We recently used positional cloning to identify the transcription factor Nrf2 (NF-E2 related factor 2) as a susceptibility gene in a murine model of oxidant-induced acute lung injury (ALI). NRF2 binds to antioxidant response elements (ARE) and up-regulates protective detoxifying enzymes in response to oxidative stress. This led us to investigate NRF2 as a candidate susceptibility gene for risk of development of ALI in humans. We identified multiple single nucleotide polymorphisms (SNPs) by resequencing NRF2 in ethnically diverse subjects, and one (-617 C/A) significantly (P<0.001) diminished luciferase activity of promoter constructs containing the SNP and significantly decreased the binding affinity (P<0.001) relative to the wild type at this locus (-617 CC). In a nested case-control study, patients with the -617 A SNP had a significantly higher risk for developing ALI after major trauma (OR 6.44; 95% CI 1.34, 30.8; P=0.021) relative to patients with the wild type (-617 CC). This translational investigation provides novel insight into the molecular mechanisms of susceptibility to ALI and may help to identify patients who are predisposed to develop ALI under at risk conditions, such as trauma and sepsis. Furthermore, these findings may have important implications in other oxidative stress related illnesses.

Severe respiratory syncytial virus (RSV) infection is a major cause of morbidity and mortality in infants <2 years-old. Here we describe that high-fiber diet protects mice from RSV infection. This effect was dependent on intestinal microbiota and production of acetate. Oral administration of acetate mediated interferon-β (IFN-β) response by increasing expression of interferon-stimulated genes in the lung. These effects were associated with reduction of viral load and pulmonary inflammation in RSV-infected mice. Type 1 IFN signaling via the IFN-1 receptor (IFNAR) was essential for acetate antiviral activity in pulmonary epithelial cell lines and for the acetate protective effect in RSV-infected mice. Activation of Gpr43 in pulmonary epithelial cells reduced virus-induced cytotoxicity and promoted antiviral effects through IFN-β response. The effect of acetate on RSV infection was abolished in Gpr43 − / − mice. Our findings reveal antiviral effects of acetate involving IFN-β in lung epithelial cells and engagement of GPR43 and IFNAR.

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Acute exposure to ozone has been related to a wide spectrum of health effects in susceptible individuals. Genetic factors may influence interindividual variation in ozone response. The current authors investigated the relationships between common polymorphisms in two genes involved in response to oxidative stress, i.e. glutathione S-transferases M1 (GSTM1) and P1 (GSTP1), and both respiratory symptoms and lung function in response to ozone among childhood asthmatics.A total of 151 asthmatic children, who were participants in a randomised controlled trial of antioxidant vitamin supplementation in Mexico City, were studied. Children were genotyped using PCR methods and followed from October 1998-April 2000.Increases in reported breathing difficulty were associated with ozone exposure in children with GSTM1 null (8%, 95% confidence interval (CI) 1-15%, per 20-ppb increase in 1-h maximum daily average over 7 days) or GSTP1 Valine/Valine (Val/Val) genotypes (14%, 95% CI 5-25%). In children with both GSTM1 null and GSTP1 Val/Val genotypes, the increase in breathing difficulty associated with a 20-ppb increase in ozone exposure was even greater (21%, 95% CI 5-39%). GSTP1 genotypes were not significantly associated with ozone-related lung function changes.In conclusion, asthmatic children with glutathione S-transferase M1 null and glutathione S-transferase P1 Valine/Valine genotypes appear more susceptible to developing respiratory symptoms related to ozone exposure.

Nuclear factor (erythroid derived)-2 like 2 (NFE2L2), also known as nuclear factor erythroid 2 (NF-E2)-related factor 2 (Nrf2), is a ubiquitous transcription factor essential for protecting cells and tissues from oxidative stress-induced injury. Positional cloning and studies with Nrf2 knockout mice have identified important roles for this transcription factor in disease phenotypes for many organ systems. Studies have also characterized the means through which human Nrf2 is regulated and the mechanisms of interaction with antioxidant response elements (ARE) in promoters of effector genes. Moreover, single nucleotide polymorphisms (SNPs) in Nrf2 have been identified and evaluated for effects on gene expression and function, and translational investigations have sought to determine whether loss of function SNPs associate with disease progression. In this review, we present 1) an overview of the human Nrf2 gene and protein domain, 2) identification of genetic mutations in Nrf2 and associations of the mutations with multiple diseases, and 3) the role of somatic mutations in Nrf2 in diseases, primarily various cancers.

Objective Oxidative stress is integral to the development of endothelial dysfunction and cardiovascular disease. As NRF2 is a key transcription factor in antioxidant defense, we aimed to determine whether polymorphisms within the promoter region of the gene encoding NRF2 (NFE2L2) would significantly modify vasodilator responses in humans. Methods Associations between the – 653A/G (rs35652124), – 651G/A (rs6706649), and – 617C/A (rs6721961) polymorphisms within the NFE2L2 promoter and vascular function were evaluated in healthy African-American (n= 64) and white (n= 184) individuals. Forearm blood flow (FBF) was measured by strain-gauge venous occlusion plethysmography at baseline and in response to incremental doses of bradykinin or sodium nitroprusside. Forearm vascular resistance (FVR) was calculated as the mean arterial pressure/FBF. Results In African Americans, – 653G variant allele carriers had significantly lower FBF and higher FVR under basal conditions as well as in response to bradykinin or sodium nitroprusside compared with wild-type individuals (P< 0.05 for each comparison). In whites, although no significant associations were observed with the – 653A/G genotype, – 617A variant allele carriers had significantly higher FVR at baseline and in response to bradykinin or sodium nitroprusside compared with wild-type individuals (P < 0.05 for each comparison). The – 651G/A polymorphism was not associated with vasodilator responses in either racial group. Conclusion Polymorphisms within the NFE2L2 promoter were associated with impaired forearm vasodilator responses in an endothelial-independent manner, suggesting an important role of NRF2 in the regulation of vascular function in humans.

Aims: Nrf2 is a master transcription factor for antioxidant response element (ARE)-mediated cytoprotective gene induction. A protective role for pulmonary Nrf2 was determined in model oxidative disorders, including hyperoxia-induced acute lung injury (ALI). To obtain additional insights into the function and genetic regulation of Nrf2, we assessed functional single nucleotide polymorphisms (SNPs) of Nrf2 in inbred mouse strains and tested whether sequence variation is associated with hyperoxia susceptibility. Results: Nrf2 SNPs were compiled from publicly available databases and by re-sequencing DNA from inbred strains. Hierarchical clustering of Nrf2 SNPs categorized the strains into three major haplotypes. Hyperoxia susceptibility was greater in haplotypes 2 and 3 strains than in haplotype 1 strains. A promoter SNP -103 T/C adding an Sp1 binding site in haplotype 2 diminished promoter activation basally and under hyperoxia. Haplotype 3 mice bearing nonsynonymous coding SNPs located in (1862 A/T, His543Gln) and adjacent to (1417 T/C, Thr395Ile) the Neh1 domain showed suppressed nuclear transactivation of pulmonary Nrf2 relative to other strains, and overexpression of haplotype 3 Nrf2 showed lower ARE responsiveness than overexpression of haplotype 1 Nrf2 in airway cells. Importantly, we found a significant correlation of Nrf2 haplotypes and hyperoxic lung injury phenotypes. Innovation and Conclusion: The results indicate significant influence of Nrf2 polymorphisms and haplotypes on gene function and hyperoxia susceptibility. Our findings further support Nrf2 as a genetic determinant in ALI pathogenesis and provide useful tools for investigators who use mouse strains classified by Nrf2 haplotypes to elucidate the role for Nrf2 in oxidative disorders. Antioxid. Redox Signal. 22,[325][326][327][328][329][330][331][332][333][334][335][336][337][338]

Lightfoot JT, Turner MJ, Knab AK, Jedlicka AE, Oshimura T, Marzec J, Gladwell W, Leamy LJ, Kleeberger SR. Quantitative trait loci associated with maximal exercise endurance in mice. J Appl Physiol 103: 105-110, 2007. First published April 5, 2007 doi:10.1152/japplphysiol.01328.2006.-The role of genetics in the determination of maximal exercise endurance is unclear. Six-to nine-week-old F2 mice (n ϭ 99; 60 female, 39 male), derived from an intercross of two inbred strains that had previously been phenotyped as having high maximal exercise endurance (Balb/cJ) and low maximal exercise endurance (DBA/2J), were treadmill tested to estimate exercise endurance. Selective genotyping of the F2 cohort (n ϭ 12 high exercise endurance; n ϭ 12 low exercise endurance) identified a significant quantitative trait locus (QTL) on chromosome X (53.7 cM, DXMit121) in the entire cohort and a suggestive QTL on chromosome 8 (36.1 cM, D8Mit359) in the female mice. Fine mapping with the entire F2 cohort and additional informative markers confirmed and narrowed the QTLs. The chromosome 8 QTL (EE8 F ) is homologous with two suggestive human QTLs and one significant rat QTL previously linked with exercise endurance. No effect of sex (P ϭ 0.33) or body weight (P ϭ 0.79) on exercise endurance was found in the F 2 cohort. These data indicate that genetic factors in distinct chromosomal regions may affect maximal exercise endurance in the inbred mouse. Whereas multiple genes are located in the identified QTL that could functionally affect exercise endurance, this study serves as a foundation for further investigations delineating the identity of genetic factors influencing maximum exercise endurance. candidate genes; aerobic capacity; genotyping SEVERAL RECENT STUDIES have shown that the maximal exercise endurance of an individual can impact all-cause mortality rates (31), mortality rates from hypertension (7), smoking-related and non-smoking-related cancers (21), and stroke (22). A tremendous amount of research has considered the modifying role of environmental factors on maximal aerobic exercise (e.g., training). It is well accepted that the variation seen in human maximal exercise endurance is due to the influence of genetic factors (3), and current estimations of the contribution of genetics to maximal exercise endurance range from Ϸ51% in humans (3) to 58 -90% in mice (23, 26) to 39% in rats (18).