Journal
AMERICAN JOURNAL OF PATHOLOGY
Volume 175, Issue 2, Pages 519-532Publisher
ELSEVIER SCIENCE INC
DOI: 10.2353/ajpath.2009.090016
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Funding
- [NSC95-2320-B182-010]
- [NSC95-2314-B182-040]
- [NSC95-2314-13182-053]
- [CMRPD170331]
- [CMRPG350652]
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Oxidative stresses are believed to play an important role in the induction of both cell adhesion molecules and pro-inflammatory cytokines, a key event in a variety of Inflammatory processes. The enzyme heme oxygenase-1 (HO-1) functions as an antioxidant and serves to protect against tissue injury. In this study, we report that HO-1 was induced in cultured human tracheal smooth muscle cells after either treatment with a potent inducer of HO-1 activity, cobalt protoporphyrin IX, or infection with a recombinant adenovirus that carries the human HO-1 gene. Overexpression of HO-1 protected against tumor necrosis factor (TNF)-alpha-mediated airway inflammation via the down-regulation of oxidative stress, adhesion molecules, and interleukin-6 in both cultured human tracheal smooth muscle cells and the airways of mice. In addition, HO-1 overexpression inhibited TNF-alpha-induced intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 expression, adherence of THP-1 cells, generation of interleukin-6, p47(phox) translocation, and nuclear factor-kappa B activation. HO-1 overexpression also attenuated TNF-a-induced oxidative stress, which was abrogated in the presence of both the HO-1 inhibitor, zinc protoporphyrin IX, as well as a carbon monoxide scavenger in addition, HO-1 overexpression reduced the formation of a TNFR1/c-Src/p47(phox), complex. These results suggest that HO-1 functions as a suppressor of TNF-alpha signaling, not only by inhibiting the expression of adhesion molecules and generation of interleukin-6, but also by diminishing intracellular reactive oxygen species production and nuclear factor-kappa B activation In both cultured human tracheal smooth muscle cells and the airways of mice. (Am J Pathol 2009,175:519-532; DOI: 10.2353/ajpath.2009.090016)
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