Chronic Obstructive Respiratory Disease: COPD

Chronic Obstructive Respiratory Disease:

COPD is known to be a progressive respiratory disease that makes it harder to breathe over time. Since COPD is a collection of conditions such as emphysema as well as chronic obstructive bronchitis, usually characterized with persistent airflow limitation, which is not reversable by broncho-dilators. One suggestion is that cigarette smoking predisposes to bacterial colonization and that bacterial products then contribute to inflammation, activation of proteases, and alteration in subsequent host responses to inhaled toxicants. (C)

The relationships between mucous hyper-secretion, pathogenetic mechanisms of emphysema, and airways obstruction are to this day not well understood. Early epidemiological studies of occupational cohorts have failed to associate mucous hyper-secretion with the rapid progression of COPD. The term COPD actually includes 2 different respiratory conditions: Chronic Bronchitis and Emphysema.

 

Chronic Bronchitis:

This is a long term condition of COPD, where the airways swell so much so that they cause phlegmy cough and wheezing, making it hard to breathe. This inflammation of the airways which causes these coughs and production of mucus lasts for most days for several months within the time span of two years occurring in a row. Mucous Hypersecretion is often induced by inflammation where the substantial gland enlargement does not occur.

Bronchitis is related to the hyperplasia of epithelial goblet cells and submucosal glands that are located in the airways. Many of the cellular pathways which vary in different forms of stimuli such as reactive oxygen species, increase of epithelial mucin secretion still need to be identified. There is even more ambiguity of how submucosal glands are regulated. (C)

 

Emphysema:

Emphysema occurs when there is damage to the air sacs in the lungs, where individuals experience shortness of breath and a tight feeling in the chest. Emphysema condition of COPD is a disease that damages the air sacs and may damage the small airways in the lungs. (A)

To reverse emphysema, researchers have to find a way to accomplish this by increasing the number of alveoli. During late fetal and postnatal development, the seperation of the alveoli occurs. Often times it is assumed that the lungs of an adult lack any alveolar plasticity if the emphysema is caused by 'elastase' in adult rats that reversed by treatment of all trans retinoic acid.

Currently, studies are being performed to identify the chemical markers of COPD. Subjects with stable COPD had elevated markers of oxidative stress in exhaled air. of inflammation in serum and sputum, and elastin degradation in urine. The results suggest that multifaceted characterization of COPD patients may be possible by noninvasive means.(C)

 Diagnosis:

Individuals who experience wheezing, coughing, tightening of the chest, and shortness of breath for long periods of time where breathing becomes progressively difficult it is quiet possible that they are suffering from Chronic Lower Respiratory Disease or COPD. Symptoms usually vary on a daily basis. To determine whether a patient has COPD, the physician performs a test called 'spiro-metry'. This measures how much air the lungs can hold and how much force is needed to breathe out. (D)

Diagnosis of COPD during its later stages is very dangerous because the disease has progressed so much so that it has already caused such severe damage that it cannot be reversed. The slow progression of COPD comes with acute exacerbation with increased dyspnea, and mucous production. (Many times the cause of exacerbation, role of pathogens, and acute exacerbations as well as their influence in the progression of COPD are still ambigious and unknown. There needs to be more research in COPD and how to reverse these damages.)

Often times it is difficult to be able to recognize the varying symptoms between COPD and asthma. Not only is COPD a more severe disease than asthma, but inflammatory cells and cytokines (found in allergy diseases) are elevated in patients' COPD's airways. Patients with COPD tend to show considerable, albeit partial, reversal of airflow limitation with bronchodilators. A hallmark characteristic of asthema is methacholine reactivity which is associated with deceleration of FEV1 in patients with COPD. However, there have been observations from studies and research where transgenic mice are over expressing mediators related to asthma and allergy diseases that have shown airway neutrophilia and emphysema (common characteristics of COPD). (C)

Treatment:

Although COPD is a serious and progressive disease, there are medicines available—including bronchodilators—that may help manage its symptoms. Bronchodilators are a type of medicine that help open the airways to make it easier to breathe. Beta-agonists are a type of bronchodilator that work by relaxing tightened muscles around the airways. Beta-agonists may be long-acting, also known as maintenance medicines, or short-acting, also known as rescue medicines. Long-acting maintenance medicines are taken on a regular basis every day. They do not treat sudden symptoms.

 Short-acting rescue medicines start working within minutes. They are taken for sudden symptoms. (D)

There is a degradation of elastic fibers and other components of the extracellular matrix including proteases that are now believed to be patho-physiologically relevant to COPD pathogenesis. Proteases function to facilitate antigen presentation, an inactive host-defensive surfactant protein A. This surfactant protein A stimulates serous and mucous secretions, liberate chemotaxins from the extracellular matrix, inhibit removal of apoptotic cells, induce and inactivate interleukin 8, and activate tumor necrosis factor and interleukin 1 beta.(C)

Rational therapeutic agents may possibly be developed by clarification of which alpha protease actions are of importance in COPD, identification of which of the many proteases elaborated by inflammatory and lung septal (endothelial, epithelial, smooth muscle, and fibroblast) cells perform those actions, and design of small molecules with an appropriate spectrum of protease inhibitory activity. (C)

Management:

Quit smoking Smoking and COPD have long been linked. It is very important for individuals who smoke it quit so that in the future, the rate of decline in lung function can slow down. Although there is no cure for COPD once diagnosed, there are things that can be done to help manage the symptoms. These managing skills include:

Practice breathing is one of many coping mechanisms that help individuals with COPD. Breathing exercises can also be an important part of your COPD treatment plan and may include diaphragmatic breathing, pursed-lip breathing, or controlled coughing. Stay active through exercise which may help improve overall strength and endurance, and may even strengthen the muscles that are used to breathe. It is also important to keep things simple and give oneself more time to accomplish everyday activities. There is no need to become overwhelmed with all tasks all at once. Eating a healthy diet will give any individual the energy needed to accomplish these. If overweight, an individual can plan to lose weight so that their ability to perform daily chores and tasks become easier as well as make it easier to breathe.(D)

Because of COPD alone there are 100,000 deaths per year and increasing. According to WHO, it is the 4th leading cause of death in America and is expected to rise to the 3rd position by 2020. Cigarette smoking is the number one cause of COPD and 25% of Americans smoke. (C)

 

 Causes of COPD:

Long-term smokers are usually the individuals who develop COPD. They are usually associated with a progressive decline in pulmonary function, more rapid than that associated with normal aging. A variety of damaging stimuli such as cigarette smoke, pancreatic elastase, bacterial lipopolysaccharides, cadmium, chloramine-T, oxidants, silica, and severe starvation, can induce changes in animal lungs. (C)

A long term exposure to other lung toxins, chemicals, or irritants such as air pollution or chemical fumes also contribute to COPD. This respiratory disease makes airflow into and out of your lungs difficult therefore reducing your lung function. COPD includes chronic bronchitis, emphysema, or both. (A)

Smoking cigarettes causes oxidant injury. In other words, smoking causes severe oxidative stress on the lungs directly via reactive species in the smoke or indirectly through activation of inflammatory cells. Such oxidative stress on COPD through various biological actions (i.e. cellular injury, oxidation and nitration of proteins, changes in gene expression, stimulation of mucous secretion, inactivation of antiproteases, expression of proinflammatory mediators, remodeling of blood vessels, and enhancement of apoptosis).

Markers of oxidative stress (e.g., hydrogen peroxide, 8-isoprostane, and lipid peroxides) are elevated in the breath or serum of subjects with COPD, and epidemiological studies have demonstrated negative associations of dietary antioxidant intake with pulmonary function and with obstructive airway disease. (C)

Airway inflammation and parenchymal inflammation are consistent findings in COPD. The connection between COPD and airways inflammation is complex. 

•  First, inflammation is observed in the lungs of smokers who do not meet clinical criteria for diagnosis of COPD. 
• Second, inflammation persists long after smoking cessation. 
• Third, there is overlap in the profiles of inflammatory cells and mediators expressed in COPD and in asthma.
• Fourth, inhaled corticosteroids do not prevent the progressive loss of lung function in subjects with COPD. 
• Fifth, the increased numbers of infiltrating macrophages, neutrophils, and lymphocytes in the lungs of individuals with COPD are less than those observed in other inflammatory lung conditions that are not associated with the development of COPD.

Characterizing lung inflammation associated with COPD have been compared in studies to the extensive profiling of patients with asthma. Increased numbers of CD8⁺ T cells in the airways and lung parenchyma of smoking subjects with COPD were witnessed. There was a negative (aka: as one factor increases the other decreases and vice versa) correlation between FEV1 (% predicted) and CD8+ T cell number.

The large airways of smokers with severe COPD show increased numbers of neutrophils, macrophages, and natural killer lymphocytes in comparison with smokers without clinically defined COPD; and each of these cell types is negatively associated with FEV1. Neutrophils tend to localize with the airway epithelium, but nodules of B lymphocytes are found in the submucosa and adventitia. Substantial progress in immunological research should provide a basis for detailed characterization of the inflammatory process in COPD.

Genetic Risk Factors:

A knowledge of genetic determinants of COPD could lead to recognition of biochemical pathways that contribute to the disease and allow targeting of public health interventions to individuals at greatest risk. A program for identification of genes related to COPD should consider several issues: First, simultaneous characterization of multiple phenotypes will be necessary because different genes may be related to different aspects of the disease (e.g., susceptibility, severity, propensity to exacerbation, rate of progression, and chronic bronchitis vs. emphysema). Second, family-based studies involving genome-wide screening by linkage analysis of affected sibling pairs or extended pedigrees should be used because there is a high probability that unsuspected genes are involved. Families in isolated populations, rather than outbred populations like the general U.S.
 population, may be studied more efficiently.

Genetic factors could also contribute to an individual's physical body to be greater predisposed to developing and at a higher risk of progression of COPD. Identification of these genes should be a goal for the near future because pulmonary function is indeed influenced by heredity which is also associated with COPD. 

 

Research:

Advances in lung development and alveolar regeneration have been achieved through various animal studies. These studies were focused on observing alveolar development in the late fetal and postnatal period of the animals' lifespan. Such studies have given much hope in the field of medicine for stimulation of alveolar regeneration because now it is an exciting possibility for developing disease modifying therapies for patients with COPD.

Within this umbrella of animal studies for COPD, research included gene expression and proteomic analysis of the developing lung, how relevant genes that are expressed are regulated, vascularization and lung development and repair, transgenic mice used to evaluate the role of specific growth factors in the lung, and lastly, toxins (such as in utero nicotine) that impair lung growth.

However, it is important to note that in order to determine alveolar regeneration in adults of various species, future studies must focus on the capacity of lungs to mature, capacity for alveolar regrowth, as well as the proper conditions where alveolar regeneration is possible and successful. Research conducted for long-term oxygen therapy, management of sleep disturbance in COPD, alleviation of nocturnal hypoxemia, prevention and treatment of exacerbations, and better tools for disease monitoring should be conducted under controlled circumstances in order for the results to be seen as valid.

More research is needed where COPD is not linked to cigarette neutrophil protease theory. The Neutrophil Protease Theory is the theory that assumes that smoking cigarettes is the only factor that contributes to the causation of COPD. There are far too many unknown and unrelated pathways which cause emphysema and bronchitis. Scientists and researchers alike should aim, through various observations of studies, to conclude a single theory of COPD that encompasses the known pathways/relationships that lead to this chronic disease. (C)

The presence of latent viral infections in the lungs could possibly be another risk factor that leads to COPD. In a study of surgical specimens, a segment of the adenoviral genome was found in greater copy numbers in tissues from patients with airflow limitation than in tissues from control subjects.(C)

In a guinea pig model, latent adenoviral infection potentiated the inflammatory effects of cigarette smoke, and transfection of cells in vitro with adenoviral DNA was shown to activate nuclear factor B and potentiate corticosteroid-resistant production of interleukin 8(C).

The reason as to why animal models are used so often is because they can identify genes that are candidates for pathophysiology ramifications of a specific genotype. Case-control association studies of particular candidate genes will eventually be needed to test the relevance of results obtained in particular families to the disease in the general population. Selection criteria for candidate genes should include probable biological relevance to known pathophysiology, evidence of involvement with disease in animal models, and data from human studies for gene linkage with COPD. Although clinical trials that involve large numbers of well characterized subjects with COPD is not a great or perfect way to attain valid and conclusive results when conducting genetic studies.By the end of the study an archive of the DNA samples of the subjects taking part should have been recorded and kept for later analysis.(C)


Mouse models with inducible, lung-specific expression of particular cytokines have been shown to manifest lung abnormalities that are clearly not attributable to aberrant development of the lung. Overexpression of interleukin 11 in adult mice produced peribronchiolar lymphoid nodules similar to those observed in human COPD but did not cause emphysema. Overexpression in adult mice of either interferon, a major product of CD8+ lymphocytes, or interleukin 13, a mediator associated with CD4+ T cells and asthma, produced emphysema-like changes.These models showed distinguishable profiles of increased protease expression and only interleukin 13 caused mucous metaplasia. A gene-targeting approach (loss of function) has proven useful for testing the contributions of various matrix metallo-proteinases in the development of cigarette smoke-induced emphysema in the mouse. (C)

Links:
(A) http://www.anoro.com/copd.html?rotation=71700000009793970&banner=58700000435532905&kw=6301905368&cc=38533e7470ad&pid=6301905368&google=e_
(B) http://www.theguardian.com/society/2014/feb/13/symptoms-lung-disease-overlooked-study
(C) http://www.nhlbi.nih.gov/health-pro/resources/lung/chronic-obstructive-pulmonary-disease-future-research/workshop-summary
(D)http://www.brovana.com/copd.html?utm_content=BRO_BROSEMCOPD_2_12_16_V1&utm_medium=cpc&utm_source=google&utm_campaign=Brovana_DTC_SEM_Google_FY16_NB_COPD_Exact&utm_term=what_is_copd
*Please note! These images are not mine. They were found on various tumblr sites! If any are yours please let me know so that I can give you credit for them! Also the people in the images have no relation to the diseases, illnesses, or cancers I write about. Thanks so much & enjoy~