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1-Antitrypsin Deficiency
Columbus, OH
Dr. Wewers is John A. Prior Professor of Medicine, Deputy Director, Davis Heart and Lung Research Institute.
Correspondence to: Mark D. Wewers, MD, John A. Prior Professor of Medicine, Deputy Director, 110L Davis Heart and Lung Research Institute, DHLRI, 473 W. 12th Ave, Columbus, OH 43210; e-mail: wewers.2{at}osu.edu
Does the protease-antiprotease concept need an update? The novel observation provided by the work from Mulgrew and colleagues in this issue of CHEST (see page 1948) suggests that the process is likely much more complex than originally conceived 4 decades ago. More about that later.
In 1963, Laurell and Eriksson1 demonstrated the connection between a deficiency of 
1-antitrypsin and the fact that three of the first five individuals identified had unmistakable evidence of pulmonary emphysema. The recognition that the main function of 1-antitrypsin is to inhibit proteases (most specifically neutrophil elastase and proteinase 3), and the demonstration that these enzymes when instilled into the lung produce pulmonary emphysema, led to the genesis of this hypothesis. It has now been almost 2 decades since 1-antitrypsin infusions have been used clinically in an attempt to counterbalance the protease burden.2 Yet, to date there are only limited data to suggest that this treatment has impacted the natural history of 1-antitrypsin deficiency-associated emphysema. The largest comparison to date, the Alpha-1-Antitrypsin Deficiency Registry, which analyzed 927 subjects, failed to demonstrate an effect of augmentation therapy on FEV1 rate of decline.3 Is the concept of an imbalance between enzyme and inhibitor too simplistic? Why doesn’t augmentation therapy have a more dramatic effect on the progression of a disease that is the most classic example of the protease antiprotease hypothesis? These questions certainly raise a number of interesting possibilities.
Perhaps, 1-antitrypsin augmentation is started too late and the initial proteolytic insult sets a process in motion that is only partly suppressed by treatment. A computer model of the elastin-centered lung structure suggests that this is a real possibility.4 Suki et al4 demonstrate that elastin breakdown may beget elastin breakdown. Mechanical strain on previously injured matrix may induce further strand breakage. Since the lung is constructed in a network that depends on the sum of the parts for its structure, loss of individual support structures may put additional stress on remaining supports that ultimately leads to further destruction. The collapse of the World Trade Center towers comes to mind. Therefore, perhaps augmentation treatment needs to be in place before any matrix is destroyed. However, given the average cost of approximately $50,000/yr,5 this hypothesis is not likely to be tested soon. Furthermore, prospective studies67 demonstrate that despite the high frequency of the PiZ allele in the world population, the incidence of clinically significant emphysema is surprisingly low. So treating everyone would likely mean treating a majority that does not need it.
Why then doesn’t everyone respond in the same way to the presumed protease imbalance? Additional risk factors are undoubtedly playing a role. For example, cigarette smoking shortens the life expectancy of an individual with 1-antitrypsin deficiency by almost 20 years.8 But individual smokers have huge variances in the severity of disease despite what appear to be similar exposures to tobacco. Additional inherited predispositions are likely to be present. Family genetic studies currently underway may answer the gene-environment question in the near future.9
Furthermore, the pathophysiology of 1-antitrypsin diseases is clearly not all due to protease excess. Panniculitis is a case in point. 1-Antitrypsin may be an anti-inflammatory agent, and its deficiency may predispose to inflammation. However, the mechanisms of its anti-inflammatory effect are not understood. We documented that 1-antitrypsin can prevent antineutrophil cytoplasmic antibodies (ANCA) from activating the release of the neutrophil chemoattractant interleukin (IL)-8 from proteinase-3–expressing monocytes.10 Although there is some evidence that ANCA-mediated disorders may be predisposed by 1-antitrypsin deficiency,11 there are likely many other anti-inflammatory actions of 1-antitrypsin. Another case in point is 1-antitrypsin–associated cirrhosis that is now believed to be due to the unfolded protein response. This response is common to mutations in the serine protease inhibitor family (serpin family). Serpins are proteins that inhibit serine proteases by means of a trapping mechanism. The protease cleaves the serpin while binding it covalently. The serpin changes conformation in a trap-like fashion ensnaring the protease. This unique propensity of serpins to undergo a major change in conformation explains their predisposition to mutations that cause misfolding. Cells in which unfolded protein is abundant experience significant toxicity. Alzheimer dementia and the cirrhosis of 1-antitrypsin deficiency are examples that have been elegantly reviewed.12
In this context, Mulgrew et al provide interesting data that may help change the way we look at 1-antitrypsin–mediated disease. First, they demonstrate that the lung itself may be a source of 1-antitrypsin. After correcting their circulating levels of 1-antitrypsin to normal by successful liver transplantation, PiZ-deficient individuals still produce detectable PiZ 1-antitrypsin at the lung epithelial surface. Although the authors do not identify the cellular source, they suggest the possibility of the lung epithelium itself. It is known that the lung epithelium can be a real source of 1-antitrypsin.1314 Secondly, and perhaps more importantly, the authors document that in the case of the PiZ-deficiency state, this 1-antitrypsin exists in a polymerized form. Polymerized 1-antitrypsin can attract neutrophils to the lung, inducing lung injury that is dependent, at least in part, on misfolding of 1-antitrypsin as opposed to its antiprotease activity. This, is reminiscent of the recognition that malfolded serpins can induce other diseases such as Alzheimer disease.12 It raises the potential that the mechanism of lung injury may be subtler than previously envisioned by the protease antiprotease hypothesis.
A review of the recent basic experimental approach to emphysema reveals another potential connection to the report of Mulgrew et al and the misfolding concept. It appears that targeting virtually any gene to the lung epithelium can induce emphysema (eg, IL-11,15 platelet-derived growth factor,16 IL-6,17 IL-13,18 interferon-
,19 tumor necrosis factor-,20 and transforming growth factor-21). Perhaps any one of these transgenic proteins can disrupt the inflammatory balance to an extent that results in lung injury and destruction. However, when viewed from the context of the report by Mulgrew et al, another interpretation might also be entertained. Perhaps these lung-targeted transgenic proteins are dysregulated in quantity or quality such that they aggregate in the lung epithelium, producing lung injury. Thus, it seems reasonable to hypothesize that PiZ-related emphysema may arise at least in part from chronic injury to lung epithelial cells as a result of locally aggregated 1-antitrypsin. Contributing further to the injury is the ability of the aggregated PiZ protein to attract neutrophils. Perhaps, some individuals are more predisposed to induce misfolded protein as a result of differences in chaperonins or differences in environmental exposures that trigger epithelial cells to produce increased amounts of 1-antitrypsin. Indeed, PiZ emphysema may target the lung bases simply because basilar epithelial cells get more of the exposures that trigger increased local 1-antitrypsin production with resultant aggregation of protein.
In summary, we have come a long way in our understanding of the nature of the diseases associated with 1-antitrypsin deficiency since its recognition 40 years ago. The protease-antiprotease hypothesis has served us well and provided the basic groundwork to begin to understand the principles that contribute to lung injury and destruction. The report by Mulgrew et al makes us question what we really do know about emphysema pathogenesis, and argues that protease excess may not be the only story.
References
-1-globulin pattern of serum in -1-antitrypsin deficiency. Scand J Clin Lab Invest 15,132-140[CrossRef][ISI]
1-antitrypsin deficiency associated with emphysema. N Engl J Med 1987;316,1055-1062[Abstract]
1-antitrypsin. Am J Respir Crit Care Med 1998;158,49-59
1-antitrypsin deficiency. Am J Respir Crit Care Med 2003;167,1387-1392-1-antitrypsin deficiency: high prevalence in the St. Louis area determined by direct population screening. Am Rev Respir Dis 1989;140,961-966[ISI][Medline]
1-antitrypsin deficiency, Pi Z. Acta Med Scand 1978;204,345-351[ISI][Medline]
-1 antitrypsin, and Fc receptors. J Clin Invest 1997;100,1416-1424[ISI][Medline]
1-Antitrypsin genetic polymorphism in ANCA-positive systemic vasculitis. Kidney Int 1993;43,1329-1332[ISI][Medline]
1-Antitrypsin deficiency: a model for conformational diseases. N Engl J Med 2002;346,45-531-antitrypsin by alveolar epithelial cells. FEBS Lett 1994;346,171-174[CrossRef][ISI][Medline]
1-proteinase inhibitor by human lung-derived epithelial cells. J Biol Chem 1997;272,8250-8255 induction of pulmonary emphysema in the adult murine lung. J Exp Med 2000;192,1587-1600 produces an increase in lung volumes and pulmonary hypertension. Am J Physiol Lung Cell Mol Physiol 2001;280,L39-L49. Am J Physiol Lung Cell Mol Physiol 2001;281,L1088-L1094
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