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The Proceedings of the American Thoracic Society 2:23-25 (2005)
© 2005 The American Thoracic Society

Emphysema

An Autoimmune Vascular Disease?

Norbert Voelkel and Laima Taraseviciene-Stewart

COPD Center, Pulmonary and Critical Care Medicine Division, University of Colorado Health Sciences Center, Denver, Colorado

Correspondence and requests for reprints should be addressed to: Norbert F. Voelkel, M.D., Division of Pulmonary Sciences and Critical Care Medicine, 4200 East Ninth Avenue, C272, Denver, CO 80262. E-mail: norbert.voelkel{at}uchsc.edu


   ABSTRACT
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 ABSTRACT
Three Animal Models of...
 CONCLUSIONS
 REFERENCES
 
We propose that an endogenous maintenance program controls lung cell turnover, apoptosis, and tissue repair, and that emphysema is a manifestation of the breakdown of the lung structure maintenance program. Emphysema can be induced experimentally in rats by three methods: blockade of vascular endothelial growth factor receptors using SU5416, a small molecule–tyrosine kinase inhibitor; methylprednisolone, which activates matrix metalloproteinase-9 and decreases Akt phosphorylation; and antibodies directed against endothelial cells (autoimmune emphysema). SU5416-induced emphysema is associated with lung induction of cytochrome P450 and oxidant stress, and a superoxide dismutase mimetic or N-acetylcysteine prevents this form of emphysema. A broad-spectrum metalloproteinase inhibitor prevents methylprednisolone-induced emphysema and, finally, autoimmune emphysema is associated with increased lung tissue metalloproteinase-9 expression and alveolar septal cell apoptosis. Athymic rats, which lack CD4+ T cells, are protected against autoimmune emphysema, whereas adoptive transfer of CD4+ T cells causes autoimmune emphysema in naive adult rats. It appears that vascular endothelial growth factor and signaling via its receptors plays a central role in the lung structural maintenance program, and oxidative stress, proteolysis, and apoptosis may coincide in the moment of lung cell destruction. Interestingly, the methylprednisolone model illustrates that inflammation is not necessary for the development of emphysema.

Key Words: autoimmune disease • emphysema • metalloproteinase-9 • methylprednisolone • vascular endothelial growth factor

We postulate that there is a lung structure maintenance program (LSMP), which may involve elements of the original fetal lung development program to maintain the integrity of the adult lung (Figure 1). Lung-specific stem cells or bone marrow–derived stem cells may also participate in the highly controlled turnover of lung cells; yet little is known about such cells. Growth factors, such as vascular endothelial growth factor (VEGF), which are critical during lung development, likely play the role of maintenance factors in the adult lung (1). This concept of an LSMP leads directly to the concept of "maintenance failure" as an explanation for destructive lung diseases, such as emphysema, and it calls for a departure from the perhaps too simplistic traditional "injury–repair" model of chronic lung diseases.



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  		Figure 1. Concept of a lung structure maintenance program. Like a building or a car, the lung structure must be maintained on an ongoing basis. Cells have to be removed (phagocytosed) and replaced properly by a genetically controlled program, which "reads" oxidant stress, protects against cellular senescence, and responds to challenge with xenobiotics.

 
In addition, accepting the concept of a failure of the normal lung maintenance program in chronic lung diseases also eventually will lead to a departure from the notion that there are neat and separate airway, interstitial, and vascular diseases (i.e., that chronic lung diseases actually respect compartment boundaries), and to the recognition that, in most chronic lung diseases, the entire lung is involved in the pathobiology. If we apply this idea to chronic obstructive pulmonary disease (COPD), it follows that airways, vessels, the interstitium, the pleura, and the immune system are all involved. That is, that the disease is more than just chronic bronchitis with the disease focus on airway tubes and mucus glands. For example, subpleural blebs are frequent occurrences in COPD, and we recognize that there is a "COPD vasculopathy." "Maintenance" of the adult lung structure differs from "repair" as, under conditions of daily living, the lung does not need to repair wounds, but needs to deal with inhaled particles, invading microorganisms, and subclinical activation of the innate immune system. Cells die constantly and must be removed, mostly by phagocytosis. Cells that have undergone apoptosis must be cleared efficiently, and this phagocytosis is accomplished not only by professional phagocytes, but also by neighboring structure cells (i.e., endothelial and epithelial cells) (2). We propose that this LSMP fails in COPD, that more cells than usual die, and that they are not efficiently removed (3), which means that they become necrotic. Necrotic cells maintain an inflammatory response, and necrotic cell debris may prompt an autoimmune response, leading to formation of antibodies directed against lung structure cells.

Intuitively, both the existence of such a maintenance program as well as the possibility of its failure makes sense, and animal models can help us to explore these concepts. Animal models provide mechanistic insights (4–7), complement clinical studies, and altogether lead to a healthy respect for the complex and redundant principles of homeostasis.


   Three Animal Models of Emphysema: Theme and Variations
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 Three Animal Models of...
CONCLUSIONS
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The three models discussed in the present article originate from different starting points, but all converge on VEGF and its receptors, which leads us to conclude that indeed VEGF is central to the adult LSMP (Figure 2).



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  		Figure 2. Vascular endothelial growth factor (VEGF) is a pleiotropic protein that is produced by many different cell types and is expressed abundantly in the adult lung. VEGF and VEGF receptor II (VEGFRII) protein and mRNA are reduced in lungs from patients with severe emphysema (30).

 
Rat Lung Emphysema Caused by a VEGF Receptor Antagonist, SU5416
A synthetic lipophilic small-molecule, SU5416 (3-[(2,4-dimethylpyrrol-5-yl)methylidenyl]-indolin-2-one), has been developed to target the tyrosine kinase activity of the VEGF receptors KDR (VEGFRII) and Flt-1 (VEGFRI) (8). In rats, a single subcutaneous injection causes pulmonary emphysema, which can be prevented by concomitant treatment with a broad-spectrum caspase inhibitor (9), with a mimetic of superoxide dismutase (5), or with N-acetylcysteine (10). Treatment of rats with {alpha}1-antitrypsin likewise prevents the development of emphysema (K.H. Choe, unpublished observation). SU5416, by virtue of VEGF receptor antagonism, jeopardizes the LSMP by inducing microvascular endothelial cell apoptosis, and the finding that antioxidant and antiprotease strategies prevent SU-5416–induced emphysema, indicates that both oxidants and proteases play a role in this model. Whether VEGF receptor blockade per se or cell apoptosis causes oxidative stress in the lung remains to be elucidated. Clearly, VEGF receptor blockade inhibits VEGF-dependent endothelial cell growth, and recently it has been shown that VEGF receptor blockade inhibits clearance of apoptotic cell debris (3).

Treatment of Adult Rats with Methylprednisolone Causes Emphysema—The "Osteoporosis" of the Lung?
It has been shown previously that glucocorticoids impair the maturation of the developing lung (11), and the effects of chronic corticosteroid use on human bone density are well known (12). Because patients with COPD routinely receive systemic corticosteroids for treatment of acute exacerbations, we questioned whether such a drug causes emphysema in adult rats. Studies were conducted with rats receiving 2 mg/kg of methylprednisolone daily, and the mean linear intercept, as a measure of airspace size, and the surface–volume ratio were assessed. The data show significant airspace enlargement already after 1 week of treatment (13). In addition, zymography of lung tissue homogenates showed increased gene activity of matrix metalloproteinase (MMP)-9. MMP-9 gene expression was also increased as determined by immunohistochemistry. To show that proteases were instrumental in this model of adult rat emphysema, animals were treated with a broad-range metalloproteinase inhibitor, GM6001. This inhibitor prevented the development of methylprednisolone-induced emphysema (13). This animal model is of interest because it illustrates that MMP activation can be induced by therapeutic interventions and can occur independent of inflammation. Gelatinase (MMP-9) expression has indeed been shown to be increased in lungs from patients with COPD (14); however, whether this finding was associated with steroid use is unknown. Recently, Wenzel and colleagues (15) showed increased MMP-9 expression in airway biopsy specimens from patients with severe asthma that had been treated with systemic steroid.

Autoimmune Emphysema in Adult Rats
Several groups of investigators have developed immunization strategies directed against angiogenesis in order to induce tumor regression, based on the notion that malignant tumors are highly dependent on their blood supply for survival (16–18). One such strategy is the immunization of animals with xenogeneic endothelial cells, with the expectation that animals will develop anti–endothelial cell antibodies, which induce apoptosis of vascular endothelial cells and cause tumor regression. Wei and colleagues (17) demonstrated the development of anti-KDR (VEGFRII) antibodies in tumor-bearing mice after injection of xenogeneic human umbilical vein endothelial cells. These authors reported that such immunotherapy, with fixed xenogeneic whole endothelial cells as a vaccine, effectively afforded protection from tumor growth and induced regression of established tumors (17).

We proposed, therefore, that injection of xenogenic human umbilical vein endothelial cells in adult rats would lead to anti-KDR antibody formation and emphysema (19). Indeed, at 2–3 weeks after immunization with human umbilical vein endothelial cells, lungs expressed caspase 3 and MMP-9, showed significantly reduced quantities of VEGF protein, and presented with the development of emphysema. Indeed, the antiserums that contained anti-KDR antibodies inhibited the growth of cultured endothelial cells. In contrast, human umbilical vein endothelial cell immunization of T cell–deficient athymic rats does not generate antiendothelial antibodies, and these animals do not develop emphysema. Although athymic rats possess B cells, T cells are required for antibody production, and without the T cell/B cell cooperation, antibodies are not being produced. We then asked whether adoptive transfer of immune-experienced CD4+ cells, which were isolated from the splenocyte population of human umbilical vein endothelial cell–immunized animals, would cause emphysema in the recipients of the adoptively transferred cells, and we consistently found severe emphysema at 3 weeks after the transfer of CD4+ T cells (19). This indicates that immune-experienced CD4+ T cells are sufficient to cause lung emphysema.


   CONCLUSIONS
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 ABSTRACT
 Three Animal Models of...
 CONCLUSIONS
REFERENCES
 
These three models of emphysema in adult rodents demonstrate that VEGF is important for the LSMP, that apoptosis, oxidative stress, and activated MMPs (5, 7) are involved in emphysema (Figure 3), and that alveolar space enlargement can develop without the overt action of inflammatory cells (13). Clearly these "proof-of-concept" studies must now be advanced into the clinical arena. Although apoptosis of lung structural cells and decreased VEGF and VEGFRII protein expression have been demonstrated in lung tissue specimens from patients with severe emphysema (20), as have markers of oxidative stress (21), the precise molecular mechanisms underlying decreased VEGFRII expression and increased oxidative stress are unknown. One hypothesis is that inhibition of VEGF signaling (e.g., because of anti-VEGFRII antibodies) generates oxidants in endothelial cells; reactive oxygen species then could start an apoptosis program. Whereas this hypothesis can be elucidated in cell culture systems, it remains to be seen whether this mechanism plays out in the lung tissue of susceptible smokers. Whether corticosteroids can worsen emphysema in patients receiving high doses during treatment of exacerbations will also be difficult to prove.



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  		Figure 3. Three models of emphysema. A VEGF receptor blocker, SU5416, immunization with xenogenic human umbilical vein endothelial cells (HUVEC), and treatment with corticosteroids (methylprednisolone) cause alveolar septal cell apoptosis and emphysema in rats.

 
Although the pulmonary vasculopathy in patients with COPD is well recognized (22–24) and frequently attributed to hypoxia or hypoxic vasoconstriction, other mechanistic aspects must be considered (25, 26). VEGF plays a role in hematopoiesis, in precursor mobilization from the bone marrow, and has been shown to promote exercise-induced capillary sprouting in skeletal muscle (27). It is tempting to speculate that impaired VEGF signaling may also explain some of the systemic manifestations of COPD, notably because tumor necrosis factor-{alpha} downregulates VEGF mRNA expression in endothelial cells (28), and leptin stimulates angiogenesis synergistically with VEGF (29).


   FOOTNOTES
 
Conflict of Interest Statement: N.V. does not have a financial relationship with a commercial entity that has an interest in the subject of this article; L.T.-S. does not have a financial relationship with a commercial entity that has an interest in the subject of this article.

(Received in original form May 4, 2004; accepted in final form October 11, 2004)


   REFERENCES
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 Three Animal Models of...
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 REFERENCES
 

  1. Voelkel NF, Cool C, Taraseviciene-Stewart L, Geraci MW, Yeager M, Bull T, Kasper M, Tuder RM. Janus face of vascular endothelial growth factor: the obligatory survival factor for lung vascular endothelium controls precapillary artery remodeling in severe pulmonary hypertension. Crit Care Med 2002;30 (Suppl.):S251–S256.[CrossRef][Medline]
  2. Fadok VA, Bratton DL, Henson PM. Phagocyte receptors for apoptotic cells: recognition, uptake, and consequences. J Clin Invest 2001;108:957–962.[CrossRef][Medline]
  3. Vandivier RW, Tuder RM, Morimoto K, Voelkel NF, Henson PM. Vascular endothelial growth factor (VEGF) regulates clearance of apoptotic complications in emphysema [abstract]. Am J Respir Crit Care Med 2004;169:A503.
  4. Voelkel NF, Tuder RM. Hypoxia-induced pulmonary vascular remodeling: a model for what human disease? J Clin Invest 2000;106:733–738.[Medline]
  5. Tuder RM, Zhen L, Cho CY, Taraseviciene-Stewart LO, Kasahara Y, Salvemini D, Voelkel NF, Flores SC. Oxidative stress and apoptosis interact and cause emphysema due to vascular endothelial growth factor receptor blockade. Am J Respir Cell Mol Biol 2003;29:88–97.[Abstract/Free Full Text]
  6. Aoshiba K, Yokohori N, Nagai A. Alveolar wall apoptosis causes lung destruction and emphysematous changes. Am J Respir Cell Mol Biol 2003;28:555–562.[Abstract/Free Full Text]
  7. Mahadeva R, Shapiro SD. Chronic obstructive pulmonary disease: 3. Experimental animal models of pulmonary emphysema. Thorax 2002;57:908–914.[Abstract/Free Full Text]
  8. Fong TA, Shawver LK, Sun L, Tang C, App H, Powell TJ, Kim YH, Schreck R, Wang X, Risau W, et al. SU-5416 is a potent and selective inhibitor of the vascular endothelial growth factor receptor (Flk-1/KDR) that inhibits tyrosine kinase catalysis, tumor vascularization, and growth of multiple tumor types. Cancer Res 1999;59:99–106.[Abstract/Free Full Text]
  9. Kasahara Y, Tuder RM, Taraseviciene-Stewart L, Le Cras TD, Abman S, Hirth PK, Waltenberger J, Voelkel NF. Inhibition of VEGF receptors causes lung cell apoptosis and emphysema. J Clin Invest 2000;106:1311–1319.[Medline]
  10. Demura Y, Taraseviciene-Stewart L, Scerbavicius R, Tuder RM, Voelkel NF. 4 A.D. N-acetylcysteine treatment protects against VEGF-receptor blockade–related emphysema. J COPD 2004;1:1–8.
  11. Tschanz SA, Damke BM, Burri PH. Influence of postnatally administered glucocorticoids on rat lung growth. Biol Neonate 1995;68:229–245.[Medline]
  12. Ionescu AA, Schoon E. Osteoporosis in chronic obstructive pulmonary disease. Eur Respir J 2003;46 (Suppl.):64s–75s.
  13. Choe KH, Taraseviciene-Stewart L, Scerbavicius R, Gera L, Tuder RM, Voelkel NF. Methylprednisolone causes matrix metalloproteinase–dependent emphysema in adult rats. Am J Respir Crit Care Med 2003;167:1516–1521.[Abstract/Free Full Text]
  14. Segura-Valdez L, Pardo A, Gaxiola M, Uhal BD, Becerril C, Selman M. Upregulation of gelatinases A and B, collagenases 1 and 2, and increased parenchymal cell death in COPD. Chest 2000;117:684–694.[Abstract/Free Full Text]
  15. Wenzel SE, Balzar S, Cundall M, Che HW. Subepithelial basement membrane immunoreactivity for matrix metalloproteinase-9: association with asthma severity, neutrophilic inflammation, and wound repair. J Allergy Clin Immunol 2003;111:1345–1352.[CrossRef][Medline]
  16. Rodriguez-Manzaneque JC, Lane TF, Ortega MA, Hynes RO, Lawler J, Iruela-Arispe ML. Thrombospondin-1 suppresses spontaneous tumor growth and inhibits activation of matrix metalloproteinase-9 and mobilization of vascular endothelial growth factor. Proc Natl Acad Sci USA 2001;98:12485–12490.[Abstract/Free Full Text]
  17. Wei YQ, Wang QR, Zhao X, Yang L, Tian L, Lu Y, Kang B, Lu CJ, Huang MJ, Lou YY, et al. Immunotherapy of tumors with xenogeneic endothelial cells as a vaccine. Nat Med 2000;6:1160–1166.[CrossRef][Medline]
  18. Niethammer AG, Xiang R, Becker JC, Wodrich H, Pertl U, Karsten G, Eliceiri BP, Reisfeld RA. A DNA vaccine against VEGF receptor 2 prevents effective angiogenesis and inhibits tumor growth. Nat Med 2002;8:1369–1375.[CrossRef][Medline]
  19. Taraseviciene-Stewart L, Scerbavicius R, Choe KH, Tuder RM, Voelkel NF. Immunization with xenogeneic endothelial cells causes emphysema in rats [abstract]. Am J Respir Crit Care Med 2002;165:B5.
  20. Kasahara Y, Tuder RM, Cool CD, Lynch DA, Flores SC, Voelkel NF. Endothelial cell death and decreased expression of vascular endothelial growth factor and vascular endothelial growth factor receptor 2 in emphysema. Am J Respir Crit Care Med 2001;163:737–744.[Abstract/Free Full Text]
  21. Rahman I, van Schadewijk AA, Crowther AJ, Hiemstra PS, Stolk J, MacNeeW, De Boer WI. 4-Hydroxy-2-nonenal, a specific lipid peroxidation product, is elevated in lungs of patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2002;166:490–495.[Abstract/Free Full Text]
  22. Santos S, Peinado VI, Ramirez R, Melgosa T, Roca J, Rodriguez-Roisin R, Barbera JA. Characterization of pulmonary vascular remodelling in smokers and patients with mild COPD. Eur Respir J 2002;19:632–638.[Abstract/Free Full Text]
  23. Yamato H, Sun JP, Churg A, Wright JL. Cigarette smoke–induced emphysema in guinea pigs is associated with diffusely decreased capillary density and capillary narrowing. Lab Invest 1996;75:211–219.[Medline]
  24. Voelkel NF, Cool CD. Pulmonary vascular involvement in chronic obstructive pulmonary disease. Eur Respir J 2003;46 (Suppl.):28s–32s.
  25. Raymond MA, Desormeaux A, Laplante P, Vigneault N, Filep JG, Landry K, Pshezhetsky AV, Hebert MJ. Apoptosis of endothelial cells triggers a caspase-dependent anti-apoptotic paracrine loop active on VSMC. FASEB J 2004;18:705–707.[Abstract/Free Full Text]
  26. Majo J, Ghezzo H, Cosio MG. Lymphocyte population and apoptosis in the lungs of smokers and their relation to emphysema. Eur Respir J 2001;17:946–953.[Abstract/Free Full Text]
  27. Amaral SL, Papanek PE, Greene AS. Angiotensin II and VEGF are involved in angiogenesis induced by short-term exercise training. Am J Physiol Heart Circ Physiol 2001;281:H1163–H1169.[Abstract/Free Full Text]
  28. Patterson C, Perrella MA, Endege WO, Yoshizumi M, Lee ME, Haber E. Downregulation of vascular endothelial growth factor receptors by tumor necrosis factor-alpha in cultured human vascular endothelial cells. J Clin Invest 1996;98:490–496.[Medline]
  29. Cao R, Brakenhielm E, Wahlestedt C, Thyberg J, Cao Y. Leptin induces vascular permeability and synergistically stimulates angiogenesis with FGF-2 and VEGF. Proc Natl Acad Sci USA 2001;98:6390–6395.[Abstract/Free Full Text]
  30. KasaharaY, Tuder RM, Cool CD, Lynch DA, Flores SC, Voelkel NF. Endothelial cell death and decreased expression of vascular endothelial growth factor and vascular endothelial growth factor receptor 2 in emphysema. Am J Respir Crit Care Med 2001;163:737–744.[Abstract/Free Full Text]



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