Nrf2‐deficient mice are highly susceptible to cigarette smoke‐induced emphysema

Abstract

Inflammation, protease/anti-protease imbalance and oxidative stress play important roles in the pathogenesis of emphysema. Nrf2 counteracts oxidative tissue damage and inflammation through transcriptional activation via the anti-oxidant responsive element (ARE). To clarify the protective role of Nrf2 in the development of emphysema, the susceptibility of Nrf2-knockout mice to cigarette smoke (CS)-induced emphysema was examined. In Nrf2-knockout mice, emphysema was first observed at 8 weeks and exacerbated by 16 weeks following CS-exposure, whereas no pathological abnormalities were observed in wild-type mice. Neutrophilic lung inflammation and permeability lung damage were significantly enhanced in Nrf2-knockout mice 8 weeks after CSexposure. Importantly, neutrophil elastase activity in bronchoalveolar lavage fluids was markedly higher in Nrf2-knockout mice preceding the pronounced neutrophil accumulation. The expression of secretory leukoprotease inhibitor, a potent inhibitor of neutrophil elastase, was inducible in wild-type, but not in Nrf2-knockout mice. This protease/anti-protease imbalance, together with the lack of inducible expression of ARE-regulated anti-oxidant/anti-inflammatory genes, may explain the predisposition of Nrf2-knockout mice to neutrophilic inflammation. Indeed, specific activators of Nrf2 induced the expression of the SLPI gene in macrophages. These results indicate that Nrf2 protects against the development of emphysema by regulating not only the oxidant/ anti-oxidant balance, but also inflammation and the protease/anti-protease balance.

Evidence that Cisplatin-induced Auditory Damage is Attenuated by Downregulation of Pro-inflammatory Cytokines Via Nrf2/HO-1

“…Yoh et al (2001) reported that Nrf2-deficient female mice developed lupus-like autoimmune nephritis. It was also demonstrated that Nrf2-deficient mice exhibit prolonged inflammation during cutaneous wound healing and display enhanced bronchial inflammation and susceptibility to cigarette smoke-induced emphysema (Iizuka et al 2005). These data suggest that Nrf2 deficiency and the resulting impaired antioxidant activity are important in the determination of susceptibility to autoimmune and inflammatory diseases.…”

Sulforaphane inhibitsde novosynthesis of IL-8 and MCP-1 in human epithelial cells generated by cigarette smoke extract

“…NRF2-dependent gene expression is a central mediator in several pulmonary inflammatory diseases such as sepsis, asthma, and emphysema (Rangasamy et al, 2004(Rangasamy et al, , 2005Iizuka et al, 2005;Thimmulappa et al, 2006a). These studies are characterized by increased pulmonary inflammation in mice with a disruption of Nrf2 (Nrf2 −/− mice) compared with wild-type mice (Nrf2 +/+ mice), resulting in more severe pulmonary disease.…”

Antioxidant N-acetyl cysteine reverses cigarette smoke-induced myocardial infarction by inhibiting inflammation and oxidative stress in a rat model

“…Exposure to tobacco smoke increases inflammation, oxidative stress [1][2][3][4][5][6][7][8][9][10] and decreases antioxidant expression. [11][12][13][14][15] Direct and indirect studies have demonstrated that oxidative stress from reactive oxygen species (ROS) generated through mitochondria, xanthine oxidase, and the NADPH oxidase system [16][17][18][19][20][21] is one of the important factors in the pathogenesis of myocardial ischemia.…”