Atus Case Study

Inflammation is the normal defensive response to inhaled toxins, and is amplified in the patient with COPD. These inflammatory and structural changes persist even after smoking cessation, and the progression corresponds with disease severity. The two primary pathogenic processes involved with COPD include the imbalance between proteases and anti-proteases in addition to the imbalance between oxidants and antioxidants.

Emphysema is the most common cause of death from respiratory disease in the United States and is generally caused by several years of heavy cigarette smoking (Olendorf, 2000). When a person smokes, the body’s immune system tries to fight off the invading smoke by using certain substances. These substances can also attack the cells of the lungs, but normally the body is able to release other substances to prevent this. In the case of people who are smokers, this doesn’t happen and the original substances that were released to fight off the smoke also end up injuring the cells of the lungs as well. Eventually, the lungs will not be able to supply enough oxygen to the blood and a host of problems can occur with this. Risk factors that have been identified for emphysema include exposure to tobacco smoke either through active or passive smoking (2nd hand smoke), occupational exposure such as dust or chemicals, ambient air pollution, or genetic abnormalities, including a deficiency of alpha-antitrypsin, an enzyme inhibitor that normally counteracts the destruction of lung tissue by certain other enzymes (Smeltzer, 2010). The symptoms of emphysema develop gradually over many years. It is generally characterized by three primary symptoms: chronic cough, sputum production, and dyspnea on exertion. Other signs and symptoms include weight loss and the development of a

Chronic obstructive pulmonary disease (COPD) is in the top five principal cause of death in the U.S. The disease is an abnormal inflammatory reaction in the lungs with limited airflow. COPD characteristically arises around the age 35. Smoking continues to be the main source of COPD, but is not the only known root cause. In many studies, smoking explanations for at least three fourths of COPD cases ("Chronic obstructive pulmonary disease | University of Maryland Medical Center," n.d.). Stopping smoking has been known to improve lung capabilities and help to prevent death from COPD. Genetic conditions and introductions to airborne toxins, irritants and gasses are correspondingly involved in the growth of the illness. A complete treatment plan could comprise of lifestyle changes, one or more medications, patient education, oxygen therapy respiratory rehabilitation, and surgery ("Chronic obstructive pulmonary disease | University of Maryland Medical Center," n.d.).

Emphysema is the third leading cause of death in the United States. It is a chronic, progressive disease that affects the morbidity and mortality of life. Like many chronic diseases, diagnosis is affected by numerous variables. There is no cure; however, there are effective treatment methods which can slow the progression of the disease and allow for a normal life. In short, the diagnosis of emphysema is not a death sentence. Rather, it is an illness that should prompt a person diagnosed with it to take the lead in the management of the disease. The primary risk factor for this disease that can be controlled is the smoking of cigarettes. Smoking cessation is the most beneficial first step to preventing or stopping the development or progression

As you already know, Chronic Obstructive Pulmonary Disease (COPD), manifests itself when the passageway of air to the lungs is severely obstructed, thus preventing sufficient flow of oxygen into the bloodstream.1 The pathophysiology of COPD is a complex process that is the result of multiple airway diseases that simultaneously contribute to the impairment of airflow in the lungs.1 Specifically, the overlapping outcome of chronic bronchitis and emphysema is the pathogenesis of COPD.1 The risk factor for the COPD is influenced by the individual’s genetics, age, gender, exposure to air pollution, socioeconomic status, and the use of tobacco products.1 The use of tobacco products can increase the development of COPD.1 However, individuals that don’t smoke can also attain COPD.1 Therefore, COPD is not exclusive to individuals that smoke on a daily basis.1 In fact, genetics and the natural aging process plays a part in the development of pulmonary issues.1 For example, it has been proven that a deficiency in the alpha -1 antitrypsin gene is correlated with the development of COPD.1 The natural deterioration of lung tissue, coupled with the long term exposure to environmental elements, explains why the risk of attaining COPD increases as one progresses to the latter stages of their lives.1 In a healthy individual, goblet cells secrete about one liter of mucous that provides a moist surface over the lungs, trachea, and esophagus.1 The cilia on the pseuodocolumnar epithelial cells continuously sweep the mucus in the lungs in an upward motion.1 The cilia sweeps the mucosal trapped debris up, and removes pathogens and other foreign particles out the pulmonary tissue.1 In individuals with COPD, the pathogenesis of the disease creates structural modifications of the lung tissue, which result in deformed and nonfunctioning cilia.2 The lack of functioning cilia leads to the buildup of mucous, pathogens, and subsequent respiratory infections.2 Furthermore, the body tries to combat

Half of the animals will be euthanized on day 28 (before the second DSS cycle), and the other half on day 56. This will allow us to study ROS production and DNA stability before the onset of neoplasia (28 days), and once it is established (56 days). We have an extensive experience in this animal model6,8,10. Power calculations indicate we will need an n=8 mice per group to obtain significant results31. Colon will be processed for histology and epithelial cell isolation by chelation in EDTA. Part of these epithelial cells will be kept for RNA isolation, part will be used for ROS determination, and the rest will be seeded in extracellular matrices to grow them as organoids. Organoids will be cultured for 7 days to allow for additional divisions in the presence or absence of 1µg/mL LPS32. Epithelial cells in tissues and culture will be analyzed for DNA damage and genetic instability via γH2AX immunofluorescence (a marker for DNA damage), presence of anaphase bridges, and telomere staining. Dr. Verdun´s lab is very experienced in these techniques33,34. Epithelial cells will be interrogated for the expression of Duox2, SOD1, CAT, GPX2, and GPX4 (quantitative PCR) as markers of oxidative stress in epithelial cells35, and production of ROS will be measured by staining with DCFDA and Amplex Red probes. These experiments will indicate to which extent DNA damage induced by ROS is mediated by TLR4 activation in the

Emphysema and Asthma are progressive diseases where the lung tissue is gradually destroyed and narrowing of the air passages obstructs oxygen uptake, causing shortness of breath. The lung damage caused by Emphysema typically occurs as a result of long-term inhalation of irritant gases and particles, such as tobacco smoke.

This study sought to analyse the expression of empiric classic EMT structural and mesenchymal biomarkers, epithelial activation, and also vascular changes, in matching large and small airways from smoking (current or recently quit) patients with airflow obstruction (CAL). We have previously demonstrated that in large airway biopsies from smokers compared to normal control tissue, epithelial activation, EMT biomarkers and related classic structural changes are highly expressed, and that these changes are greatest in those with COPD [12]. Here we show that small airways from this group of CAL patients also demonstrated active EMT significantly above normal but uniformly less so than in large airway. However, in small airways, EMT changes are not associated with hypervascularity i.e, could be considered as the pro-fibrotic Type-2 EMT rather than the more malignancy-associated Type-3 EMT.

Chronic Obstructive Pulmonary Disease (COPD) is a long term respiratory disease. It is characterised by a slowly progressive irreversible airflow obstruction that is due to a loss of lung elasticity resulting from parenchymal destruction and peripheral airflow obstruction. It is estimated that 80 % to 90 % of all cases of COPD are caused by cigarette, but it can also be caused by genetic disorders. Identification of genetic markers that predict the rate of loss of lung function may help in disease prevention and improved management in the future (1).

Human lungs were donated for medical research by the Gift of Life Donor Program from deidentified control non-smoker and smoker organ donors. We selected donors with lung function with a PaO2/FIO2 ratio of >250, a clinical history and x-ray that did not indicate infection, and limited time on a ventilator. Non-smokers were individuals who never smoked and smokers smoked 5-20 cigarettes per day for at least 3 years. Lung tissue from patients with emphysema (GOLD IV) was obtained from lung volume reduction surgery through Temple Biobank at Temple University, Philadelphia, PA (N = … per group). ATII cells were isolated as we previously described (REF). Briefly, after elastase (Roche Diagnostics,

Cigarette smoke induces oxidative stress, which may lead to lung injury and emphysema development. We found high mitochondrial DNA damage in alveolar type II cells isolated from individuals with this disease. We have discovered that XLF is involved in repair of mitochondrial DNA in these cells. XLF oxidation causes its degradation leading to mitochondrial dysfunction and mitophagy in these cells. Targeting XLF may provide potential therapeutic strategy against emphysema

Emphysema effects not only the respiratory system through the destruction of lung tissue, the condition also impacts the cardiovascular system. As seen in the diagram below [Appendix 2], the alveoli have a network of capillaries surrounding them. These capillaries are a vital component in the gas exchange which takes place within the lungs. Inhaled oxygen travels down to the alveoli and is diffused into the body via the capillaries, the newly oxygenated blood is then transported around the body within the cardiovascular system.

Emphysema is described as a change in airflow related to both destruction of the alveolar walls and also gas-exchange airway expansion with a loss of the elastic recoil abilities of the lungs (McCance & Huether, 2014). These changes are secondary to exposure to airway pollutants like tobacco or chemicals that trigger an inflammatory response causing a release of cytokines. This process then creates and imbalance of both proteases and antiproteases along with oxidative stress leading to cellular death within the lungs. The decrease in lung cells, with the creation of airspaces and a decrease in pulmonary capillaries perpetuates the interruption of the ventilation process (McCance & Huether, 2014). Furthermore, the inward elastic recoil ability

Pollutants in cigarettes calls Polycyclic aromatic hydrocarbons cause genetic damage in a matter or minutes. Our bodies are intended to deal with a little harm but it’s difficult for the body to manage the quantity of injurious chemicals in tobacco smoke. Each cigarette can damage DNA in many lung cells, but it is the formation of damage in the same cell that can lead to cancer. Smoking weakens the body’s defenses. We all have cleaner proteins called ‘detoxification enzymes’ that clean up harmful chemicals and change them into harmless ones. But the chemicals in smoke, such as cadmium, can overwhelm these cleaners. Cigarette smoke also impacts the immune system – increasing cells which can encourage tumor growth in the lungs and suppressing the ones which kill cancer

The presence of these components in the sputum may cause mutations in the smokers genes, which may lead to the formation to cancerous tumors. The risk of developing lung cancer is directly related to the number of cigarettes smoked (Schaadt, 1992).