ToxSci Advance Access originally published online on February 18, 2003
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Toxicological Sciences 72, 150-157 (2003)
Copyright © 2003 by the Society of Toxicology
RESPIRATORY TOXICOLOGY |
Induction of Chemokines by Low-Dose Intratracheal Silica Is Reduced in TNFR I (p55) Null Mice
,1
* Department of Pediatrics and
Department of Environmental Medicine, Strong Children’s Research Center, University of Rochester School of Medicine and Dentistry, Rochester, New York 14642
Previous studies suggest that tumor necrosis factor alpha (TNF-
) and the TNFRI (p55) and TNFRRII (p75) receptors mediate the pulmonary fibrotic response to silica. In order to further define the role of the TNFRI (p55) receptor in induction of profibrotic chemokines by low-dose silica/crystalline silica (50 µg/50 µl/mouse) or control diluent saline was instilled into the trachea of TNFRI gene ablated (–/–) and C57BL/6 (WT) control mice. Lung tissue was harvested and bronchoalveolar lavage (BAL) performed 24 h and 28 days following silica administration. Selected profibrotic chemokine mRNAs were quantified by ribonuclease protection assay, normalized to ribosomal protein L32 mRNA content and expressed relative to saline control treated lungs. Induction of MIP-1ß, MIP-1, MIP-2, IP-10, and MCP-1 mRNAs was attenuated in the TNFRI–/– mice, in comparison to WT mice, particularly at 28 days after exposure. ELISA assays for MIP-1 and MIP-2 in homogenized lung tissue similarly demonstrated marked induction of both chemokines 24 h after silica treatment, which was persistent at 28 days in WT but not in TNFRI–/– mice. The percentage of BAL cells that was neutrophils was comparably increased in WT and RI–/– lungs at 24 h (49 ± 12% vs. 46 ± 10%) and 28 days (6.2 ± 1.5% vs. 4.5 ± 1%). The increase in total lavagable cells and BAL protein was also independent of strain. Histology revealed mild alveolitis without granuloma formation in both strains, slightly decreased in TNFRI–/–. This study demonstrates an increase in pro-fibrotic chemokines in response to a single intratracheal exposure to crystalline silica that was sustained at 28 days after treatment in WT but not in TNFRI–/– mice. Silica dependent recruitment of neutrophils to the alveolar space and alveolar protein leak were, however, not altered by the absence of the TNF receptor.
Key Words: silica; tumor necrosis factor (TNF-); TNF receptor; chemokine; intratracheal.
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