Apoptotic alveolar macrophages play a role in the development of pulmonary inflammatory disease in rats.
Wang-L; Scabilloni-J; Antonini-J; Rojanasakul-Y; Castranova-V; Lu-B; Mercer-RR
Toxicologist 2003 Mar; 72(S-1):358
Increasing evidence suggests that apoptosis plays an important role in pulmonary diseases; however, the molecular mechanism underlying this relationship is unclear. Previous studies from our laboratory have shown that pulmonary instillation of dimethyl sulfoxide (DMSO) induced apoptotic alveolar macrophage (AM) resulted in pulmonary inflammation and fibrosis. In this study, we further investigated the effect of intratracheal instillation of DMSO or UVB induced apoptotic AM and documented the time course of the resulting inflammatory and fibrotic responses in the Brown Norway rat lung. Morphological and immunohistochemical analyses of lung tissues showed an inflammatory response and increased connect tissue in the treatment groups, but not in control groups which were instilled with normal non-apoptotic AM. Instilled apoptotic cells were cleared at 4 weeks post-treatment, but the number of apoptotic lung cells was still higher than those in the control rats. Caspase 8 was elevated in the treatment group at 4 weeks post-treatment, suggesting a continuous induction of apoptosis in vivo via the death receptor-mediated pathway. Consistent with this finding, we observed a concomitant increase in TNF-alpha expression in treated lung tissues. In vitro studies also showed an increase in TNF-alpha production by naive AM incubated with apoptotic AM, but not when exposed to untreated AM. Together, our results indicate a role for AM apoptosis in the induction of inflammatory and fibrotic lung disorders, which may be mediated though cytokines, such as TNF-alpha.
Pulmonary-system; Pulmonary-system-disorders; Diseases; Laboratory-animals; Animal-studies; Animals; Alveolar-cells; Fibrosis; Lung-tissue; Lung-cells; In-vitro-studies; In-vivo-studies; Lung-disorders
The Toxicologist. Society of Toxicology 42nd Annual Meeting and ToxExpo, Cutting-Edge Science, Networking, New Perspectives, March 9-13, 2003, Salt Lake City, Utah