Potential role of apoptotic macrophages in pulmonary inflammation and fibrosis.
Wang-L; Antonini-JM; Rojanasakul-Y; Castranova-V; Scabilloni-JF; Mercer-RR
J Cell Physiol 2003 Feb; 194(2):215-224
Induction of apoptosis has been associated with a variety of exposures which result in inflammatory and fibrotic lung disorders. Macrophages are key regulatory cells in the lung; however, the role of apoptotic macrophages in those pulmonary disorders is not well characterized. In the present investigation, apoptotic macrophages were instilled into the lungs of rats to study directly the pulmonary responses to apoptotic cells. The effects of apoptotic macrophages on lung inflammation and fibrosis, as well as associated protein expression of TNF-alpha, TGF-beta, and matrix metalloproteinases (MMPs) were examined. Induction of macrophage apoptosis was carried out in vitro using a variety of known apoptosis inducers. Intratracheal administration of apoptotic macrophages (5 x 10(6) cells/rat) into the lung of rats caused an increase in pulmonary infiltration of macrophages and lung cell apoptosis 4 weeks after the treatment as indicated by terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) assay. In contrast, pulmonary instillation of saline or normal control macrophages had no effect. Histological analysis of lung sections showed collagen deposition and fibrotic lesions after apoptotic cell treatment but not in control groups. Immunohistochemical studies revealed increased expression of TNF-alpha, TGF-beta, MMP2, and MMP9 in the treatment group 4 weeks after the treatment. These results suggest a role for macrophage apoptosis in the initiation of these lung disorders. This study provides direct evidence that apoptotic macrophages can induce lung inflammation and fibrosis and that this induction may be associated with increased expression of TNF-alpha, TGF-beta, MMP2, and MMP9.
Pulmonary-system; Fibrosis; Lung-disorders; Lung-fibrosis; Pulmonary-system-disorders; Laboratory-animals; Animal-studies; Animals; In-vitro-studies
Liying Wang, National Institute for Occupational Safety and Health, Pathology and Physiology Research Branch, 1095 Willowdale Road, Morgantown, WV 26505
67-68-5; 60-00-4; 10043-35-3
Journal of Cellular Physiology