Transcription Factor Nrf2 Plays a Pivotal Role in Protection against Elastase-Induced Pulmonary Inflammation and Emphysema

Abstract

Emphysema is one of the major pathological abnormalities associated with chronic obstructive pulmonary disease. The protease/antiprotease imbalance and inflammation resulting from oxidative stress have been attributed to the pathogenesis of emphysema. Nrf2 is believed to protect against oxidative tissue damage through the transcriptional activation of a battery of antioxidant enzymes. In this study, we investigated the protective role of Nrf2 in the development of emphysema using elastase-induced emphysema as our model system. We found that elastase-provoked emphysema was markedly exacerbated in Nrf2-knockout (KO) mice compared with wild-type mice. The severity of emphysema in Nrf2-KO mice correlated intimately with the degree of lung inflammation in the initial stage of elastase treatment. The highly inducible expression of antioxidant and antiprotease genes observed in wild-type alveolar macrophages was significantly attenuated in the lungs of Nrf2-KO mice. Interestingly, transplantation of wild-type bone marrow cells into Nrf2-KO mice retarded the development of initial lung inflammation and subsequent emphysema, and this improvement correlated well with the appearance of macrophages expressing Nrf2-regulated antiprotease and antioxidant genes. Thus, Nrf2 appears to exert its protective effects through the transcriptional activation of antiprotease and antioxidant genes in alveolar macrophages.

Rapamycin inhibits the secretory phenotype of senescent cells by a Nrf2-independent mechanism

“…Our data show that tissue and plasma from Nrf2KO mice present higher levels of inflammation at 4 month of age (measured by the cytokine levels), corroborating previous reports (Ishii et al ., 2005; Khor et al ., 2008). This inflammatory status was attenuated by rapamycin treatment, and the inhibition of the inflammatory phenotype by rapamycin was correlated with an inhibition of the Stat3 pathway in both cell and mouse models (Xu et al ., 2015).…”

Increased colonic inflammatory injury and formation of aberrant crypt foci in Nrf2‐deficient mice upon dextran sulfate treatment

“…The increased expression of antioxidative enzymes, in an Nrf2-dependent manner, has been demonstrated in a number of inflammation animal models, including LPS-induced sepsis, 23 allergen-induced airway inflammation, 16 DSS-mediated colitis 21 and emphysema due to exposure to either cigarette smoke or elastase. 19,20 In these models, increased oxidative stress represents a potential stimulus for enhanced expression of cytoprotective genes. 13,14 Therefore, in the present study, it is likely that the lack of an effect of DSS on inflammation and oxidative damage in the colons from WT mice reflected an Nrf2-dependent upregulation of antioxidative enzymes.…”

“…15 Numerous in vivo studies have illustrated that Nrf2 plays an important role in modulating acute inflammation in a variety of experimental models. Nrf2-deficient (N0) mice have been shown to exhibit increased allergen-driven airway inflammation, 16 carrageenan-induced pleurisy, 17 multiorgan autoimmune inflammation, 18 emphysema after exposure to cigarette smoke and elastase, 19,20 dextran sulfate sodium (DSS)-mediated colitis 21 and increased inflammation during skin wound healing 22 compared to Nrf2 wild-type (WT) mice. Nrf2 has also been shown to be a critical regulator of the innate immune response and survival during experimental sepsis.…”

Pharmacodynamic characterization of chemopreventive triterpenoids as exceptionally potent inducers of Nrf2-regulated genes

“…Triterpenoid treatment resulting in induction of cytoprotective enzymes in the heart could also provide protection against several cardiac disorders (47). In addition, induction of Nrf2 signaling in the lung can provide protection against hyperoxic lung injury (48), emphysema (49), and asthma (50).…”