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

Abstract

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.

Limonene and its ozone-initiated reaction products attenuate allergic lung inflammation in mice

“…The regulation of HO-1 is biphasic and as a response to oxidative stress, HO-1 is upregulated within 6 h (Risom et al 2003;Sunil et al 2013). At later time points (including in the lung), HO-1 is involved in suppressing inflammation and initiating wound healing (Lee et al 2009;Ryter et al 2006), which may be the reason for a comparable upregulation in the groups of allergic mice.…”

The PPARγ agonist, rosiglitazone, attenuates airway inflammation and remodeling via heme oxygenase-1 in murine model of asthma

“…Increased HO-1 activity is found protective against inflammation, excessive cell proliferation and interstitial fibrosis [29] . Previous study suggested HO-1 could protect against airway inflammation by down-regulating tumor necrosis factor receptor (TNFR)1 dependent oxidative stress [30] . In asthma particularly, it was considered that the increase of HO-1 expression and activity were protective [31] .…”

Lipopolysaccharide induces ICAM-1 expression via a c-Src/NADPH oxidase/ROS-dependent NF-κB pathway in human pulmonary alveolar epithelial cells

“…c-Src has been shown to regulate ICAM-1 expression in various cell types (9,16). In addition, LPS can mediate c-Src activation and then cause the inflammatory responses (7,10).…”

“…Raised levels of adhesion molecules might contribute to the recruitment of PMNs to the regions of inflammatory tissue. These adhesion molecules are classified into two major families: the Ig superfamily [e.g., ICAM-1 and VCAM-1] and the selectins (e.g., P-selectin and E-selectin) (9). ICAM-1 is an inducible cell surface glycoprotein on several cell types, which mediates the tight adhesiveness of PMNs and thus facilitates PMN migration across the vascular endothelium barrier and then interacts with lung epithelium (8).…”