Potential of NRF2 Pathway in Preventing Developmental and Reproductive Toxicity of Fine Particles.

Air pollution is associated with significant adverse health effects. Recent studies support the idea that inhalation of fine particles can instigate extrapulmonary effects on the cardiovascular system through several pathways. The systemic transfer of ultrafine particles (UFPs) or soluble particle components (organic compounds and metals) is of particular concern. An integral role of reactive oxygen species (ROS)-dependent pathways has been suggested in systemic inflammatory responses and vascular dysfunction at the molecular level. Accumulating lines of evidence suggest that fine particles affect fetal development, giving rise to low birth weight and a reduction in fetal growth, and also affect the immune, cardiovascular, and central nervous systems. Oxidative stress plays an important role in fine particles toxicity; pre-treatment with antioxidants partially suppresses the developmental toxicity of fine particles. On the other hand, Nuclear factor erythroid-derived 2-like 2 (Nfe2l2), also known as NRF2, is a transcription factor essential for inducible and/or constitutive expression of phase II and antioxidant enzymes. Studies using Nrf2-knockout mice revealed that NRF2 dysfunction is intimately involved in the pathogenesis of various human diseases. Multiple single nucleotide polymorphisms (SNPs) have been detected in human NRF2 locus. An NRF2 gene SNP (-617C > A; rs6721961), located in the upstream promoter region, affects the transcriptional level of NRF2 and thereby the protein level and downstream gene expression. It has been reported that the SNP-617 is associated with various diseases. The onset and exacerbation of the diseases are regulated by genetic predisposition and environmental factors; some people live in the air-polluted environment but are not affected and remain healthy, suggesting the presence of individual differences in the susceptibility to air pollutants. NRF2 polymorphisms may also be associated with the fetal effects of fine particles exposure. Screening high-risk pregnant women genetically susceptible to oxidative stress and prevention by antioxidant interventions to protect fetal development in air-polluted areas should be considered. This article reviews the recent advances in our understanding of the fetal health effects of fine particles and describes potential chemoprevention via the NRF2 pathway to prevent the developmental and reproductive toxicity of fine particles.

Nrf2 Lowers the Risk of Lung Injury via Modulating the Airway Innate Immune Response Induced by Diesel Exhaust in Mice.

In the present study, we investigated the role of Nrf2 in airway immune responses induced by diesel exhaust (DE) inhalation in mice. C57BL/6J Nrf2+/+ and Nrf2-/- mice were exposed to DE or clean air for 8 h/day and 6 days/week for 4 weeks. After DE exposure, the number of neutrophils and macrophage inflammatory protein (MIP)-2 level in bronchoalveolar lavage fluid (BALF) and interleukin (IL)-17 level in the lung tissue increased in Nrf2-/- mice compared with Nrf2+/+ mice; however, the lack of an increase in the level of tumor necrosis factor (TNF)-α in the lung tissue in Nrf2+/+ mice and mild suppression of the level of TNF-α in Nrf2-/- mice were observed; the level of granulocyte macrophage colony-stimulating factor (GM-CSF) in the lung tissue decreased in Nrf2-/- mice than in Nrf2+/+ mice; the number of DE particle-laden alveolar macrophages in BALF were larger in Nrf2-/- mice than in Nrf2+/+ mice. The results of electron microscope observations showed alveolar type II cell injury and degeneration of the lamellar body after DE exposure in Nrf2-/- mice. Antioxidant enzyme NAD(P)H quinone dehydrogenase (NQO)1 mRNA expression level was higher in Nrf2+/+ mice than in Nrf2-/- mice after DE exposure. Our results suggested that Nrf2 reduces the risk of pulmonary disease via modulating the airway innate immune response caused by DE in mice.

Nrf2 Regulates the Risk of a Diesel Exhaust Inhalation-Induced Immune Response during Bleomycin Lung Injury and Fibrosis in Mice.

The present study investigated the effects of diesel exhaust (DE) on an experimental model of bleomycin (BLM)-induced lung injury and fibrosis in mice. BLM was intravenously administered to both Nrf2+/+ and Nrf2-/- C57BL/6J mice on day 0. The mice were exposed to DE for 56 days from 28 days before the BLM injection to 28 days after the BLM injection. Inhalation of DE induced significant inhibition of airway clearance function and the proinflammatory cytokine secretion in macrophages, an increase in neutrophils, and severe lung inflammatory injury, which were greater in Nrf2-/- mice than in Nrf2+/+ mice. In contrast, inhalation of DE was observed to induce a greater increase of hydroxyproline content in the lung tissues and significantly higher pulmonary antioxidant enzyme mRNA expression in the Nrf2+/+ mice than in Nrf2-/- mice. DE is an important risk factor, and Nrf2 regulates the risk of a DE inhalation induced immune response during BLM lung injury and fibrosis in mice.

Prostaglandin E2 switches from a stimulator to an inhibitor of cell migration after epithelial-to-mesenchymal transition.

Epithelial-mesenchymal transition (EMT) is critical for embryonic development, and this process is recapitulated in adults during wound healing, tissue regeneration, fibrosis and cancer progression. Cell migration is believed to play a key role in both normal wound repair and in abnormal tissue remodeling. Prostaglandin E2 (PGE2) inhibits fibroblast chemotaxis, but stimulates chemotaxis in airway epithelial cells. The current study was designed to explore the role of PGE2 and its four receptors on airway epithelial cell migration following EMT using both the Boyden blindwell chamber chemotaxis assay and the wound closure assay. EMT in human bronchial epithelial cells (HBECs) was induced by TGF-ß1 and a mixture of cytokines (IL-1ß, TNF-α, and IFN-γ). PGE2 and selective agonists for all four EP receptors stimulated chemotaxis and wound closure in HBECs. Following EMT, the EP1 and EP3 agonists were without effect, while the EP2 and EP4 agonists inhibited chemotaxis as did PGE2. The effects of the EP2 and EP4 receptors on HBEC and EMT cell migration were further confirmed by blocking the expected signaling pathways. Taken together, these results demonstrate that PGE2 switches from a stimulator to an inhibitor of cell migration following EMT of airway epithelial cells and that this inhibition is mediated by an altered effect of EP2 and EP4 signaling and an apparent loss of the stimulatory effects of EP1 and EP3. Change in the PGE2 modulation of chemotaxis may play a role in repair following injury.

Nrf2 is a protective factor against oxidative stresses induced by diesel exhaust particle in allergic asthma.

Epidemiological studies have shown that air pollutants, such as diesel exhaust particle (DEP), are implicated in the increased incidence of allergic airway disorders. In vitro studies of molecular mechanisms have focused on the role of reactive oxygen species generated directly and indirectly by the exposure to DEP. Antioxidants effectively reduce the allergic inflammatory effects induced by DEP both in vitro and in vivo. On the other hand, Nrf2 is a transcription factor essential for the inducible and/or constitutive expression of phase II and antioxidant enzymes. Disruption of Nrf2 enhances susceptibility to airway inflammatory responses and exacerbation of allergic inflammation induced by DEP in mice. Host responses to DEP are regulated by a balance between antioxidants and proinflammatory responses. Nrf2 may be an important protective factor against oxidative stresses induced by DEP in airway inflammation and allergic asthma and is expected to contribute to chemoprevention against DEP health effects in susceptible individuals.

EM, EM703 inhibit NF-kB activation induced by oxidative stress from diesel exhaust particle in human bronchial epithelial cells: importance in IL-8 transcription.

Diesel exhaust particle (DEP) is the major components of PM2.5, and much attention has focused on PM2.5 in relation to adverse health effects, and many pulmonary diseases. In the present study, we used a human bronchial epithelial cell (HBEC) line to investigate the anti-inflammatory effects of erythromycin (EM) and EM703 - a new derivative of erythromycin without antibacterial effects on the expressions of IL-8 caused by DEP exposure. DEP showed a dose-dependent stimulatory effect on IL-8 product in HBEC. Increases of IL-8 expression by DEP stimulation were significantly blocked by both EM and EM703 pretreatment. Furthermore, NF-κB and Nrf2 activation, the antioxidant enzymes such as HO-1, NQO-1 mRNA expression were increased by DEP exposure and these increases were blocked by both of EM and EM703 pretreatment. Our results suggest that, EM and EM703 may have an inhibitory effect on expression inflammatory cytokines in HBEC induced by DEP not only as an anti-inflammation but also an antioxidant drug. EM and EM703 might contribute to chemical prevention of the risk of pulmonary diseases induced by oxidative stress from environmental pollutant, such as DEP.

Depressive state and subsequent weight gain in workers: A 4-year follow-up study.

OBJECTIVE: It has been suggested that the presence of a depressive state is a predictor of increase of the body weight. However, to precisely understand the nature of this relationship, the data should be controlled for other factors that can also be associated with weight gain. METHODS AND PARTICIPANTS: To test the hypothesis that the presence of a depressive state is associated with future weight gain, a 4-year prospective occupation-based cohort study was conducted in male adult workers (N=1730) at a railway company. Following the initial screening, follow-up information was obtained via a legally required annual health examination. The presence of a depressive state was identified using the Zung Self-Rating Depression Scale (SDS). The weight of each participant was measured to the nearest kilogram. Multiple logistic regression analysis was used to test the association between the depressive state and a weight gain of 4 kg or more over the 4-year study period after controlling for potentially confounding variables such as the age, smoking status, alcohol intake status, and physical activity. RESULTS: A weight gain of 4 kg or more over the 4-year study period was significantly associated with the depressive state, even after controlling for confounding variables (p< 0.05). Short-term longitudinal analysis also revealed an association between the depressive state and subsequent increase of the body weight. CONCLUSION: Since the depressive state was demonstrated to be an important risk factor for increase of the body weight, further research on depression should be conducted with a view to providing effective health education.

Prostaglandin E2 inhibits human lung fibroblast chemotaxis through disparate actions on different E-prostanoid receptors.

The migration of fibroblasts is believed to play a key role in both normal wound repair and abnormal tissue remodeling. Prostaglandin E (PGE)(2), a mediator that can inhibit many fibroblast functions including chemotaxis, was reported to be mediated by the E-prostanoid (EP) receptor EP2. PGE(2), however, can act on four receptors. This study was designed to determine if EP receptors, in addition to EP2, can modulate fibroblast chemotaxis. Using human fetal lung fibroblasts, the expression of all four EP receptors was demonstrated by Western blotting. EP2-selective and EP4-selective agonists inhibited both chemotaxis toward fibronectin in the blindwell assay and migration in a wound-closure assay. In contrast, EP1-selective and EP3-selective agonists stimulated cell migration in both assay systems. These results were confirmed using EP-selective antagonists. The role of both EP2 and EP4 receptors in mediating the PGE(2) inhibition of chemotaxis was also confirmed by small interfering RNA suppression. Furthermore, the role of EP receptors was confirmed by blocking the expected signaling pathways. Taken together, these results demonstrate that PGE(2) can act on multiple EP receptors in human lung fibroblasts, to exert disparate effects. Alterations in EP receptor expression may have the potential to alter PGE(2) action. Targeting specific EP receptors may offer therapeutic opportunities in conditions characterized by abnormal tissue repair and remodeling.

Relationship among lifestyles, aging and psychological wellbeing using the General Health Questionnaire 12-items in Japanese working men.

INTRODUCTION. The relationship among lifestyle, aging and psychological wellbeing was evaluated in Japanese working men. METHODS. Self-administered questionnaire on six lifestyle factors and the General Health Questionnaire 12-item version (GHQ12) were administered to 3306 male workers. Health practice index (HPI) was calculated as a desirable lifestyle score by summing up each binary lifestyle score (0, 1), ranging from 0 to 6. To check validity of the study outcome, the authors repeated twice with 1 year interval. HPI was categorised into three groups by the score of 0-2, 3-4 and 5-6. RESULTS. The number of subjects categorised by HPI was 532, 1967 and 807, respectively. The mean value of GHQ12 significantly decreased as the HPI increased by adjusting age. Multiple regression analysis was conducted to predict GHQ12 by six lifestyle scores, and age, sleep, night snacking and exercise were significantly related to GHQ12. Multiple logistic regression analysis was conducted and age in 50s, two-shift work, sleep, night snacking and exercise were significantly associated with GHQ12. CONCLUSION. Although cause-effect relationship cannot make clear, some of desirable health practices and aging were closely related to psychological wellbeing judged by GHQ12.

Serum insulin is significantly related to components of the metabolic syndrome in Japanese working women.

BACKGROUND: The aim of this study was to examine the association between serum insulin levels and components of the metabolic syndrome (MetS) in working women. METHODS: The target subjects were 141 working women. Serum triglyceride, HDL cholesterol, uric acid, plasma insulin and plasma glucose were measured in addition to waist circumference and blood pressure. RESULTS: MetS was diagnosed based on the modified criteria of the International Diabetes Federation, and was present in 7.1% (10/141) of the study subjects. Stepwise multiple regression analysis showed that some components of MetS were significantly associated with log-transformed values of the serum insulin. The standardized regression coefficient for the waist circumference, high density lipoprotein cholesterol, systolic blood pressure and age were 0.238, -0.333, 0.309 and -0.156, respectively. CONCLUSIONS: A statistically significant relationship existed between the components of MetS and the serum insulin levels in working women.

Optimal cut-off levels of body mass index and waist circumference in relation to each component of metabolic syndrome (MetS) and the number of MetS component.

AIMS: There is an ethnic difference of obesity index to diagnose metabolic syndrome. The authors explored the optimal cut-off levels for body mass index (BMI) and waist circumference (WC) in relation to each component of metabolic syndrome. MATERIALS AND METHODS: Receiver operating characteristics (ROC) analysis was used to determine the optimal cut-off levels for each component of metabolic syndrome. This study included 4572 workers aged 42.5±9.9 years. RESULTS: The optimal BMI cut-off values for diabetes mellitus, hypertension or dyslipidemia varied from 23.0 to 24.3 kg/m(2). As for WC, the optimal cut-off values varied from 83.0 to 83.7 cm. The optimal BMI cut-off values relating with one to three components of metabolic syndrome varied from 23.2 to 25.3 kg/m(2). As for WC, the optimal cut-off values varied from 83.0 to 85.0 cm. Pair-wise comparison of ROC curves showed that WC has an advantage in relation to metabolic syndrome and its components compared with BMI. By logistic regression analysis, odds ratios of obesity indices for hypertension, dyslipidemia or the number of metabolic component were all significantly increased. As for diabetes mellitus, odds ratios of BMI ≥25 and WC ≥85 significantly increased, respectively. CONCLUSIONS: Japanese criteria of obesity in metabolic syndrome in man may be appropriate for diabetes mellitus. Ethnic difference in criteria of obesity in Asian metabolic syndrome exists, and mutual comparisons in the prevalence of metabolic syndrome have a difficulty to conduct.

Role of oxidative stresses induced by diesel exhaust particles in airway inflammation, allergy and asthma: their potential as a target of chemoprevention.

Epidemiological studies have shown that particulate air pollutants, such as diesel exhaust particles (DEPs) are implicated in the increased incidence of allergic airway disorders. DEPs induce and exaggerate allergic airway inflammation in vitro and in vivo. Studies of molecular mechanisms have focused on the role of reactive oxygen species (ROS) generated directly and indirectly by exposure to DEPs. The ROS play an important role in proinflammatory reaction in airways. Nuclear erythroid 2 P45-related factor Nrf2 is a key transcription factor that regulates host antioxidant and contributes to regulate airway inflammation and exacerbation of allergic inflammation induced by DEPs. The authors demonstrated that DEPs-induced oxidants stress and resultant inflammatory changes were blocked by antioxidants such as N-acetyl cysteine (NAC). Therefore, chemoprevention against DEPs health effects in susceptible individuals may become a choice for future environmental protection policy.

Nrf2 is closely related to allergic airway inflammatory responses induced by low-dose diesel exhaust particles in mice.

We have recently reported that disruption of nuclear erythroid 2 P45-related factor 2 (Nrf2) enhances susceptibility to airway inflammatory responses induced by low-dose diesel exhaust particles (DEP) in mice. C57BL/6 Nrf2 knockout (Nrf2(-/-)) mice and wild-type (Nrf2(+/+)) mice were further exposed to low-dose DEP for 7h/day, 5 days/week, for a maximum of 8 weeks. After exposure to DEP for 5 weeks, allergic airway inflammation was generated in the mice by intraperitoneal sensitization with OVA followed by intranasal challenge. Nrf2(-/-) mice exposed to relatively low-dose DEP showed significantly increased percentage changes relative to the OVA alone group in terms of airway hyperresponsiveness (AHR) and inflammatory cells, levels of IL-5 and thymus and activation regulated chemokine (TARC) in bronchoalveolar lavage (BAL) fluid than did Nrf2(+/+) mice. Lung tissues of Nrf2(-/-) mice after DEP exposure showed inflammatory cell infiltrates, and increased PAS staining-positive mucus cell hyperplasia. In contrast, the percentage changes relative to the OVA group in the reduced glutathione (GSH)/oxidized glutathione (GSSG) ratio in whole blood was higher in Nrf2(+/+) mice than in Nrf2(-/-) mice. By using Nrf2(-/-) mice, it was shown for the first time that relatively low-dose DEP exposure induces oxidant stress, and that host anti-oxidant responses play a key role in the development of DEP-induced exacerbation of allergic airway inflammation.

Increase in the prevalence of metabolic syndrome among workers according to age.

INTRODUCTION: Statistical information regarding the prevalence of metabolic syndrome among a wide age range of workers is insufficient. METHODS: A total of 4278 men between the ages of 20 and 59 years participated in the study. Metabolic syndrome was diagnosed according to the International Diabetes Federation (IDF) and the National Cholesterol Education Program (NCEP) III criteria. RESULTS: Overall, the prevalences of metabolic syndrome according to the IDF and NCEPIII criteria were 13.6% and 14.8%, respectively. The prevalence of metabolic syndrome according to the IDF (NCEPIII) criteria among workers in their 20s, 30s, 40s, and 50s were 4.8% (6.1%), 9.9% (12.2%), 18.4% (21.6%) and 25.8% (34.0%), respectively. A plot of the prevalence of metabolic syndrome according to the NCEPIII criteria versus age had a steep gradient and increased sharply for men in their 50s. In contrast, a plot of the prevalence of metabolic syndrome according to the IDF criteria versus age increased in a linear manner. CONCLUSION: The prevalence of metabolic syndrome increased among workers according to age, but the increasing trend and the absolute prevalence of metabolic syndrome differed according to the two sets of diagnostic criteria used in this study.

A cross-sectional study on the shift work and metabolic syndrome in Japanese male workers.

INTRODUCTION: Shift work has been reported to be associated with an increase in the metabolic syndrome (MetS). To clarify the association between the type of shift work and the risk of MetS, a cross-sectional field survey was conducted after adjusting for age and lifestyle factors. METHODS: The subjects were 3007 Japanese males, aged 34-64 years old, who were employees (1700 day and 1307 shift workers) of a car-manufacturing company. The standard Japanese criteria for the diagnosis of MetS was used. Age, smoking habit, drinking habit, sleeping habit and exercise habit were used as the independent variables. RESULTS: The prevalence of MetS in the day workers, two-shift workers, and three-shift workers were 13.8% (234/1700), 10.7% (120/1125) and 17.6% (32/182), respectively. There was a significant difference in the prevalence between the two-shift workers and the day workers. Estimation of the odds ratios (95% confidence intervals) of age, two-shift work and habitual exercise for MetS were 1.03 (1.01-1.04), 0.77 (0.61-0.98) and 0.64 (0.51-0.81), respectively. CONCLUSION: Two-shift work was associated with lower risk of MetS, which is not in accordance with past reports. This finding should therefore be re-analysed, including investigation of the job content in each group.

Insulin resistance, as expressed by HOMA-R, is strongly determined by waist circumference or body mass index among Japanese working men.

OBJECTIVE: This study was intended to identify significant determinant factors of insulin resistance. METHODS: Insulin resistance was assessed using the homeostasis model assessment for insulin resistance (HOMA-R) and was calculated as "Fasting plasma glucose × Fasting serum insulin)/405". The target subjects were 3008 working men. The serum lipid profiles, uric acid level, insulin level, plasma glucose level, hemoglobin A1C level, and blood pressure, in addition to the waist circumference or body mass index, were also measured. A stepwise multiple regression analysis was performed using log-transformed values of HOMA-R as the dependent variable. RESULTS: The standardized regression coefficient for waist circumference was about six times larger than that for hemoglobin A1c (0.45 and 0.08, respectively). The standardized regression coefficients for the other factors were 0.15 for diastolic blood pressure, 0.10 for the low-density lipoprotein cholesterol level, -0.06 for age, -0.04 for habitual exercise, 0.14 for no habitual drinking, and 0.07 for no smoking. When body mass index was substituted for waist circumference, almost the same results were obtained. The adverse effects of no smoking and no habitual drinking on the HOMA-R score might be explained, at least in part, by the relation of these factors with obesity. Regular exercise had a protective effect on lowering insulin resistance. CONCLUSIONS: A close relation exists between obesity-related indices (waist circumference and body mass index) and insulin resistance, independent of age and other vascular risk factors in Japanese working men.

Association of smoking status, insulin resistance, body mass index, and metabolic syndrome in workers: A 1-year follow-up study.

OBJECTIVE: We performed a 1-year follow-up study to determine the effects of smoking status and insulin resistance on the prevalence of metabolic syndrome. METHODS: This study included 2136 workers without metabolic syndrome at baseline who were followed for 1 year. The subjects were divided into four categories of smoking and work history, respectively. Insulin resistance was evaluated using the homeostasis model assessment for insulin resistance (HOMA-R). RESULTS: The prevalence of metabolic syndrome after 1 year was 6.3%. A multiple logistic regression analysis showed that the current smokers category versus the non-smokers category, a 0.1-point increase in the HOMA-R score, a 1-point increase in the uric acid level, age, and body mass index were significantly correlated with increased odds for metabolic syndrome, yielding odds ratios (95% confidence intervals) of 1.61 (1.09-2.39), 1.14 (1.04-1.25), 1.31 (1.12-1.54), and 1.06 (1.03-1.09), and 1.23 (1.15-1.31), respectively. CONCLUSIONS: Current smoking, insulin resistance, uric acid level, and age contributed positively to the prevalence of metabolic syndrome. In contrast, smoking cessation within 1 year and work history did not contribute to metabolic syndrome.

Patterns in self-rated health according to age and sex in a Japanese national survey, 1989-2004.

BACKGROUND: Perceived good health or good self-rated health is considered to be a predictor of longer survival and maintenance of good quality of life, which is a public health goal. OBJECTIVE: This study assessed trends in the percentage of self-rated poor health among Japanese residents, based on data from the National Comprehensive Survey of the Living Conditions of People on Health and Welfare. METHODS: Results of the survey (which is conducted in Japan every 3 years to determine the living conditions of people receiving health and welfare services) were analyzed using multistage and stratified cluster sampling of households. Self-rated health was measured by response to the question, "Recently, would you say that in general your health has been good, fairly good, fair, fairly poor, or poor?" The trend in fairly poor or poor health status during the period from 1989 through 2004 was stratified by sex and age group. RESULTS: The rates of response to the survey were 90.9% (246,892/271,588) in 1995 and 79.8% (220,836/276,682) in 2004. Target subjects were aged >or=20 years in each year of the study. The prevalence of self-reported fairly poor or poor health was lowest in 1995 and then increased every year until 2001, when it appeared to reach a plateau. The prevalence of having fairly poor or poor health among women aged 35 to 44, 45 to 54, 55 to 64, and 65 to 74 years were as follows in 1995: 9.2%, 11.7%, 15.3%, and 19.8%, respectively. In 2004, the rates were 13.3%, 17.2%, 22.1%, and 31.7%, respectively. By comparison, the prevalence of self-reported fairly poor or poor health was 8.1%, 9.3%, 13.7%, and 17.9% among men aged 35 to 44, 45 to 54, 55 to 64, and 65 to 74 years, respectively, in 1995. In 2004, these rates were 12.8%, 14.8%, 19.0%, and 27.9%, respectively. CONCLUSIONS: In this survey, conducted every 3 years between 1989 and 2004 in Japanese households, older subjects had a greater prevalence of self-reported fairly poor or poor health than did younger subjects. The proportion of respondents who described their health as poor or fairly poor was highest in 1995. Women generally had a greater prevalence of self-reported poor or fairly poor health.

The effects of oxidative stress induced by prolonged low-dose diesel exhaust particle exposure on the generation of allergic airway inflammation differ between BALB/c and C57BL/6 mice.

We have recently reported that airway inflammatory responses to the oxidative stress induced by prolonged low-dose diesel exhaust particle (DEP) exposure differ markedly between BALB/c and C57BL/6 mice. In the present study, the effects of genetic differences in the response to prolonged low-dose DEP exposure on the generation of ovalbumin-induced allergic airway inflammation were further explored using the same mouse strains. In BALB/c mice, eosinophils and mucous goblet cells in histopathological pulmonary specimens increased significantly after DEP exposure, and were more marked than in C57BL/6 mice. Interleukin (IL)-5 and IL-13 levels in bronchoalveolar lavage (BAL) fluid were increased significantly by DEP exposure only in BALB/c mice. The DEP-induced increases in peribronchial eosinophils and mucous goblet cells in the lung tissues, and of IL-5 and IL-13 in the BAL fluid, were significantly attenuated by the antioxidant N-acetylcysteine. Thus, the effects of prolonged low-dose DEP exposure on the generation of allergic airway inflammation differed markedly between the mouse strains. These differences may be caused by different antioxidant responses to the oxidative stress induced by DEP exposure. Our results contribute more information to the search for genetic susceptibility factors in the response to DEP, and may thus assist in the discovery of new biomarkers for DEP-related disease.

Disruption of Nrf2 enhances susceptibility to airway inflammatory responses induced by low-dose diesel exhaust particles in mice.

To test our hypothesis that diesel exhaust particle (DEP)-induced oxidative stress and host antioxidant responses play a key role in the development of DEP-induced airway inflammatory diseases, C57BL/6 nuclear erythroid 2 P45-related factor 2 (Nrf2) knockout (Nrf2(-/-)) and wild-type mice were exposed to low-dose DEP for 7 h/day, 5 days/week, for 8 weeks. Nrf2(-/-) mice exposed to low-dose DEP showed significantly increased airway hyperresponsiveness and counts of lymphocytes and eosinophils, together with increased concentrations of IL-12 and IL-13, and thymus and activation-regulated chemokine (TARC), in BAL fluid than wild-type mice. In contrast, expression of antioxidant enzyme genes was significantly higher in wild-type mice than in Nrf2(-/-) mice. We have first demonstrated that disruption of Nrf2 enhances susceptibility to airway inflammatory responses induced by inhalation of low-dose DEP in mice. These results strongly suggest that DEP-induced oxidative stress and host antioxidant responses play some role in the development of DEP-induced airway inflammation.