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An Animal Model of Autoimmune Emphysema

Division of Pulmonary Sciences and Critical Care, Departments of Medicine and Immunology, University of Colorado Health Sciences Center, Denver, Colorado; Division of Cardiopulmonary Pathology, Department of Pathology, Johns Hopkins University, Baltimore, Maryland

Correspondence and requests for reprints should be addressed to Norbert F. Voelkel, M.D., Department of Medicine, Division of Pulmonary Sciences, UCHSC, 4200 East Ninth Ave, C272, Denver, CO 80262. 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. We show, in a novel animal model, that immunocompetent, but not athymic, nude rats injected intraperitoneally with xenogeneic endothelial cells (ECs) produce antibodies against ECs and develop emphysema. Immunization with ECs also leads to alveolar septal cell apoptosis and activation of matrix metalloproteases MMP-9 and MMP-2. Anti-EC antibodies cause EC 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 immunocompetent animal also results in emphysema. This study shows 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: apoptosis • autoimmunity • CD4+ T cells • emphysema • endothelial cells

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