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Role of macrophage apoptosis in pulmonary inflammation.

Wang-L; Antonini-JM; Rojanasakul-Y; Castranova-V; Scabilloni-JF; Mercer-RR
Toxicologist 2001 Mar; 60(1):81
Apoptosis is a gene-controlled process of cellular self-destruction implicated in pathogenesis of inflammatory and fibrotic lung disorders. Macrophages are key regulatory cells in the lung; however, the role of apoptotic macrophages in pulmonary disorders is not known. We instilled apoptotic macrophages into the lungs of Fischer 344 rats to study lung response to apoptotic cells and products. The effects on apoptosis induction, lung histopathology, and fibrosis-related gene expression of matrix metalloproteinase (MMP) and TGF-B were examined. Apoptosis was determined by DNA ladder and TUNEL TdT assays, while lung pathology and protein expression were determined by histological analysis and immunohistochemistry of lung sections. To induce macrophage apoptosis, several known apoptosis inducers including salicylates, TGF-B, ethanol, silica, and DMSO were evaluated. Maximal apoptosis (-30%) was obtained using either DMSO or silica DMSO was chosen in all subsequent studies. Instillation of apoptotic macrophages (1-5 million cells/rat) with or without Survanta (a bovine surfactant) resulted in increased accumulation of macrophages and apoptotic lung cells after 4 weeks of treatment. In contrast, PBS- and normal macrophage-instilled controls showed no stimulatory effects. Increased expressions of MMP-9 and TGF-B were also observed in the apoptotic treatment group, but not in control groups. No significant effects were seen in rats treated with surfactant alone. Because MMP and TGF-B have been demonstrated to play crucial roles in the pathogenesis of inflammatory and fibrotic lung disorders, our results suggest a role for macrophage apoptosis in lung pathologies. In summary, we demonstrated that apoptotic macrophages can induce increased expression of MMP and TGF-B and that this induction may be associated with the development of lung pathology.
Pulmonary-system; Genes; Pathogenesis; Lung-disorders; Pulmonary-system-disorders; Histopathology; Lung-fibrosis
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Priority Area
Other Occupational Concerns; Pulmonary System Disorders
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The Toxicologist. Society of Toxicology 40th Annual Meeting, March 25-29, 2001, San Francisco, California