Sulforaphane enriched transcriptome of lung mitochondrial energy metabolism and provided pulmonary injury protection via Nrf2 in mice

Abstract

Nrf2 is essential to antioxidant response element (ARE)-mediated host defense. Sulforaphane (SFN) is a phytochemical antioxidant known to affect multiple cellular targets including Nrf2-ARE pathway in chemoprevention. However, the role of SFN in non-malignant airway disorders remain unclear. To test if pre-activation of Nrf2-ARE signaling protects lungs from oxidantinduced acute injury, wild-type (Nrf2 +/+) and Nrf2-deficient (Nrf2 −/−) mice were given SFN orally or as standardized broccoli sprout extract diet (SBE) before hyperoxia or air exposure. Hyperoxiainduced pulmonary injury and oxidation indices were significantly reduced by SFN or SBE in Nrf2 +/+ mice but not in Nrf2 −/− mice. SFN upregulated a large cluster of basal lung genes that are

Dietary Antioxidants Significantly Attenuate Hyperoxia-Induced Acute Inflammatory Lung Injury by Enhancing Macrophage Function via Reducing the Accumulation of Airway HMGB1

“…The treatment of animals subjected to prolonged hyperoxic exposure with either i.p. AA or SFN significantly attenuates hyperoxia-induced accumulation of leukocytes in the airways ( Figure 5) [22]. The decrease in the accumulation of leukocytes in the mouse airways, produced by the antioxidant-attenuated inflammatory responses in hyperoxic animals, could be due to 1) after binding to pneumocytes, neutrophils, and macrophages, the instilled airway HMGB1 could produce potent proinflammatory effects that induce the release of other proinflammatory cytokines, such as TNF-a, IL-1b, IL-8, MCP-1, and IL-6.…”

“…Hyperoxia impairs macrophage function in phagocytosis, thereby diminishing the host defense in clearing apoptotic neutrophils, resulting in pronounced accumulation of leukocytes in the airways [14,18,28,29]. To determine if SFN, which was recently shown to-attenuate HALI [22], can enhance macrophage functions, the phagocytic function of macrophages was determined using cultured macrophages. Prolonged exposure to hyperoxia significantly impaired the phagocytic function of RAW 264.7 cells (49.1 ± 4.1% in hyperoxia versus 99 ± 2.1% in room air, p < 0.05, Figure 2A).…”

“…Isothiocyanates, such as SFN, scavenge free radicals and produce anti-inflammatory efficacy by activating the Nrf2-mediated expression of antioxidant enzymes such as peroxidase 2, peroxiredoxin 1 and 6, glutathione reductase and glutamate cysteine ligase [45][46][47]. Furthermore, Cho et al [22] reported that Nrf2 is induced by SFN in a mouse model of HALI and SFN is efficacious in decreasing the inflammatory response and markers of ALI. In this study, our results indicate that hyperoxia-induced levels of intracellular ROS in cultured macrophages can be significantly decreased by SFN in a concentration-dependent manner (Figure 3).…”

“…Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor that regulates the antioxidant response element (ARE)-mediated transcriptional activation of several endogenous phase 2 detoxifying and antioxidant enzymes [21,22]. Nrf2 has been shown to provide protection against hyperoxia-induced lung injury [21,23].…”

“…Mice exposed to 95%-98% O 2 with a site-directed mutation in the Nrf2 gene had an exacerbation of pulmonary hyper-permeability, neutrophilic inflammation and epithelial injury compared to wild type mice [21]. Furthermore, wild type mice treated with the Nrf2 activator, sulforaphane (SFN), orally or in their diet preceding hyperoxia exposure, had reduced hyperoxia-induced pulmonary injury and oxidation indices compared to wild type mice [22]. However, it remains unknown as to whether the attenuation of HALI by supplemental SFN is due to attenuated hyperoxia-impaired macrophage phagocytosis produced by inhibiting hyperoxia-induced HMGB1 release into the extracellular milieu.…”