Published online before print July 16, 2009

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(American Journal of Pathology. 2009;175:519-532.)
© 2009 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2009.090016

Overexpression of HO-1 Protects against TNF--Mediated Airway Inflammation by Down-Regulation of TNFR1-Dependent Oxidative Stress

I-Ta Lee^*, Shue-Fen Luo, Chiang-Wen Lee, Shyi-Wu Wang^*, Chih-Chung Lin, Chia-Chi Chang^*, Yuh-Lien Chen^¶, Lee-Young Chau^|| and Chuen-Mao Yang^*

From the Departments of Physiology and Pharmacology,^* Internal Medicine, and Anesthetics, Chang Gung University, Kwei-San, Tao-Yuan; the Department of Nursing, Division of Basic Medical Sciences, Chang Gung Institute of Technology, Chia-Yi; the Department of Anatomy and Cell Biology,^¶ College of Medicine, National Taiwan University, Taipei; and the Institute of Biomedical Sciences,|| Academia Sinica, Taipei, Taiwan

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)--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--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-B activation. HO-1 overexpression also attenuated TNF--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- 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-B activation in both cultured human tracheal smooth muscle cells and the airways of mice.