Introduction Chronic obstructive pulmonary disease (COPD) is a progressive inflammatory response that presents itself in the main airways

(bronchi) and diffusive layers (alveolar sacs) of the lungs (Pride et al, 1995). COPD is the collective name for two distinct diseases, the nature of which depends on its location of action (Pride, 1984). The more common of them, emphysema, results in destruction of the interalveolar septumthe cell barrier between adjacent alveoli (Shapiro et al, 2003). This results in a decreased surface area for respiratory diffusion, and a loss of elasticity in the walls of the alveoli. The symptoms of emphysema include difficulty breathing (dyspnea) and wheezing with activity. As the condition worsens, onsets of dyspnea emerge more frequently and for more prolonged periodseven at rest. Even more troubling is the fact that until very recently, emphysema was thought to be irreversible. Still, even the most advanced treatment methods are far from flawless. Smokers who quit must still deal with a majority of the symptoms for life (Hautamaki et al, 1997). Although a small percentage of the American population develops emphysema due to a genetic deficiency of -1-antitrypsin (AAT), the disease is most apparent in individuals above the age of 50 who smoke, a concept illustrated in Figure 1 (Hutchison et al, 1971). COPDand thus, emphysemais much more common in males than females, but its greatest increase in death rate in some recent time periods has occurred in white women. These increases reflect the growing number of women in America who smoke cigarettes (Association of Schools of Public Health, 1975). It is also one of the only leading causes of death whose prevalence has risen in recent years, highlighting the need to find an effective treatment (Shapiro et al, 2003).
Figure 1: Correlation between smoking duration and incidence of emphysema. It is evident that emphysematous development is reliant on both environmental factors as well as biological predisposition. (Hogg, 2004)

More so than any other leading cause of death, the onset of emphysema can be expedited by behavioral and environmental factors. As a result, it affects many people at a relatively young age, precluding them from finding employment and placing heavy burdens on the healthcare industry. COPD costs consist of direct medical costs plus productivity losses attributed to morbidity, disability, and premature death. COPD is the 5th leading cause of death in the United States, and in 1993, smoking-related health expenditures constituted 11.8% of total personal health expenditures (Warner et al, 1999). microscopic and macroscopic effects of emphysema are costly and require sincere attention. Discussion In normal respiration, the expansion of the thoracic cavity during inhalation creates a pressure difference that encourages the alveolar sacs to open and fill with air. Upon exhalation, the elastic recoil from the walls of the alveoli allows them to contract, forcing the air back out through the bronchioles. Elastin fibers are generally considered the most important component of the alveolar tissue membrane in producing this recoil (Sobin et al, 1988). Emphysema is characterized by decreased elastic recoil in the alveoli. This can be attributed to a loss of elastin in the walls of the alveolar sacs (Sobin et al, 1988). As a result of decreased recoil ability, the alveoli remain inflated with CO2-rich air, even during exhalation, limiting the overall proficiency of respiration. A number of physiological phenomena rely on functional recoil of the alveolar tissue. Without proper contraction of the alveoli, there will be significant mixing of incoming atmospheric air with stagnant, CO 2rich air. The resultant rise in carbon dioxide partial pressure will lead to an increased rate of ventilation. The body will also respond by altering the diameter of the pulmonary arteries to decrease blood velocity past the alveoli, allowing oxygen more time to diffuse into the bloodstream. This increase in pressure causes pulmonary hypertension, and an enlarged right ventricle. The smoke from tobacco products, among other exogenous toxins, initiates an immune response in the lung tissue. This response has been heavily correlated to increased concentrations of neutrophils and Both the

macrophages surrounding the alveoli (Saetta et al, 1997). These cells contain a number of proteolytic molecules, whose activity has been linked to smoke-induced emphysema (Hautamaki et al, 1997). Of the proteinases that have been studied, neutrophil elastase (NE) is the one most closely related to incidence of pulmonary emphysema (Shapiro et al, 2003). Shapiro et al showed in a 2003 study that NE not only played a part in the immune response, but was necessary to the development of emphysema. The precise mechanism of initiation is still unknown, but the presence of cigarette smoke has been repeatedly coupled with the release of proteolytic molecules, including NE. Upon release, NE degrades many of the elastin fibers in the walls of the alveoli, leading to decreased tissue elasticity and increased alveolar volume. As mentioned, emphysematous degradation of alveolar tissue is somewhat irreversible. (Newly developed drugs used for alveologenesis are discussed later.) Still, there are a few treatment methods that have been developed to reduce the rate of degradation. Of course, the most effective treatment method will necessarily include removing the environmental factor that led to the emphysematous response. The cessation of smoking alone has been proven to drastically lessen the rate of degradation of alveolar tissue, a concept illustrated in Figure 2 (Walsh, 2008).
Figure 2: Illustration showing the effect of quitting smoking on the degradation of alveolar tissue. Note that, in the absence of environmental factors, tissue degradation is comparable to that in non-smoking individuals.

To maximize recovery from emphysema, the removal of environmental causes can be supplemented with other treatment methods. Current options can be separated into two categories: (1) those that treat the symptoms of emphysema and (2) those that treat the pathophysiology underlying the observed symptoms (Martorana et al, 2005). Two of the most popular symptomatic methods target oxygen delivery: supplying supplemental oxygen and chemical bronchodilation. A third option, involving surgical removal of damaged lung tissue, attempts to improve the efficiency of diffusion at the alveolar level. Alternatively, the treatment methods that target the underlying physiology primarily aim to inhibit the inflammatory immune response

that causes emphysematous symptoms. One of the more recent drugs being tested to treat emphysema was described in a 2005 paper by Martorana et al. The drug is called Roflumilast, and it is a phosphodiesterase (PDE) inhibitor. PDE4, one of the enzymes in the family of PDEs, degrades proteins in a secondary messenger system designed to prevent the inflammatory response in lung tissue. Roflumilast inhibits the PDE4 enzyme, thus promoting anti-inflammation. Shown to be very efficacious, Roflumilast shows potential as a novel drug treatment for patients with emphysema. Conclusion Smoking-induced emphysema represents an enormous healthcare debacle in the United States. It constitutes a significant portion of health-related expenditures and is one of the only major causes of death whose incidence is increasing. Perhaps even more significant than the macroscopic aspects of emphysema are its individual effects. Though the factors that lead to the development of emphysema are fairly well understood, their mechanisms of action are still unknown. Exogenous toxinsincluding smoke from tobacco productstrigger an inflammatory response within the lung. This response involves the release of a number of immune cells, which contribute to the degradation of elastin, the protein responsible for the elastic recoil of alveoli. The disruption in alveolar tissue leads ultimately to decreased respiratory function and a host of other aforementioned symptoms. In a 2008 paper, Gardi et al separate current endogenous treatment methods into two categories. In the present work, previous discussion of such methods was limited to the first categorytreatments aimed at simply slowing the rate of degradation of alveolar tissuebecause progress in that category is much further along. An example of such a treatment was given earlier by way of the PDE inhibitor Roflumilast. The second of these two treatment options, and the more promising of the two, incorporates the use of retinoidsthe class of chemicals related to vitamin Ato reverse the degradation process and stimulate alveolar growth. Takahashi et al (2008) found that they were able to stimulate alveologenesis in mice with a chemical called simvastatin. This is a very promising finding, as it underscores the possibility to reverse the

hugely detrimental effects of smoking. While the more invasive techniques, such as surgical removal of damaged lung tissue, are useful at increasing respiratory efficiency in extreme cases, it is likely that they will be phased out as these novel treatments progress. An interesting feature of emphysema is how the disease can be quantitatively characterized by pulmonary lung function parameters which were discussed and measured in biology 151 lab such as FEV 1 and FVC (Mead et al, 1967). FVC is the forced vital capacity, which is essentially the maximum amount of air that can be moved into and out of the lungs, and FEV1 is the amount of that air that was expired within the first second of exhalation (Eason V, 2009). Therefore, a common diagnostic measure of respiratory function is the FEV1/FVC ratio. This value is indicative of an individuals ability to exhale quickly, and thus provides a measure of resistance to flow within the airways. The ratio distinguishes between individuals with restrictive and obstructive pulmonary diseases. Restrictive pulmonary diseases such as fibrosis are

characterized by small lung volumes, but the FEV1/FVC ratios are in the normal range of .8-1.0 whereas obstructive diseases such as emphysema reduced ratios, often as low as .3-.4 (Eason V, 2010). The applicability of lab experiments in assessing pathophysiology is helpful in understanding real medical conditions and diagnoses in scientific journals. Another interesting feature of emphysema is the wide spectrum of socioeconomic groups it affects. An individual is likely to develop emphysema if his lungs are exposed to toxins such as smoke, pollution, or dust for a prolonged period. This makes sense in light of the finding that, when matched for age and sex and, emphysema is much more apparent in coal mining populations than in non-coal mining groups (Ryder et al, 1970). While many of the miners engage in this dangerous and laborious line of work out of economic desperation, most people, from a variety of income brackets, smoke cigarettes for recreational purposes. Emphysema, like many other diseases, does not discriminate based on wealth or status, so reckless habits such as smoking are fatal even in the presence of a clean environment and access to health care.