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Pulmonary and Critical Care Medicine Division, University of Colorado at Denver and Health Sciences Center, Denver, Colorado; and Cardiopulmonary Pathology Division, Department of Pathology, Johns Hopkins University, Baltimore, Maryland
Correspondence and requests for reprints should be addressed to Norbert F. Voelkel, M.D., University of Colorado Health Sciences Center, 4200 East Ninth Avenue, BRB, Room 621, Mail Stop: C272, Denver, CO 80262. E-mail: norbert.voelkel{at}uchsc.edu
ABSTRACT
The alveolar destruction leading to airspace enlargement in patients with end-stage chronic obstructive pulmonary disease (COPD) is frequently progressive, despite smoking cessation. Several laboratories have accumulated data demonstrating the presence of immune cells in bronchial biopsy specimens and lung tissue sections from patients with COPD. Recently, the accumulation of T and B lymphocytes, often forming follicles, in the lung parenchyma from patients with severe COPD has been reported. In addition, it has been postulated that there might be an autoimmune component to COPD. T-cell receptor analysis has provided data consistent with the concept of T-cell clones in the lung tissue from patients with COPD. Against this background, we developed a model of autoimmune emphysema in adult rats. Based on published data showing that immunization of mice with human umbilical vein endothelial cells (HUVECs) causes production of anti–vascular endothelial growth factor (VEGF) receptor II (KDR) antibodies, and our own data indicating that administration of a VEGF receptor blocker in adult rats causes emphysema, we reasoned that intraperitoneal injection of HUVECs in rats would generate both anti-VEGF receptor antibodies and emphysema. Indeed, intraperitoneal injection of HUVECs caused emphysema. We further explored the autoimmune nature of this model, identified KDR antibodies in the serum of HUVEC-immunized rats, and injected serum from the emphysematous rats into naive rats and mice, which resulted in emphysema. Presently, we are in the process of investigating whether cigarette smoke extract causes emphysema. We recently identified anti–endothelial cell antibodies in the serum of patients with end-stage emphysema.
Key Words: emphysema • apoptosis • autoimmune disease
Hidden within chronic obstructive pulmonary disease (COPD) is a group of disorders with an impressively wide spectrum of clinical manifestations (1–4). The pulmonary manifestations certainly include chronic bronchitis, small airway disease, varying degrees of emphysema, with and without formation of subpleural bullae, loss of lung capillaries, remodeling of precapillary arterioles, and areas of fibrosis (5–7). In addition, there has, in recent years, been an increasing recognition that COPD is associated, in its late stages, with osteoporosis (8), muscle wasting, and cardiovascular diseases (9, 10). New questions are being asked: for example, is COPD also a systemic disorder (11–13)? Or, for the purpose of this discussion: are we lumping different diseases together under the rubric of COPD? In other words, what is the essence of COPD? Is it possible that we may have so far missed an integral part of the disease by focusing too much on the obvious airway component? Although the focus on the small airways is necessary and important, it is, at the same time, also important to question an exquisitely airway-centric view, as this allows one to see aspects of COPD that may have so far been overlooked.
APOPTOSIS AS A CENTRAL MECHANISM OF ALVEOLAR SEPTAL DESTRUCTION
Segura-Valdez and coworkers (14) and Kasahara and coworkers (15) demonstrated the presence of apoptotic cells in the lungs from patients with COPD and emphysema, and Mayo and coworkers (16) related lymphocytes and apoptosis to emphysema in the lungs of smokers. Several experimental strategies in mice (17, 18) and rats showed that chronic cigarette exposure and administration of a vascular endothelial growth factor (VEGF) receptor blocker (19, 20) caused lung cell apoptosis and significant airspace enlargement. Aoshiba and colleagues instilled active caspase intratracheally in mice, proving that one consequence of lung structure cell apoptosis was emphysema (21). These data are complemented by data showing that a broad-spectrum caspase inhibitor prevented VEGF receptor blockade–induced emphysema (19) and by data that show that antioxidant (20) treatment (or strategies to increase plasma levels of 
1-antitrypsin [18]) prevented both apoptosis and emphysema. We have previously proposed the concept of a lung structure maintenance program (22), which, in normal adult lung functions, works well to replace dying cells and to protect against widespread apoptotic cell loss, and to effectively remove dead cells, by a mechanism now named efferocytosis (26). The consequences of faulty removal of apoptosed cells are continuation of inflammation (23, 24) and a greater risk of triggering an autoimmune response (25). One hypothesis is that the lung microvascular endothelial cells (ECs)—including the alveolar septal capillary cells—are particularly vulnerable and dependent on VEGF (26) for their survival. Whether or not lung microvascular endothelial cell apoptosis dominates over epithelial cell apoptosis, or whether, in fact, one depends on the other, has not been systemically investigated in any of the experimental models. Apoptosis of endothelial cells, leading to loss of capillaries, may well be a central disease mechanism in patients with emphysema and muscle wasting. For example, Tang and coworkers (27) demonstrated that skeletal muscle–specific conditional knockout of VEGF in mice caused endothelial cell apoptosis and capillary loss at the sites of VEGF knockout. These observations support the concept of capillary loss (28) via endothelial cell apoptosis in animal models of emphysema.
IS THERE AN AUTOIMMUNE DISEASE COMPONENT TO COPD/EMPHYSEMA?
This is the question that Agusti and colleagues asked in an editorial in 2003 (29). They and others noticed that the disease is frequently progressive in spite of smoking cessation. Similarly, J. Hogg more recently asked, "Why does airway inflammation persist after smoking stops?" (30), after he had described lymph follicles in the vicinity of airways in lungs from patients with GOLD (Global Initiative for Chronic Obstructive Lung Disease) classification stage 3 and 4 disease (5) (Figure 1). M. Saetta and colleagues had pointed out in several publications that there are T-lymphocyte clusters in the lung parenchyma and the airway mucosa in patients with COPD (31). Agusti and coworkers compared COPD with rheumatoid arthritis (29), and other investigators have explained these immune manifestations as a consequence of a chronic—perhaps viral—infection. Indeed, latent viral infection and autoimmune response are not mutually exclusive. If, however, a viral infection is not the root cause of an autoimmune response in the context of progressive lung tissue destruction, then what else could be? Is it possible that ingredients in cigarette smoke cause lung tissue damage (apoptosis of endothelial cells), that neoantigens are presented to antigen-presenting cells, and, after complex T-cell/B-cell interactions, that antibodies against lung cells (including ECs) are generated?
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production (32). The existence of lymph follicles with germinal centers in COPD lungs supports, perhaps, a similar pathobiology of tissue destruction, as considered in rheumatoid arthritis. Similar lymph follicles have recently been shown in mice after cigarette smoke exposure (33). Our laboratory sought to connect the mechanism of alveolar structure loss due to apoptosis with autoimmune mechanisms. Based on a report by Wei and coworkers (34), we injected xenogeneic human umbilical vein endothelial cells (HUVECs) into rats with the expectation that these animals would (1) develop antibodies against Ecs, including antibodies against lung capillary ECs, and (2) emphysema. This indeed occurred, and the model provides proof of principle that an autoimmune attack can cause alveolar destruction (35). Disease developed in naive animals after passive transfer of CD4+ T cells or serum from emphysematous animals (35). In keeping with this model truly being a model of autoimmune emphysema, we postulated that tolerizing strategies should protect against emphysema development. Indeed, both pristane (a saturated terpenoid alkane adjuvant) and Poly-IC (double-stranded DNA) treatment protected the animals against HUVEC-induced emphysema, as did a central tolerance-inducing strategy—intrathymic injection of HUVECs (unpublished observations). Thus, this model of autoimmune emphysema not only confirms the central role of lung cell apoptosis in alveolar destruction, it also points the way to new therapies. FROM HUVEC TO CIGARETTE SMOKE
In the xenogeneic HUVEC model of autoimmune emphysema, the ECs are being injected intraperitoneally. This strategy has little to do with smoking cigarettes. Certainly, that is true. In the first scenario, antigens are delivered to an immunologically privileged space—the peritoneal cavity; in the second scenario, antigens are delivered to the respiratory and gastrointestinal tract. Cigarette smoke extract (CSE) has been used for several years to experimentally assess the effect of cigarette smoke components on target cells (36, 37) in an attempt to explain findings in smokers' tissues. We described, for example, the loss of expression of the prostacyclin synthase protein in precapillary arterioles, in the lungs from patients with COPD, and that CSE impairs the gene expression in cultured lung ECs (38). Indeed, CSE also induces EC apoptosis, as does acrolein, an aggressive aldehyde present in the volatile phase of cigarette smoke and also in CSE (39). Acrolein is cytotoxic, altering membrane and cytosolic proteins by forming adducts. Recently, we demonstrated the presence of acroleinated proteins in the lung tissue from long-term smokers. Acroleinated proteins are increased in the plasma of smokers (39). We now have applied CSE intraperitoneally and intratracheally to normal adult rats, and have found that the animals develop profound airspace enlargement in association with lung EC apoptosis. In this new emphysema model, we test the effect of the xenobiotics contained in cigarette smoke, but also consider that they themselves could be antigenic, or indirectly—via apoptosis induction and processing by immune cells (25)—trigger an immune response (Figure 2).
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Smoking causes airway inflammation, damages cells through the attack of oxidants, damages DNA, and causes apoptosis—all components of an environment of damage and repair, and activation of the innate immune system, and an environment that can also lead to formation of anti-EC antibodies. Indeed, smoking has already been identified as a potential risk factor for autoimmune diseases—for example, as a risk factor for Graves' disease and autoimmune hypothyroidism (40, 41), rheumatoid arthritis (42), primary biliary cirrhosis (43), and accelerated atherosclerosis in patients with autoimmune rheumatoid arthritis (44).
If in some patients with progressive lung parenchyma–destructive COPD—perhaps a subgroup of genetically susceptible patients—there was a component of autoimmune disorder in the lung, but perhaps also systemically (13), this might explain why conventional antiinflammatory drugs (including steroids) are relatively ineffective and do not stop disease progression.
FOOTNOTES
Conflict of Interest Statement: L.T.-S. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; I.S.D. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; P.S.N.-S. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; J.D.L. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; R.M.T. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; M.R.N. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; N.F.V. served as a consultant for Pfizer and received lecture fees from United Therapeutics in 2006; he received $90,000 in 2005–2006 from GlaxoSmithKline as research grants.
(Received in original form May 1, 2006; accepted in final form July 15, 2006)
REFERENCES
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J. L. Curtis, C. M. Freeman, and J. C. Hogg The Immunopathogenesis of Chronic Obstructive Pulmonary Disease: Insights from Recent Research Proceedings of the ATS, October 1, 2007; 4(7): 512 - 521. [Abstract] [Full Text] [PDF]
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K. F. Rabe, B. Beghe, F. Luppi, and L. M. Fabbri Update in Chronic Obstructive Pulmonary Disease 2006 Am. J. Respir. Crit. Care Med., June 15, 2007; 175(12): 1222 - 1232. [Full Text] [PDF]
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