Genetic ablation of Nrf2 enhances susceptibility to cigarette smoke–induced emphysema in mice

Abstract

Although inflammation and protease/antiprotease imbalance have been postulated to be critical in cigarette smoke-induced (CS-induced) emphysema, oxidative stress has been suspected to play an important role in chronic obstructive pulmonary diseases. Susceptibility of the lung to oxidative injury, such as that originating from inhalation of CS, depends largely on its upregulation of antioxidant systems. Nuclear factor, erythroid-derived 2, like 2 (Nrf2) is a redox-sensitive basic leucine zipper protein transcription factor that is involved in the regulation of many detoxification and antioxidant genes. Disruption of the Nrf2 gene in mice led to earlier-onset and more extensive CS-induced emphysema than was found in wild-type littermates. Emphysema in Nrf2-deficient mice exposed to CS for 6 months was associated with more pronounced bronchoalveolar inflammation; with enhanced alveolar expression of 8-oxo-7,8-dihydro-2'-deoxyguanosine, a marker of oxidative stress; and with an increased number of apoptotic alveolar septal cells--predominantly endothelial and type II epithelial cells--as compared with wild-type mice. Microarray analysis identified the expression of nearly 50 Nrf2-dependent antioxidant and cytoprotective genes in the lung that may work in concert to counteract CS-induced oxidative stress and inflammation. The responsiveness of the Nrf2 pathway may act as a major determinant of susceptibility to tobacco smoke-induced emphysema by upregulating antioxidant defenses and decreasing lung inflammation and alveolar cell apoptosis.

Nrf2 is a critical regulator of the innate immune response and survival during experimental sepsis

“…Under normal conditions, nuclear levels of Nrf2 are low; however, under stress such as oxidative stimuli, nuclear accumulation of Nrf2 increases, resulting in enhanced transcriptional activation of its targets, which in turn confers protection against various environmental stresses (7)(8)(9)(10)(11)(12). Here, we report that Nrf2 is a novel regulator of the innate immune response that dramatically improves survival during experimental sepsis by protecting against dysregulated inflammation.…”

“…Nuclear proteins were isolated from tissue or cells by using the protocol described previously (7). The NF-kB probe (5′-GTTGAGGGGACTTTCCCAGGC-3′) (Promega) was end-labeled by T4 polynucleotide kinase in the presence of [ 32 P] ATP g. For EMSA, 5 mg of nuclear proteins was incubated with the labeled NF-kB probe in the presence of poly(dI-dC) in binding buffer (Promega) at 4°C for 20 minutes.…”

“…Nuclear factor-erythroid 2-related factor 2 (Nrf2), a basic leucine zipper redox-sensitive transcription factor, is a pleiotropic protein that regulates the basal and inducible expression of a battery of antioxidant and other cytoprotective genes by binding to a cis-acting enhancer sequence known as the antioxidant response element (5)(6)(7)(8). Under normal conditions, nuclear levels of Nrf2 are low; however, under stress such as oxidative stimuli, nuclear accumulation of Nrf2 increases, resulting in enhanced transcriptional activation of its targets, which in turn confers protection against various environmental stresses (7)(8)(9)(10)(11)(12).…”

Toll-like receptor 4 deficiency causes pulmonary emphysema

“…Interestingly, researchers have found that disruption of the Nrf2 gene, a transcriptional regulator of antioxidant enzymes, led to accelerated and more extensive cigarette smoke-induced emphysema in mice (12,47). Furthermore, elastase-provoked emphysema was markedly exacerbated in Nrf2-deficient mice compared with WT mice (48).…”

“…These trends indicate that the development of pulmonary emphysema is affected by other important factors. Several candidate genes have been implicated in determining susceptibility to pulmonary emphysema: α-1 antitrypsin (α1-AT) (7), macrophage elastase (8), klotho (9), surfactant D (10), microsomal epoxide hydrolase (11), and nuclear factor erythroid 2-related factor 2 (Nrf2) (12). Alterations in these genes have been shown to lead to oxidant/antioxidant or protease/antiprotease imbalances, which are pivotal to the pathogenesis of emphysema (4).…”