Clinical problems caused by obesity

Over the past few decades the incidence of obesity has doubled worldwide and current estimates classify more than 1.5 billion adults as overweight and at least 500 million of them as clinically obese, with body mass index (BMI) over 25 kg/m2 and 30 kg/m2, respectively. Obesity prevalence rates are steadily rising in the majority of the modern Western societies, as well as in the developing world. Moreover, alarming trends of weight gain are reported for children and adolescents, undermining the present and future health status of the pediatric population. To highlight the related threat to public health, the World Health Organization has declared obesity a global epidemic, also stressing that it remains an under-recognized problem of the public health agenda

Lung injury after cigarette smoking is particle related

The specific component responsible and the mechanistic pathway for increased human morbidity and mortality after cigarette smoking are yet to be delineated. We propose that 1) injury and disease following cigarette smoking are associated with exposure to and retention of particles produced during smoking and 2) the biological effects of particles associated with cigarette smoking share a single mechanism of injury with all particles. Smoking one cigarette exposes the human respiratory tract to between 15,000 and 40,000 μg particulate matter; this is a carbonaceous product of an incomplete combustion. There are numerous human exposures to other particles, and these vary widely in composition, absolute magnitude, and size of the particle. Individuals exposed to all these particles share a common clinical presentation with a loss of pulmonary function, increased bronchial hyperresponsiveness, pathologic changes of emphysema and fibrosis, and comorbidities, including cardiovascular disease, cerebrovascular disease, peripheral vascular disease, and cancers. Mechanistically, all particle exposures produce an oxidative stress, which is associated with a series of reactions, including an activation of kinase cascades and transcription factors, release of inflammatory mediators, and apoptosis. If disease associated with cigarette smoking is recognized to be particle related, then certain aspects of the clinical presentation can be predicted; this would include worsening of pulmonary function and progression of pathological changes and comorbidity (eg, emphysema and carcinogenesis) after smoking cessation since the particle is retained in the lung and the exposure continues

Chronic Obstructive Pulmonary Disease and Lung Cancer: Underlying Pathophysiology and New Therapeutic Modalities

Chronic obstructive pulmonary disease (COPD) and lung cancer are major lung diseases affecting millions worldwide. Both diseases have links to cigarette smoking and exert a considerable societal burden. People suffering from COPD are at higher risk of developing lung cancer than those without, and are more susceptible to poor outcomes after diagnosis and treatment. Lung cancer and COPD are closely associated, possibly sharing common traits such as an underlying genetic predisposition, epithelial and endothelial cell plasticity, dysfunctional inflammatory mechanisms including the deposition of excessive extracellular matrix, angiogenesis, susceptibility to DNA damage and cellular mutagenesis. In fact, COPD could be the driving factor for lung cancer, providing a conducive environment that propagates its evolution. In the early stages of smoking, body defences provide a combative immune/oxidative response and DNA repair mechanisms are likely to subdue these changes to a certain extent; however, in patients with COPD with lung cancer the consequences could be devastating, potentially contributing to slower postoperative recovery after lung resection and increased resistance to radiotherapy and chemotherapy. Vital to the development of new-targeted therapies is an in-depth understanding of various molecular mechanisms that are associated with both pathologies. In this comprehensive review, we provide a detailed overview of possible underlying factors that link COPD and lung cancer, and current therapeutic advances from both human and preclinical animal models that can effectively mitigate this unholy relationship

Reactive Oxygen Species and Antioxidative Defense in Chronic Obstructive Pulmonary Disease

The respiratory system is continuously exposed to endogenous and exogenous oxidants. Chronic obstructive pulmonary disease (COPD) is characterized by chronic inflammation of the airways, leading to the destruction of lung parenchyma (emphysema) and declining pulmonary function. It is increasingly obvious that reactive oxygen species (ROS) and reactive nitrogen species (RNS) contribute to the progression and amplification of the inflammatory responses related to this disease. First, we described the association between cigarette smoking, the most representative exogenous oxidant, and COPD and then presented the multiple pathophysiological aspects of ROS and antioxidative defense systems in the development and progression of COPD. Second, the relationship between nitric oxide system (endothelial) dysfunction and oxidative stress has been discussed. Third, we have provided data on the use of these biomarkers in the pathogenetic mechanisms involved in COPD and its progression and presented an overview of oxidative stress biomarkers having clinical applications in respiratory medicine, including those in exhaled breath, as per recent observations. Finally, we explained the findings of recent clinical and experimental studies evaluating the efficacy of antioxidative interventions for COPD. Future breakthroughs in antioxidative therapy may provide a promising therapeutic strategy for the prevention and treatment of COPD.</p

Systemic inflammatory markers as predictors of longitudinal outcomes in COPD : Results from the Bergen COPD Cohort Study

Background: Chronic obstructive pulmonary disease (COPD) is major cause of morbidity and mortality worldwide. The prevalence is increasing worldwide, as a result of an increase in cigarette smoking the last decades. The main symptom of COPD is chronic and progressive dyspnea, often accompanied with cough and increased amounts of phlegm. A significant share of the patients suffers episodes with exacerbation of the disease, which may negatively impact quality of life, disease burden and survival. COPD pathophysiology is complex and consists of different disease mechanisms. Inflammation is a central component of COPD, and increased number of immune cells and cytokines are found both in the airways and in the systemic circulation. The COPD pathophysiology is incompletely understood, and there is comprehensive research on inflammatory biomarkers in order to improve diagnosis, identify patients with increased risk of adverse outcome, and to find targets for medical treatment. Aims: 1-Identify diagnostic biomarkers of stable COPD and acute exacerbation of COPD. 2 -Identify inflammatory biomarkers as predictors for longitudinal outcome using longitudinal data: a. as predictors for future exacerbations b. as predictors for change in lung function c. as predictors for mortality and cause of death d. as predictors for lung cancer Methods: The Bergen COPD cohort study (BCCS) included 433 COPD patients and 325 controls between 2006 and 2009. The COPD patients were aged between 40-76, all were former or current smokers. The COPD diagnosis was based on a clinical evaluation combined with an obstructive post-bronchodilator spirometry. Of the 433 COPD patients, 356 patients living in the vicinity of Haukeland University Hospital were also included in the Bergen COPD Exacerbation Study (BCES). All patients and controls went through an extensive examination at inclusion including medical history, physical examination, lung function testing, bioelectrical impedance measurements, HRCT, blood sampling, and microbiological testing. The patients and a selection of the controls were followed up during study visits each 6 months for 3 years, repeating lung function tests and blood sampling each 6 months, bioelectrical impedance each 12 months. In addition, patients were followed up to 9 years regarding mortality and cause of death as well as lung cancer development. Acute exacerbations of COPD (AECOPD) were registered both at each 6-month visit, in addition the patients in the BCES were telephoned each month and asked about symptoms regarding AECOPD. A selection of the patients was also examined at exacerbation where additional blood sampling was performed. The inflammatory biomarkers were evaluated at baseline and at AECOPD using both non-parametric and multiple regression models. For the analysis of the inflammatory biomarkers as predictors of future exacerbations, decline in lung function, mortality and lung cancer development, bi-level longitudinal regression models and cox-regression models were used. Results: Systemic inflammatory markers were measured in all 433 patients and 325 controls at inclusion, and in 149 patients at AECOPD. Macrophage migration inhibitory factor (MIF) was identified as potential biomarker both for stable COPD as well as AECOPD in Paper 2. Within the three years of the BCES, 350 of 403 COPD patients suffered 933 moderate and 370 severe COPD exacerbations. A history of exacerbations, female sex, chronic cough and a lower FEV1 were identified as predictors for future AECOPD in Paper 1. In Paper 3, high levels of GDF-15 were identified as a predictor for a higher future AECOPD count. The COPD patients experienced an average yearly FEV1 decline of 61 ml (1.31 %) in men and 36 ml (0.76 % women) in women. High levels of GDF-15 were identified as a predictor of a faster decline of both FEV1 and FVC in Paper 3. Other factors associated with a faster FEV1 decline were male sex and cachexia. Thirty-six COPD patients died with the first three years of follow up, 159 within 9 years. High levels of GDF-15 were identified as a predictor of a higher mortality in Paper 3. Other factors associated with a higher mortality were a low FEV1, cachexia, obesity and a high degree of comorbidity. Twenty-eight patients developed lung cancer within 9 years. COPD was significantly associated with a higher lung cancer risk. Within COPD patients, emphysema and obesity was associated with a higher lung cancer risk. Of 44 inflammatory biomarkers, only IP-10 was associated with a higher lung cancer risk, whereas systemic inflammation evaluated by a PCA-analysis did not show any correlation with lung cancer development. Conclusion: 1 Macrophage migration inhibitory factor (MIF) was identified as potential biomarker for both for stable COPD as well as AECOPD. 2 a. High levels of GDF-15 were identified as a predictor for a higher future AECOPD count in addition to several clinical characteristics. b. High levels of GDF-15 were identified as a predictor of a faster decline of both FEV1 and FVC. c. High levels of GDF-15 were identified as a predictor of all-cause mortality as well as mortality due to respiratory disease. d. IP-10 was significantly associated with a higher lung cancer risk, whereas systemic inflammation did not show any correlation with lung cancer development.Doktorgradsavhandlin