Bidirectional modulation of TNF-alpha production by alveolar macrophages in asbestos-induced pulmonary fibrosis.
Bronchoalveolar lavage (BAL) cells were isolated from rats 1, 3, and 6 weeks after a single intratracheal instillation of saline, UICC chrysotile asbestos (5 mg), or silica (5 mg). In asbestos-exposed rats, the pulmonary response was characterized by a significant increase in the number of alveolar macrophages (AMs) and the appearance of fibrotic lesions within 1 week. By contrast, mixed macrophage and neutrophil accumulations were observed in the silica group without evidence of fibrosis. Tumor necrosis factor-alpha (TNF-alpha) production by lipopolysaccharide (LPS)-stimulated BAL cells from asbestos-treated rats was significantly lower than controls 1 and 3 weeks after exposure. However, by 6 weeks higher levels of TNF-alpha production were noticeable in this group. Decreases in LPS-induced TNF-alpha production were also observed with BAL cells from silica-treated animals at all time points studied. Lower levels of TNF-alpha were not related to decreased BAL cell viability or the presence of a significant proportion of neutrophils in the silica group. Furthermore, biphasic changes in TNF-alpha production seen in the asbestos group were correlated with concomitant decreases (3 weeks) and increases (6 weeks) in levels of TNF-alpha mRNA in AMs. These data indicate that lower levels of TNF-alpha resulted from inhibition at the gene expression level and provide evidence for bidirectional modulation of TNF-alpha production by AMs during inflammatory reactions.
Ouellet
S
S
Department of Pharmacology, Faculty of Medicine, University of Ottawa, Ottawa, Canada.
Yang
H
H
Aubin
R A
RA
Hawley
R G
RG
Wenckebach
G F
GF
Lemaire
I
I
D000818:Animals; D001194:Asbestos / Q000009:adverse effects*; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D002470:Cell Survival; D015536:Down-Regulation; D005786:Gene Expression Regulation; D016676:Macrophages, Alveolar / Q000378:metabolism*; D008297:Male; D009504:Neutrophils / Q000502:physiology; D011658:Pulmonary Fibrosis / Q000209:etiology* / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation
D014409:Tumor Necrosis Factor-alpha; D001194:Asbestos