The effect of real-ambient PM2.5 exposure on the lung and gut microbiomes and the regulation of Nrf2.

The influence of air pollution on human health has sparked widespread concerns across the world. Previously, we found that exposure to ambient fine particulate matter (PM2.5) in our "real-ambient exposure" system can result in reduced lung function. However, the mechanism of organ-specific toxicity is still not fully elucidated. The balance of the microbiome contributes to maintaining lung and gut health, but the changes in the microbiome under PM2.5 exposure are not fully understood. Recently, crosstalk between nuclear factor E2-related factor 2 (Nrf2) and the microbiome was reported. However, it is unclear whether Nrf2 affects the lung and gut microbiomes under PM2.5 exposure. In this study, wild-type (WT) and Nrf2-/- (KO) mice were exposed to filtered air (FA) and real ambient PM2.5 (PM) in the " real-ambient exposure" system to examine changes in the lung and gut microbiomes. Here, our data suggested microbiome dysbiosis in lung and gut of KO mice under PM2.5 exposure, and Nrf2 ameliorated the microbiome disorder. Our study demonstrated the detrimental impacts of PM2.5 on the lung and gut microbiome by inhaled exposure to air pollution and supported the protective role of Nrf2 in maintaining microbiome homeostasis under PM2.5 exposure.

Wood smoke exposure affects lung aging, quality of life, and all-cause mortality in New Mexican smokers.

BACKGROUND: The role of wood smoke (WS) exposure in the etiology of chronic obstructive pulmonary disease (COPD), lung cancer (LC), and mortality remains elusive in adults from countries with low ambient levels of combustion-emitted particulate matter. This study aims to delineate the impact of WS exposure on lung health and mortality in adults age 40 and older who ever smoked. METHODS: We assessed health impact of self-reported "ever WS exposure for over a year" in the Lovelace Smokers Cohort using both objective measures (i.e., lung function decline, LC incidence, and deaths) and two health related quality-of-life questionnaires (i.e., lung disease-specific St. George's Respiratory Questionnaire [SGRQ] and the generic 36-item short-form health survey). RESULTS: Compared to subjects without WS exposure, subjects with WS exposure had a more rapid decline of FEV1 (- 4.3 ml/s, P = 0.025) and FEV1/FVC ratio (- 0.093%, P = 0.015), but not of FVC (- 2.4 ml, P = 0.30). Age modified the impacts of WS exposure on lung function decline. WS exposure impaired all health domains with the increase in SGRQ scores exceeding the minimal clinically important difference. WS exposure increased hazard for incidence of LC and death of all-cause, cardiopulmonary diseases, and cancers by > 50% and shortened the lifespan by 3.5 year. We found no evidence for differential misclassification or confounding from socioeconomic status for the health effects of WS exposure. CONCLUSIONS: We identified epidemiological evidence supporting WS exposure as an independent etiological factor for the development of COPD through accelerating lung function decline in an obstructive pattern. Time-to-event analyses of LC incidence and cancer-specific mortality provide human evidence supporting the carcinogenicity of WS exposure.

Exposure to outdoor and indoor air pollution and risk of overweight and obesity across different life periods: A review.

Due to the highly evolved industrialization and modernization, air quality has deteriorated in most countries. As reported by the World Health Organization (WHO), air pollution is now considered as one of the major threats to global health and a principal risk factor for noncommunicable diseases. Meanwhile, the increasing worldwide prevalence of overweight and obesity is attracting more public attentions. Recently, accumulating epidemiological studies have provided evidence that overweight and obesity may be partially attributable to environmental exposure to air pollution. This review summarizes the epidemiological evidence for the correlation between exposure to various outdoor and indoor air pollutants (mainly particulate matter (PM), nitrogen oxides (NOx), ozone (O3), and polycyclic aromatic hydrocarbons (PAHs)) and overweight and obesity outcomes in recent years. Moreover, it discusses the multiple effects of air pollution during exposure periods throughout life and sex differences in populations. This review also describes the potential mechanism underlying the increased risk of obesity caused by air pollution, including inflammation, oxidative stress, metabolic imbalance, intestinal flora disorders and epigenetic modifications. Finally, this review proposes macro- and micro-measures to prevent the negative effects of air pollution exposure on the obesity prevalence.

GLIS3 mediated by the Rap1/PI3K/AKT signal pathway facilitates real-ambient PM2.5 exposure disturbed thyroid hormone homeostasis regulation.

Exposure to fine particulate matter (PM2.5) could damage multiple organs and systems. Recent epidemiological studies have shown that PM2.5 can disrupt dynamic balance of thyroid hormone (TH). However, the underlying mechanism by which PM2.5 interferes with TH remains unclear. This study evaluated the role of Gli-similar3 (GLIS3) in the effect of PM2.5 on TH synthesis in mice using a real-ambient exposure system, in Shijiazhuang City, Hebei Province. The PM2.5exposure group (PM) and filtered air group (FA) were placed in the exposure device for four and eight weeks. The results showed that the PM2.5 exposure altered the structure of the thyroid gland. Moreover, after PM2.5 exposure for eight weeks, the exposure level of free thyroxine (FT4) increased and the expression level of thyroid stimulating hormone (TSH) decreased in serum of mice. In addition, PM2.5 exposure significantly increased the expression of proteins related to thyroid hormone synthesis, such as sodium iodide transporter (NIS), thyroid peroxidase (TPO) and thyroglobulin (TG). Next, we found that GLIS3 and thyroid transcription factor Paired box 8 (PAX8) also increased after PM2.5 exposure. In order to further explore the potential molecular mechanism, we carried out transcriptome sequencing. KEGG analysis of the top 10 pathways revealed that the Ras-associated protein 1 (Rap1) signaling pathway could activate transcription factors and is related to thyroid cell survival. Additionally, PM2.5 exposure significantly increased the protein levels of Rap1 and its active form (Rap1 +GTP). We speculate that the active state of Rap1 is believed to be involved in activating the expression of transcription factor GLIS3. In conclusion, PM2.5 exposure induces histological changes in the thyroid gland and thyroid dysfunction in mice. The exposure activates GLIS3 through the Rap1/PI3K/AKT pathway to promote the expression of proteins related to thyroid hormone synthesis, leading to increased dysregulating TH homeostasis.

Chronic exposure to diesel exhaust may cause small airway wall thickening without lumen narrowing: a quantitative computerized tomography study in Chinese diesel engine testers.

BACKGROUND: Diesel exhaust (DE) is a major source of ultrafine particulate matters (PM) in ambient air and contaminates many occupational settings. Airway remodeling assessed using computerized tomography (CT) correlates well with spirometry in patients with obstructive lung diseases. Structural changes of small airways caused by chronic DE exposure is unknown. Wall and lumen areas of 6th and 9th generations of four candidate airways were quantified using end-inhalation CT scans in 78 diesel engine testers (DET) and 76 non-DETs. Carbon content in airway macrophage (CCAM) in sputum was quantified to assess the dose-response relationship. RESULTS: Environmental monitoring and CCAM showed a much higher PM exposure in DETs, which was associated with higher wall area and wall area percent for 6th generation of airways. However, no reduction in lumen area was identified. No study subjects met spirometry diagnosis of airway obstruction. This suggested that small airway wall thickening without lumen narrowing may be an early feature of airway remodeling in DETs. The effect of DE exposure status on wall area percent did not differ by lobes or smoking status. Although the trend test was of borderline significance between categorized CCAM and wall area percent, subjects in the highest CCAM category has a 14% increase in wall area percent for the 6th generation of airways compared to subjects in the lowest category. The impact of DE exposure on FEV1 can be partially explained by the wall area percent with mediation effect size equal to 20%, Pperm = 0.028). CONCLUSIONS: Small airway wall thickening without lumen narrowing may be an early image feature detected by CT and underlie the pathology of lung injury in DETs. The pattern of changes in small airway dimensions, i.e., thicker airway wall without lumen narrowing caused by occupational DE exposure was different to that (i.e., thicker airway wall with lumen narrowing) seen in our previous study of workers exposed to nano-scale carbon black aerosol, suggesting constituents other than carbon cores may contribute to such differences. Our study provides some imaging indications of the understanding of the pulmonary toxicity of combustion derived airborne particulate matters in humans.

Genome-wide identification and expression analysis of the 2OG-Fe(II) oxygenase gene family in upland cotton (Gossypium hirsutum L.).

The 2OG-Fe(II) oxygenase (RF) family of enzyme proteins can affect bulliform cells and cause leaf curling. However, there are few studies related to this family in cotton, and there has been no systematic analysis of RF genes. Here, we determined 25 RF genes in the complete genome sequence of upland cotton (Gossypium hirsutum L.) and 11 RF genes in the complete genome sequence of Arabidopsis thaliana. Cotton RF proteins can be divided into three categories. Whole genome/fragment and scattered replication events played an important role in the expansion of the RF gene family. qRT-PCR analysis results showed that RF genes respond to drought stress Pairwise comparison results showed that the expression of RF genes in Shi yuan 321 was higher than that in Kui 85-174. Overall, genome-wide identification approach was used to further analyze the related functions of the RF gene family, which may include the response to drought stress, in cotton. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s12298-021-01065-4.

CD11b regulates obesity-induced insulin resistance via limiting alternative activation and proliferation of adipose tissue macrophages.

Obesity-associated inflammation is accompanied by the accumulation of adipose tissue macrophages (ATMs), which is believed to predispose obese individuals to insulin resistance. CD11b (integrin αM) is highly expressed on monocytes and macrophages and is critical for their migration and function. We found here that high-fat diet-induced insulin resistance was significantly reduced in CD11b-deficient mice. Interestingly, the recruitment of monocytes to adipose tissue is impaired when CD11b is deficient, although the cellularity of ATMs in CD11b-deficient mice is higher than that in wild-type mice. We further found that the increase in ATMs is caused mainly by their vigorous proliferation in the absence of CD11b. Moreover, the proliferation and alternative activation of ATMs are regulated by the IL-4/STAT6 axis, which is inhibited by CD11b through the activity of phosphatase SHP-1. Thus, CD11b plays a critical role in obesity-induced insulin resistance by limiting the proliferation and alternative activation of ATMs.

Plasma Folate and Vitamin B12 Levels in Patients with Hepatocellular Carcinoma.

Folate and vitamin B12 involved in the one-carbon metabolism may play a key role in carcinogenesis and progression of hepatocellular carcinoma (HCC) through influencing DNA integrity. The purpose of this study is to evaluate the association of plasma folate and vitamin B12 levels with HCC in a case-control study on 312 HCC patients and 325 cancer-free controls. Plasma concentrations of folate and vitamin B12 in all the subjects were measured by electrochemiluminescence immunoassay. Meanwhile, the information of HCC patients' clinical characteristics including tumor-node-metastasis (TNM) stage, tumor size and tumor markers were collected. The patients of HCC had significantly lower folate levels than those of controls; there was no significant difference in the mean of plasma vitamin B12 levels. We also observed an inverse association between the levels of plasma folate and HCC: the adjusted odds ratios (OR) (95% confidence intervals (CI)) of HCC from the highest to lowest quartile of folate were 0.30 (0.15-0.60), 0.33 (0.17-0.65), and 0.19 (0.09-0.38). Compared to the subjects in the lowest quartile of plasma vitamin B12, only the subjects in the highest quartile of vitamin B12 exhibited a significant positive relationship with HCC, the adjusted OR was 2.01 (95% CI, 1.02-3.98). HCC patients with Stage III and IV or bigger tumor size had lower folate and higher vitamin B12 levels. There was no significant difference in the mean plasma folate levels of the HCC cases in tumor markers status (AFP, CEA and CA19-9 levels), whereas patients with higher CEA or CA19-9 levels retained significantly more plasma vitamin B12 than those with normal-CEA or CA19-9 level. In conclusion, plasma folate and vitamin B12 levels could be associated with HCC, and might be used as predictors of clinical characteristics of HCC patients. However, further prospective studies are essential to confirm the observed results.

miR-155 regulates immune modulatory properties of mesenchymal stem cells by targeting TAK1-binding protein 2.

MSCs possess potent immunosuppressive capacity. We have reported that mouse MSCs inhibit T cell proliferation and function via nitric oxide. This immune regulatory capacity of MSCs is induced by the inflammatory cytokines IFNγ together with either TNFα or IL-1ß. This effect of inflammatory cytokines on MSCs is extraordinary; logarithmic increases in the expression of iNOS and chemokines are often observed. To investigate the molecular mechanisms underlying this robust effect of cytokines, we examined the expression of microRNAs in MSCs before and after cytokine treatment. We found that miR-155 is most significantly up-regulated. Furthermore, our results showed that miR-155 inhibits the immunosuppressive capacity of MSCs by reducing iNOS expression. We further demonstrated that miR-155 targets TAK1-binding protein 2 (TAB2) to regulate iNOS expression. Additionally, knockdown of TAB2 reduced iNOS expression. In summary, our study demonstrated that miR-155 inhibits the immunosuppressive capacity of MSCs by reducing iNOS expression by targeting TAB2. Our data revealed a novel role of miR-155 in regulating the immune modulatory activities of MSCs.

Yield-based drought tolerance index evaluates the drought tolerance of cotton germplasm lines in the interaction of genotype-by-environment.

Background: Cotton is an economically important crop in China, and drought has seriously affected cotton production. Understanding genetic variation, genotype ×environment interactions, and the associations between these traits is critical for developing improved cotton varieties with high drought tolerance. Methods: To screen ideal drought-resistant cotton germplasm lines and excellent genotypes, the yield traits of 103 cotton germplasm lines were analyzed. Cotton resource material was planted under normal watering and water deficit conditions for three consecutive years. The yield traits under normal irrigation and water stress conditions were measured, and then five screening indicators were calculated based on the cotton yield per plant under the two water treatments to determine the ideal genotype and most accurate identification indicators. Results: The results of correlation analysis and principal component analysis showed that the geometric mean productivity (GMP), mean productivity (MP), and stress tolerance index (STI) were significantly positively correlated with yield under water stress and could be used to distinguish genotypes with high drought tolerance. Among the experimental germplasm lines, some had higher STI and GMP values, indicating their higher drought tolerance. This result indicates that best linear unbiased prediction (BLUP) analysis of the STI and GMP under drought stress can effectively improve screening for drought tolerance in cotton germplasm lines. The results from the screening index, three-dimensional map, and genotype ×environment (GGE) biplots were consistent with the above results. We determined that CQJ-5, Xin lu zao 45, Bellsno, Zhong R 2016 and ND 359-5 are drought-tolerant genotypes that can be used to breed drought-tolerant germplasm lines that produce high and stable yields.

Nrf2-/- regulated lung DNA demethylation and CYP2E1 DNA methylation under PM2.5 exposure.

Cytochrome P450 (CYP450) can mediate fine particulate matter (PM2.5) exposure leading to lung injury. Nuclear factor E2-related factor 2 (Nrf2) can regulate CYP450 expression; however, the mechanism by which Nrf2-/- (KO) regulates CYP450 expression via methylation of its promoter after PM2.5 exposure remains unclear. Here, Nrf2-/- (KO) mice and wild-type (WT) were placed in a PM2.5 exposure chamber (PM) or a filtered air chamber (FA) for 12 weeks using the real-ambient exposure system. The CYP2E1 expression trends were opposite between the WT and KO mice following PM2.5 exposure. After exposure to PM2.5, CYP2E1 mRNA and protein levels were increased in WT mice but decreased in KO mice, and CYP1A1 expression was increased after exposure to PM2.5 in both WT and KO mice. CYP2S1 expression decreased after exposure to PM2.5 in both the WT and KO groups. We studied the effect of PM2.5 exposure on CYP450 promoter methylation and global methylation levels in WT and KO mice. In WT and KO mice in the PM2.5 exposure chamber, among the methylation sites examined in the CYP2E1 promoter, the CpG2 methylation level showed an opposite trend with CYP2E1 mRNA expression. The same relationship was evident between CpG3 unit methylation in the CYP1A1 promoter and CYP1A1 mRNA expression, and between CpG1 unit methylation in the CYP2S1 promoter and CYP2S1 mRNA expression. This data suggests that methylation of these CpG units regulates the expression of the corresponding gene. After exposure to PM2.5, the expression of the DNA methylation markers ten-eleven translocation 3 (TET3) and 5-hydroxymethylcytosine (5hmC) was decreased in the WT group but significantly increased in the KO group. In summary, the changes in CYP2E1, CYP1A1, and CYP2S1 expression in the PM2.5 exposure chamber of WT and Nrf2-/- mice might be related to the specific methylation patterns in their promoter CpG units. After exposure to PM2.5, Nrf2 might regulate CYP2E1 expression by affecting CpG2 unit methylation and induce DNA demethylation via TET3 expression. Our study revealed the underlying mechanism for Nrf2 to regulate epigenetics after lung exposure to PM2.5.

Multi-omics reveals hypertrophy of adipose tissue and lipid metabolism disorder via mitochondria in young mice under real-ambient exposure to air pollution.

Air pollution has become one of the most serious health risks as a result of industrialization, especially in developing countries. More attention has been drawn to the relationship between obesity/overweight and fine particulate matter (PM2.5). Especially for susceptible populations, the impact of air pollution on children and adolescents has attracted more public attentions. However, the detailed underlying mechanism influencing obesity or overweight under PM2.5 exposure is still unknown. Therefore, young mice were exposed to PM2.5 using the real-ambient exposure system that we previously established in Shijiazhuang city. Compared with the traditionally concentrated air particle (CAP) system, our real-ambient exposure system provides similar PM2.5 concentrations and characteristics as outdoor ambient air and minimizes the influence of external interfering factors. After 8 weeks of exposure to PM2.5, the weight of gonadal white adipose tissue (gWAT) and subcutaneous white adipose tissue (sWAT) was considerably increased, accompanied by a significantly enlarged size of adipocytes in sWAT. Importantly, multiomics analysis indicated altered metabolites involved in the lipid metabolism pathway, and transcriptomic analysis revealed notably changed signaling pathways related to fatty acid metabolism. Moreover, the mtDNA copy number, mitochondrial activity and fatty acid oxidation (FAO) were increased in the liver under PM2.5 exposure. Taken together, our research investigated the hypotrophy of adipose tissue in young mice, supported an imbalance in lipid metabolism based on multiomics analysis, and revealed disordered mitochondrial function under PM2.5 exposure. Our study provided new insight into the hazardous effects of air pollution, and extended our understanding on the underlying mechanism.

Application of artificial intelligence in quantifying lung deposition dose of black carbon in people with exposure to ambient combustion particles.

BACKGROUND: Understanding lung deposition dose of black carbon is critical to fully reconcile epidemiological evidence of combustion particles induced health effects and inform the development of air quality metrics concerning black carbon. Macrophage carbon load (MaCL) is a novel cytology method that quantifies lung deposition dose of black carbon, however it has limited feasibility in large-scale epidemiological study due to the labor-intensive manual counting. OBJECTIVE: To assess the association between MaCL and episodic elevation of combustion particles; to develop artificial intelligence based counting algorithm for MaCL assay. METHODS: Sputum slides were collected during episodic elevation of ambient PM2.5 (n = 49, daily PM2.5 > 10 µg/m3 for over 2 weeks due to wildfire smoke intrusion in summer and local wood burning in winter) and low PM2.5 period (n = 39, 30-day average PM2.5 < 4 µg/m3) from the Lovelace Smokers cohort. RESULTS: Over 98% individual carbon particles in macrophages had diameter <1 µm. MaCL levels scored manually were highly responsive to episodic elevation of ambient PM2.5 and also correlated with lung injury biomarker, plasma CC16. The association with CC16 became more robust when the assessment focused on macrophages with higher carbon load. A Machine-Learning algorithm for Engulfed cArbon Particles (MacLEAP) was developed based on the Mask Region-based Convolutional Neural Network. MacLEAP algorithm yielded excellent correlations with manual counting for number and area of the particles. The algorithm produced associations with ambient PM2.5 and plasma CC16 that were nearly identical in magnitude to those obtained through manual counting. IMPACT STATEMENT: Understanding lung black carbon deposition is crucial for comprehending health effects of combustion particles. We developed "Machine-Learning algorithm for Engulfed cArbon Particles (MacLEAP)", the first artificial intelligence algorithm for quantifying airway macrophage black carbon. Our study bolstered the algorithm with more training images and its first use in air pollution epidemiology. We revealed macrophage carbon load as a sensitive biomarker for heightened ambient combustion particles due to wildfires and residential wood burning.

Screening of Key Drought Tolerance Indices for Cotton at the Flowering and Boll Setting Stage Using the Dimension Reduction Method.

Drought is one of the main abiotic stresses that seriously influences cotton production. Many indicators can be used to evaluate cotton drought tolerance, but the key indicators remain to be determined. The objective of this study was to identify effective cotton drought tolerance indicators from 19 indices, including morphology, photosynthesis, physiology, and yield-related indices, and to evaluate the yield potential of 104 cotton varieties under both normal and drought-stress field conditions. Combined with principal component analysis (PCA) and a regression analysis method, the results showed that the top five PCs among the 19, with eigenvalues > 1, contributed 65.52, 63.59, and 65.90% of the total variability during 2016 to 2018, respectively, which included plant height (PH), effective fruit branch number (EFBN), single boll weight (SBW), transpiration rate (Tr) and chlorophyll (Chl). Therefore, the indicator dimension decreased from 19 to 5. A comparison of the 19 indicators with the 5 identified indicators through PCA and a combined regression analysis found that the results of the final cluster of drought tolerance on 104 cotton varieties were basically consistent. The results indicated that these five traits could be used in combination to screen cotton varieties or lines for drought tolerance in cotton breeding programs, and Zhong R2016 and Xin lu zao 45 exhibited high drought tolerance and can be selected as superior parents for good yield performance under drought stress.

Nrf2 modulated the restriction of lung function via impairment of intrinsic autophagy upon real-ambient PM2.5 exposure.

Compelling studies approve that fine particle matter (PM2.5) exposure was associated with high risk of respiratory disorders. However, the available data assessing the detailed influence of PM2.5 on lung was limited. To overcome the difficulty of inhalational PM2.5 exposure, the real-ambient PM2.5 exposure system was constructed. The mice were exposed to filtered air (FA) or real-ambient PM2.5 (PM2.5), and the adverse effect on lung was determined. Nuclear factor E2-related factor 2 (Nrf2) as a transcription factor, was reported to affect autophagy. Autophagy was proposed as a two-edge sword in respiratory disorders. Here, our data presented that PM2.5 exposure dramatically reduced the lung function of WT mice rather than Nrf2-/- mice. Consistently, thickened alveolar walls was observed in WT mice in PM2.5 exposure group, whereas the histological phenotype of Nrf2-/- mice exhibited no obvious alteration. Furthermore, PM2.5 exposure triggered low-grade production of inflammatory profile in WT and Nrf2-/- mice. Moreover, the protein levels of p62, Beclin1 and LC3B of WT mice rather than Nrf2-/- mice were also altered in PM2.5 exposure group. Taken together, the present study applied the real-ambient exposure system, revealed the adverse effect of air pollution on lung, and proposed the underlying mechanism.

Effects of Real-Ambient PM2.5 Exposure on Lung Damage Modulated by Nrf2-/.

Previous studies have shown that long-term exposure to fine particulate matter (PM2.5) increases the morbidity and mortality of pulmonary diseases such as asthma, chronic obstructive pulmonary disease and pulmonary emphysema. Oxidative stress and inflammation play key roles in pulmonary damage caused by PM2.5. Nuclear factor erythroid 2-related factor 2 (Nrf2) could regulate the expression of antioxidant and anti-inflammatory genes and is pivotal for protection against PM2.5-induced oxidative stress. In this study, a real-ambient exposure system was constructed with the outdoor ambient air in north China. Wild-type (WT) and Nrf2-/- (KO) mice were exposed to the real-ambient system for six weeks. After PM2.5 exposure, our data showed that the levels of inflammatory factors and malondialdehyde were significantly increased in WT and KO mice. Moreover, the lung function and pathological phenotype of the WT mice were altered but there was no obvious change in the Nrf2-/- mice. To further explore the potential molecular mechanisms, we performed RNA-sequencing. The RNA-sequence analysis results showed that the CYP450 pathway in the first ten pathways of KEGG was related to the metabolism of PM2.5. In WT and KO mice, the expression of CYP2E1 in the CYP450 pathway showed opposite trends after PM2.5 exposure. The data showed that the expression of the CYP2E1 gene in WT-PM mice increased while it decreased in KO-PM; the expression of the CYP2E1 protein showed a similar trend. CYP2E1 is primarily distributed in the endoplasmic reticulum (ER) where it could metabolize various exogenous substances attached to PM2.5 and produce highly toxic oxidation products closely related to ER stress. Consistently, the expression level of GRP94, a biomarker of ER stress, was increased in WT mice and reduced in KO mice under PM2.5 exposure. Persistent ER stress is a mechanism that causes lung damage under PM2.5 exposure. Nrf2 facilitates lung injury during PM2.5 exposure and CYP2E1 metabolism is involved in this process.

The Role of Nrf2 in the PM-Induced Vascular Injury Under Real Ambient Particulate Matter Exposure in C57/B6 Mice.

Short-and long-term exposure to particulate matter (PM) has been associated with cardiovascular disease (CVD). It is well recognized that oxidative stress is a potential major mechanism in PM-induced vascular injuries, in which the nuclear factor E2-related factor 2 (Nrf2) signaling pathway plays a critical role. In the current study, a Nrf2 knockout mouse model was used in combination with an individual ventilated cage (IVC)-based real-ambient PM exposure system to assess the potential vascular injury and the potential role of Nrf2 in the angiotensin II (Ang II)-associated vascular injury. After 6-or 11-week exposure to PM, the histopathology assay revealed that PM exposure resulted in the thickening of the walls of vascular. After 6 weeks exposure to PM, the ELISA assay revealed that PM exposure resulted in the elevated plasma concentration of Ang II. The expression levels of genes of interest were then further investigated with quantitative real-time PCR. Notably, the results showed that Angiotensinogen (AGT), Angiotensin converting enzyme (ACE) and Angiotensin type I receptor (AT1R) were involved in PM-induced pathological changes. Western blotting for ACE showed similar results. Moreover, the extent of vascular thickening and the Ang II elevation was most prominent in the Nrf2 gene knockout PM exposure group (KOE). Furthermore, the expression of Nrf2 downstream relevant genes (HO1, Nqo1, Gclc, Gsta4) were significantly enhanced in the wildtype PM exposure group (WTE), while those were remarkably suppressed in the Nrf2 gene knockout groups. The ELISA result of monocyte chemoattractant protein-1 (MCP-1) serum levels in the KOE group was significantly higher in relation to that in the Nrf2 knockout control group (KOC). In summary, PM exposure is associated with thickening of vascular wall, while Nrf2 knockout may further enhance this effect. A potential mechanistic contributor of such effects is the activation of ACE/ANGII/AT1R axis, in which Nrf2 played a regulatory role.

Phosphatase SHP1 impedes mesenchymal stromal cell immunosuppressive capacity modulated by JAK1/STAT3 and P38 signals.

BACKGROUND: Mesenchymal stromal cells (MSCs) are multiple stromal cells existing in various tissues and have already been employed in animal models and clinical trials to treat immune disorders through potent immunosuppressive capacity. Our previous reports have suggested that MSC immunosuppression is not intrinsic but is acquired upon combined inflammatory cytokine treatment. However, the understanding of detailed molecular mechanisms involved in MSC immunomodulation remains incomplete. RESULTS: In the study, we report that MSCs derived from viable motheaten (me v ) mice, with deficiency in SH2 domain-containing phosphatase-1 (SHP1), exhibited remarkable increased suppressive effect on activated splenocyte proliferation. Consistently, when MSCs were treated with combined inflammatory cytokines, SHP1-deficient MSCs produced dramatically more iNOS expression compared with wild-type MSCs. SHP1 was found to suppress the phosphorylation of JAK1/STAT3 and P38 signals. The classical animal model of concanavalin A (ConA)-induced liver injury was applied to examine the role of SHP1 in modulation MSC-therapeutic effect in vivo. Consistent with the results in vitro, SHP1-deficient MSCs exhibited dramatically more effective protection against ConA-induced hepatitis, compared to WT MSCs. CONCLUSION: Taken together, our study reveals a possible role for SHP1 in modulation of MSC immunosuppression regulated by JAK1/STAT3 and P38 signals.

Real-ambient exposure to air pollution exaggerates excessive growth of adipose tissue modulated by Nrf2 signal.

Air pollution was becoming a global threat to the public health, which was primarily mediated by PM2.5 induced cardiovascular diseases and pulmonary diseases. Recently, observational epidemiologic studies proposed the link between PM2.5 and obesity. Consistently, the link was also supported by limited animal researches. However, the potential mechanism mediating the harmful effects of PM2.5 was still elusive. In this study, we applied the "real-ambient exposure" system to conduct the experiments, which was closer to the status of ambient air pollution compared with the method of intratracheal instillation and concentrated air particles (CAPs) exposure system. Nuclear factor E2-related factor 2 (Nrf2) was previously reported to protect against inflammation and oxidative stress when exposed to PM2.5. Here, we reported that Nrf2-/- mice developed overgrowth of adipose tissue after "real-ambient exposure" to PM2.5, compared to filtered air (FA) group. Consistently, compared to FA group, adipocytes from subcutaneous (sWAT) and gonadal (gWAT) white adipose tissue of Nrf2-/- mice exhibited enlarged cell size in PM2.5 exposure group. Furthermore, the levels of high-density lipoprotein (HDL) and low-density lipoprotein (LDL) in serum and liver of Nrf2-/- mice were also altered statistically in PM2.5 exposure group. Importantly, when the expression of lipogenic enzymes was analyzed, the levels of the related specific genes in adipose tissue and liver of Nrf2-/- mice were altered in PM2.5 exposure group. Interestingly, the key transcription factors modulating expression of lipogenic enzymes in liver of Nrf2-/- mice were also found altered in PM2.5 exposure group, such as peroxisome proliferator-activated receptor (PPARα, PPARγ). Taken together, our study mimicked the status of ambient air pollution, revealed new insights into the adverse effect of PM2.5 exposure, provided new link between air pollution and overgrowth of adipose tissue, and supported the vital role of Nrf2 in mediating the side effects of PM2.5.

Small Airway Wall Thickening Assessed by Computerized Tomography Is Associated With Low Lung Function in Chinese Carbon Black Packers.

Nanoscale carbon black as virtually pure elemental carbon can deposit deep in the lungs and cause pulmonary injury. Airway remodeling assessed using computed tomography (CT) correlates well with spirometry in patients with obstructive lung diseases. Structural airway changes caused by carbon black exposure remain unknown. Wall and lumen areas of sixth and ninth generations of airways in 4 lobes were quantified using end-inhalation CT scans in 58 current carbon black packers (CBPs) and 95 non-CBPs. Carbon content in airway macrophage (CCAM) in sputum was quantified to assess the dose-response. Environmental monitoring and CCAM showed a much higher level of elemental carbon exposure in CBPs, which was associated with higher wall area and lower lumen area with no change in total airway area for either airway generation. This suggested small airway wall thickening is a major feature of airway remodeling in CBPs. When compared with wall or lumen areas, wall area percent (WA%) was not affected by subject characteristics or lobar location and had greater measurement reproducibility. The effect of carbon black exposure status on WA% did not differ by lobes. CCAM was associated with WA% in a dose-dependent manner. CBPs had lower FEV1 (forced expiratory volume in 1 s) than non-CBPs and mediation analysis identified that a large portion (41-72%) of the FEV1 reduction associated with carbon black exposure could be explained by WA%. Small airway wall thickening as a major imaging change detected by CT may underlie the pathology of lung function impairment caused by carbon black exposure.