $ pm$ 6 g protein/d (p = 0.059). Although the treatment subjects improved their intake over the control group, no significant improvement in nutritional status occurred in either group. / Forced vital capacity (FVC % predicted) improved significantly over the study period in treated vs control subjects (+11.10 $ pm$ 4.63 vs $-$4.50 $ pm$ 2.14; p = 0.026). Nitrogen balances were calculated for 9 subjects, and all were in negative balance ($-$8.42 $ pm$ 1.74 g nitrogen/d) with no difference between groups. / Because of the high doses of methylprednisolone administered (69.6 $ pm$ 8.3 mg/d), and their known catabolic effects, we examined whether the dose affected nitrogen balance and muscle strength. Both nitrogen balance (r = $-$0.73; p = 0.025) and grip strength (r = $-$0.76; p $<$ 0.001) worsened with higher doses of steroids. The catabolic process may have resulted from elevated energy requirements, inadequate intake of protein and energy or been induced by high doses of steroids. / Hospitalized COPD patients are highly stressed and catabolic, and the means to preventing protein wasting during an acute exacerbation of their disease remains to be established. (Abstract shortened by UMI.)