Pathophysiology
In normal breathing, air is drawn in through the bronchi and into the alveoli, which are tiny sacs surrounded by capillaries. Alveoli absorb oxygen and then transfer it into the blood. When toxins, such as cigarette smoke, are breathed into the lungs, the harmful particles become trapped in the alveoli, causing a localized inflammatory response. Chemicals released during the inflammatory response (e.g., elastase) can eventually cause the alveolar septum to disintegrate. This condition, known as septal rupture, leads to significant deformations of the lung architecture (video) that have important functional consequences. The key mechanical event consequent to septal rupture is that the resulting cavity is larger than the sum of the two alveolar spaces (see figure); in fact because of the lacking mechanical support of the broken septa the lung elastic recoil further enlarges this new space, necessarily at the expenses of the surrounding healthy parenchyma. In other words, as an immediate and spontaneous consequence of septal rupture, the elastic lung recoil resets healthy parenchyma expansion at a lower level, in proportion to the amount of septal disruption. The large cavities left by the septal rupture are known as bullae. These deformations result in a large decrease of alveoli surface area used for gas exchange, as well as decreased ventilation of the surrounding healthy parenchyma. This results in a decreased Transfer Factor of the Lung for Carbon Monoxide (TLCO). To accommodate the decreased surface area, thoracic cage expansion (barrel chest) and diaphragm contraction (flattening) take place. Expiration, which physiologically depends completely on lung elastic recoil, increasingly depends on the thoracic cage and abdominal muscle action, particularly in the end expiratory phase. Due to decreased ventilation, the ability to exude carbon dioxide is significantly impaired. In the more serious cases, oxygen uptake is also impaired. As the alveoli continue to break down, hyperventilation is unable to compensate for the progressively shrinking surface area, and the body is not able to maintain high enough oxygen levels in the blood. The body's last resort is vasoconstricting appropriate vessels. This leads to pulmonary hypertension, which places increased strain on the right side of the heart, the side responsible for pumping deoxygenated blood to the lungs. The heart muscle thickens in order to pump more blood. This condition is often accompanied by the appearance of jugular venous distension. Eventually, as the heart continues to fail, it becomes larger and blood backs up in the liver.
Patients with alpha 1-antitrypsin deficiency (A1AD) are more likely to suffer from emphysema. A1AT inhibits inflammatory enzymes (such as elastase) from destroying the alveolar tissue. Most A1AD patients do not develop clinically significant emphysema, but smoking and severely decreased A1AT levels (10-15%) can cause emphysema at a young age. The type of emphysema caused by A1AD is known as panacinar emphysema (involving the entire acinus) as opposed to centrilobular emphysema, which is caused by smoking. Panacinar emphysema typically affects the lower lungs, while centrilobular emphysema affects the upper lungs. A1AD causes about 2% of all emphysema. Smokers with A1AD are at the greatest risk for emphysema. Mild emphysema can often develop into a severe case over a short period of time (1–2 weeks).
While A1AD provides some insight into the pathogenesis of the disease, hereditary A1AT deficiency only accounts for a small proportion of the disease. Studies for the better part of the past century have focused mainly upon the putative role of leukocyte elastase (also neutrophil elastase), a serine protease found in neutrophils, as a primary contributor to the connective tissue damage seen in the disease. This hypothesis, a result of the observation that neutrophil elastase is the primary substrate for A1AT, and A1AT is the primary inhibitor of neutrophil elastase, together have been known as the "protease-antiprotease" theory, implicating neutrophils as an important mediator of the disease. However, more recent studies have brought into light the possibility that one of the many other numerous proteases, especially matrix metalloproteases might be equally or more relevant than neutrophil elastase in the development of non-hereditary emphysema.
The better part of the past few decades of research into the pathogenesis of emphysema involved animal experiments where various proteases were instilled into the trachea of various species of animals. These animals developed connective tissue damage, which was taken as support for the protease-antiprotease theory. However, just because these substances can destroy connective tissue in the lung, as anyone would be able to predict, doesn't establish causality. More recent experiments have focused on more technologically advanced approaches, such as ones involving genetic manipulation. One particular development with respect to our understanding of the disease involves the production of protease "knock-out" animals, which are genetically deficient in one or more proteases, and the assessment of whether they would be less susceptible to the development of the disease. Often individuals who are unfortunate enough to contract this disease have a very short life expectancy, often 0–3 years at most.
Read more about this topic: Emphysema