Adam Wanner, MD
University of Miami Miller School of Medicine – Miami, FL
Alpha-1 Foundation – Miami, FL
Approximately six percent of the population has COPD, and COPD has become the third leading cause of death in the United States1. Although the awareness of COPD as a global health problem is growing and although there has been a recent surge in COPD research, spawned by industry and government funding agencies, our understanding of the pathogenetic mechanisms underlying this highly prevalent disease remains fragmentary. As a result, disease-modifying treatment is still elusive. Inhaled smoke, especially cigarette smoke, has been identified as the major cause of COPD, but it is not clear why only a minority of those exposed or exposing themselves to smoke develops clinical COPD. Genetic predisposition comes to mind as a possible explanation for this phenomenon, and the study of COPD genetics therefore is in full swing2,3.
The lung disease of patients with alpha-1 antitrypsin (AAT) deficiency resembles COPD, including emphysema, chronic bronchitis and bronchiectasis. However, in contrast to COPD, the genetic defect that is responsible for and the biology of the structurally and functionally defective alpha-1 antitrypsin protein that is linked to lung disease have been well characterized in AAT deficiency4-7. Furthermore, strides are being made to discover additional gene mutations that seem to be needed for the full expression of the AAT deficiency phenotype. In this sense, AAT research has had it easier than generic COPD research, and this is exemplified by the impressive advances that have been made in our understanding of the physiopathological consequences of the misfolded and polymeric alpha-1 antitrypsin protein, the basic defect that is responsible for both the liver and lung disease of AAT deficiency8,9.
Historically, the concept that an imbalance between proteases and antiproteases is an important contributing factor to the pathogenesis of COPD in general arose from the discovery of AAT deficiency and its association with COPD9. Subsequent research showed that exogenous proteolytic enzymes cause lung damage in experimental animals that resembles human emphysema as seen in COPD, that human neutrophil elastase is inhibited by AAT, and that cigarette smoke oxidizes critical residues in AAT thereby compromising its anti-elastase function10-14. These observations were used to explain why individuals with AAT deficiency are especially susceptible to cigarette smoke induced lung disease. But the interaction between cigarette smoke and AAT also suggested that it contributes to the protease-antiprotease imbalance in smokers without AAT deficiency who develop COPD.
One could argue that the protease-antiprotease principle has had its day in the scientific world and that no other pathogenetic links should be expected between AAT deficiency and COPD. New discoveries tend to refute this argument. For example, it has now been shown that the unfolded AAT protein forms polymers, and that polymeric AAT made by lung cells or reaching the lung through the blood circulation can lead to the local release of chemokines and the recruitment of inflammatory cells to the lung, thereby contributing to neutrophilic inflammation, characteristic of COPD15-17. Another consequence of the unfolded, polymeric AAT protein is that it accumulates in the endoplasmic reticulum of hepatocytes and to a lesser extent lung epithelial cells and cannot be effectively secreted into plasma; hence the name AAT deficiency. The intracellular aggregation of unfolded AAT initiates a brisk unfolded protein response that involves caspase-3 and apoptosis18. Apoptosis of lung epithelial cells has been shown to participate not only in the pathogenesis of the lung disease associated with AAT deficiency but also in the pathogenesis of COPD in general19. Since tobacco smoke can induce the unfolded protein response and disposition of unfolded proteins that are present in low abundance in lung cells of subjects without AAT deficiency, the pro-apoptotic pathways that have been identified in AAT deficiency could shed light on the development of COPD as well20.
Another lesson to be learned from AAT research is the use of AAT as an anti-inflammatory and anti-apoptotic molecule in the treatment of COPD unrelated to AAT deficiency. In other words, exogenous AAT could be thought of as a therapeutic agent, not only as a replacement as in AAT deficiency. There is growing evidence for this paradigm. Human AAT inhibits the inflammatory activity of human monocytes in vitro, and this effect is still seen with modified forms of AAT that lack anti-protease effects21. With respect to the anti-apoptotic actions of AAT, it has it been shown in a mouse-model that AAT inhibits apoptosis-dependent lung destruction that is not caused by AAT deficiency18, and a recent paper has also demonstrated that AAT attenuates cigarette smoke induced apoptosis in vitro22. In addition to these anti-apoptotic actions in vitro and in animal models of lung disease, AAT appears to have broad anti-inflammatory effects in humans. Thus, treatment of patients with cystic fibrosis with aerosol AAT has been reported to reduce sputum neutrophil numbers, IL-8 concentration and unopposed elastase activity23. As a serin protease inhibitor, it is not surprising that inhaled AAT attenuated free elastase activity in the lung. More significant was the effect of AAT on IL-8, a chemoattractant for neutrophils, and on neutrophil recruitment to the lung. Inasmuch as neutrophils are thought to have a major role in the pathogenesis of COPD, one might consider exploring the clinical benefit of AAT in COPD. Currently, only intravenously administered AAT is available for the purpose of augmentation therapy in AAT deficiency. Intravenous AAT is hardly a therapeutic option in patients with generic COPD. However, with the likelihood that aerosol AAT will soon become available for clinical use, the idea of treating cystic fibrosis and COPD with AAT to prevent disease progression may not be far fetched.
If the protease-antiprotease principle, which was fueled by the discovery of AAT deficiency, initiated decades of COPD research, why couldn't other scientific observations derived from AAT research continue to fertilize the study of COPD?
Perhaps a renewed interest in the study of the AAT deficiency could again inform COPD at large, as it has in the past. Such research could identify novel drug targets for the treatment of COPD associated or not associated with AAT deficiency. From a scientific perspective it may no longer be acceptable to think of AAT deficiency as a rare disease that is of little interest to investigators studying COPD, to COPD research funding agencies, to the pharmaceutical industry, and ultimately to patients who suffer from COPD.