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(Chest. 2001;120:S2-S3.)
© 2001 American College of Chest Physicians

Tumor Necrosis Factor Receptor Deficiency Protects Mice From Silica-Induced Lung Fibrosis by Altering Lung Matrix Metalloproteinase-13/Tissue Inhibitor of Metalloproteinase-1 RNA Expression and Decreasing Activating Protein-1 Activation*

Luis A. Ortiz, MD, FCCP; Joseph A. Lasky, MD, FCCP; Evelyn Gozal, PhD; Arnold R. Brody, PhD; Annie Pardo, PhD; Moises Selman, MD, FCCP; Victor Ruiz, MD and Mitchell Friedman, MD, FCCP

* From the Department of Medicine (Drs. Ortiz, Lasky, Gazal, Brody, and Friedman), Tulane Medical Center, New Orleans, LA; and Instituto de Enfermedades Respiratorias (Drs. Pardo, Selman, and Ruiz), Mexico City, Mexico.

Correspondence to: Luis A. Ortiz, MD, FCCP, Department of Medicine, Section of Pulmonary Diseases, Critical Care and Environmental Medicine SL9, 1430 Tulane Ave, New Orleans, LA 70112-2699

Murine exposure to silica is associated with enhanced tumor necrosis factor (TNF) expression and upregulation of genes responsible for matrix deposition (collagen, matrix metalloproteinases [MMPs], and their inhibitors). The regulation of TNF is mediated through TNF receptor (TNFR)-dependent activation of nuclear transcription factors. We have previously shown that double TNFR-deficient mice (55-/75-) are resistant to silica-induced pulmonary fibrosis.1 We now have studied the effect of TNFR deletion upon RNA expression of interstitial collagenase (MMP-13) and its inhibitor (tissue inhibitor of metalloproteinase [TIMP]-1) in the lungs of silica-treated mice. We correlated the MMP-13/TIMP-1 RNA expression with the activation of the nuclear transcription factors activating protein (AP)-1 and nuclear factor (NF)-{kappa}B in the lungs of C57BL/6, and single [(55-/- or 75-/-)] TNFR-deficient mice exposed to silica (0.2 g/kg) or saline solution by intratracheal instillation. Animals were killed 28 days after exposure, and lung hydroxyproline, MMP-13, and TIMP-1 RNA expression and AP-1 and NF-{kappa}B activation were measured using standard methods. Mice that were p55 -/- or p 75 -/- deficient had significantly decreased lung hydroxyproline accumulation (p < 0.05). Significantly enhanced MMP-13 RNA expression was observed in all murine strains, but enhanced TIMP-1 RNA expression was observed only in C57BL/6 mice in response to silica exposure. NF-{kappa}B activation was observed in all strains, while AP-1 activation was seen only in C57BL/6 mice after silica exposure. These data suggest that (1) TNFR deletion modifies MMP-13/TIMP-1 expression in favor of matrix degradation, and (2) decreased AP-1 activation explains the suppressed TIMP-1 expression in TNFR-deficient mice.

Footnotes

Abbreviations: AP = activating protein; MMP = matrix metalloproteinase; NF = nuclear factor; TIMP = tissue inhibitor of metalloproteinase; TNF = tumor necrosis factor; TNFR = tumor necrosis factor receptor

References

  1. Ortiz, LA, Lasky, J, Lungarella, G, et al (1999) Upregulation of the p75 but not the p55 TNF-{alpha} receptor mRNA after silica and bleomycin exposure and protection from lung injury in double receptor knockout mice. Am J Respir Cell Mol Biol 20,825-833[Abstract/Free Full Text]




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