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Industry: Email Alert RSS FeedAn Animal Model of Autoimmune Emphysema
American Journal of Respiratory and Critical Care Medicine, Apr 1, 2005 by Taraseviciene-Stewart, Laimute, Scerbavicius, Robertas, Choe, Kang-Hyeon, Moore, Melissa, Et al
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.
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Keywords: apoptosis; autoimmunity; CD4+ T cells; emphysema; endothelial cells
Although cigarette smoking has been recognized as the most important factor in the development of emphysema (1, 2), the precise mechanisms that lead to the loss of alveolar structures are not well understood. Chronic inflammation and an imbalance of protease/antiprotease activities and oxidative stress are the most frequently evoked concepts used to explain the pathobiology of emphysema (3-6), yet increased numbers of T lymphocytes infiltrating the alveolar walls of patients with emphysema (7) correlate with the extent of alveolar destruction and the severity of airflow obstruction (8, 9). Although there is an increasing number of rodent models of emphysema, which implicate complex relationships among multiple gene products in the regulation of the homeostasis of alveolar septal cells (10, 11), autoimmune mechanisms have not previously been recognized to play a role in experimental emphysema models. Recently, Agusti and coworkers (12) proposed that an acquired immune response to self- or foreign antigens may be a central component of the pathogenesis of human emphysema, yet evidence in support of such a hypothesis is missing, although a descriptive study published by Birring and colleagues (13) suggests a relationship between chronic obstructive pulmonary disease in nonsmokers and organ-specific autoimmune disease, particularly thyroid disease. The best studied paradigm of autoimmunity is type I diabetes mellitus, characterized by B- and T-cell responses (14, 15), possibly occurring as a result of exposure to a new antigen (e.g., enterovirus).
We suggest that pulmonary emphysema can - at least in part - be explained as a consequence of a failure of signals that maintain normal lung structure (16), with ensuing alveolar septal cell apoptosis and enhanced oxidative stress (17). Furthermore, vascular endothelial growth factor (VEGF), an obligatory endothelial cell (EC) survival factor (18) abundantly expressed in lung tissue (19), serves as a critical lung structure maintenance factor, because lung tissue from patients with severe emphysema shows decreased VEGF gene and protein expression (20), and chronic VEGF receptor (VEGFR) blockade causes emphysema in adult rats (21) and impaired alveolization in neonatal rats (22).
Taking into account recent novel experimental approaches to control or block tumor angiogenesis, which have relied on immunization with ECs (23, 24), DNA coding for EC growth factors (25), or receptor proteins (26), we question whether these approaches may have a collateral destructive effect on lung ECs. If so, this would support the concept that dysregulation of antibody- and cell-mediated immunity can be involved in the disruption of the lung maintenance program, alveolar cell apoptosis, and the development of emphysema (12). We therefore postulated that intraperitoneal injection of rats with xenogeneic ECs would cause a pulmonary anti-EC immune response and emphysema. Furthermore, rats injected with human umbilical vein ECs (HUVECs), but not with human pulmonary artery smooth muscle cells (HPASMCs), generate within 2 to 3 weeks antibodies against ECs and develop centrilobular emphysema associated with alveolar cell apoptosis and activation of matrix metalloproteinases (MMPs) (27). We also demonstrate that rat antihuman EC antibodies induce EC apoptosis in vitro and cause emphysema in passively immunized mice. Furthermore, passive transfer of CD4+ cells from EC-immunized rats into naive immunocompetent animals resulted in emphysema. Because immunization of athymic rats with xenogeneic ECs did not cause emphysema, this indicates that T cells participate in the immune response and emphysema development. This is the first model that provides a proof of concept for an autoimmune mechanism of EC damage in the development of emphysema.
Some of the results of these studies have been previously reported in the form of abstracts (27, 28).
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