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Published ahead of print on November 24, 2004, doi:10.1164/rccm.200409-1275OC

Am. J. Respir. Crit. Care Med., Volume 171, Number 7, April 2005, 734-742

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Submitted on September 28, 2004
Accepted on November 18, 2004

An Animal Model of Autoimmune Emphysema

Laimute Taraseviciene-Stewart1, Robertas Scerbavicius1, Kang-Hyeon Choe1, Melissa Moore1, Andrew Sullivan1, Mark R Nicolls2, Andrew P Fontenot3, Rubin M Tuder4, and Norbert F Voelkel1*

1 Department of Medicine, Division of Pulmonary Sciences and Critical Care, University of Colorado Health Sciences Center, Denver, CO, USA, 2 Department of Medicine, Division of Pulmonary Sciences and Critical Care, University of Colorado Health Sciences Center, Denver, CO, USA; Department of Immunology, University of Colorado Health Sciences Center, Denver, CO, USA, 3 Department of Immunology, University of Colorado Health Sciences Center, Denver, CO, USA, 4 Department of Pathology, Division of Cardiopulmonary Pathology, Johns Hopkins University, Baltimore, MD, USA

* To whom correspondence should be addressed. E-mail: Norbert.Voelkel{at}UCHSC.edu.

Although cigarette smoking is implicated in the pathogenesis of emphysema, the precise mechanisms of chronic progressive alveolar septal destruction are not well understood. Here we show in a novel animal model that immune competent, but not athymic nude rats injected intraperitonealy with xenogeneic endothelial cells produce antibodies against endothelial cells and develop emphysema. Immunization with endothelial cells also leads to alveolar septal cell apoptosis and activation of matrix metalloproteases MMP-9 and MMP-2. Anti-endothelial cell antibodies cause endothelial cell apoptosis in vitro and emphysema in passively immunized mice. Moreover, immunization also causes accumulation of CD4+ T-cells in the lung. Adoptive transfer of pathogenic, spleen-derived CD4+ cells into naive immune-competent animal also results in emphysema. In this study we show for the first time that humoral- and CD4+ cell-dependent mechanisms are sufficient to trigger the development of emphysema, suggesting that alveolar septal cell destruction might result from immune mechanisms.
Key words: emphysema, endothelial cells, antibodies, T cells, cellular immune response




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