Mechanisms Of Particulate Matter Research Articles

PM2.5 triggers autophagic degradation of Caveolin-1 via endoplasmic reticulum stress (ERS) to enhance the TGF-β1/Smad3 axis promoting pulmonary fibrosis

Air pollution is highly associated with respiratory diseases. However, the influence and mechanism of particulate matter with aerodynamic equal to or less than 2.5 μm (PM2.5) in lung homeostasis remain unclear. Herein, we demonstrated the induction of pulmonary fibrosis (PF) by PM2.5 exposure. The animal model showed that PM2.5 exposure could activate the oxidative stress and inflammation response, promoting epithelial-mesenchymal transition and accumulation of collagen, high expression of pro-fibrotic factors, and pathological characteristics of fibrosis. The proteomic analysis indicated that PM2.5 exposure decreased the expression of caveolin-1 (Cav-1), and many differential proteins were enriched in the TGF-β1/Smad, endoplasmic reticulum stress (ERS) and autophagy pathways. Combining in vivo and in vitro experiments, it was found that PM2.5 exposure could reduce Cav-1 protein levels and activate TGF-β1/Smad3 signaling pathways through ERS and autophagy pathways, thereby inducing cell apoptosis and promoting pulmonary fibrosis. However, inhibiting ERS could alleviate the occurrence of autophagy, and blocking the autophagy system could increase the level of Cav-1 protein and inhibit TGF- β 1/Smad3 signaling pathway to improve pulmonary fibrosis. Therefore, we demonstrated that the exposure of PM2.5 could enhance the ERS induced-autophagy-mediated Cav-1 degradation, thus activating the TGF-β1/Smad3 axis to promote pneumonocytes apoptosis and overproduction of extracellular matrix (ECM), finally aggravating PF. Moreover, our findings revealed that intermittent exposure to high doses of PM2.5 was more toxic than continuous exposure to low dose.

Effects and Mechanism of Particulate Matter on Tendon Healing Based on Integrated Analysis of DNA Methylation and RNA Sequencing Data in a Rat Model.

Exposure to particulate matter (PM) has been linked with the severity of various diseases. To date, there is no study on the relationship between PM exposure and tendon healing. Open Achilles tenotomy of 20 rats was performed. The animals were divided into two groups according to exposure to PM: a PM group and a non-PM group. After 6 weeks of PM exposure, the harvest and investigations of lungs, blood samples, and Achilles tendons were performed. Compared to the non-PM group, the white blood cell count and tumor necrosis factor-alpha expression in the PM group were significantly higher. The Achilles tendons in PM group showed significantly increased inflammatory outcomes. A TEM analysis showed reduced collagen fibrils in the PM group. A biomechanical analysis demonstrated that the load to failure value was lower in the PM group. An upregulation of the gene encoding cyclic AMP response element-binding protein (CREB) was detected in the PM group by an integrated analysis of DNA methylation and RNA sequencing data, as confirmed via a Western blot analysis showing significantly elevated levels of phosphorylated CREB. In summary, PM exposure caused a deleterious effect on tendon healing. The molecular data indicate that the action mechanism of PM may be associated with upregulated CREB signaling.

Surfactin reduces particulate matter-induced VCAM-1-dependent monocyte adhesion in human gingival fibroblasts by increasing Nrf2-dependent HO-1 expression.

The mechanisms of particulate matter (PM) toxicity involve the generation of ROS and upregulation of proinflammatory molecules. Nrf2 is a multifunctional cytoprotective transcription factor that regulates the expression of various antioxidant, anti-inflammatory, and detoxifying molecules, such as HO-1. As surfactin has potential to induce Nrf2 activation and HO-1 expression, this study aimed to investigate the anti-inflammatory effects of surfactin on PM-exposed human gingival fibroblasts (HGFs) and signaling pathways engaged by surfactin. Human gingival fibroblasts were challenged by PM with or without surfactin pretreatment. The expression of Nrf2, HO-1, VCAM-1, and other molecules was determined by western blot, real-time PCR, or ELISA. Human monocytic THP-1 cells labeled with fluorescent reagent were added to HGFs, and the cell adhesion was assessed. ROS generation and NADPH oxidase activity were also measured. The involvement of Nrf2/HO-1 and ROS signaling pathways was investigated by treating HGFs with specific pathway interventions, genetically or pharmacologically. One dose of surfactin was given to mice before PM treatment to explore its in vivo effect on VCAM-1 expression in gingival tissues. Particulate matter led to VCAM-1-dependent monocyte adhesion in HGFs, which was regulated by PKCα/NADPH oxidase/ROS/STAT1/IL-6 pathway. Surfactin could attenuate monocyte adhesion by disrupting this VCAM-1-dependent pathway. Additionally, surfactin promoted Nrf2-dependent HO-1 expression in HGFs, mitigating VCAM-1 expression. PM-treated mice exhibited the lower expression of IL-6 and VCAM-1 in gingival tissues if they previously received surfactin. Surfactin exerts anti-inflammatory effects against PM-induced inflammatory responses in HGFs by inhibiting VCAM-1-dependent pathway and inducing Nrf2/HO-1 axis.

The mechanism of particulate matter on the development and progression of chronic obstructive pulmonary disease

The mechanism of particulate matter on the development and progression of chronic obstructive pulmonary disease

The role of particulate matters on methylation of IFN-γ and IL-4 promoter genes in pediatric allergic rhinitis.

Allergic rhinitis (AR) is a chronic inflammatory disorder driven by T cell activation. How particulate matter contributes to epigenetic changes that in turn influence cytokine gene expression in CD4+T cells remains unclear. In this study, 105 children diagnosed with AR and 90 healthy controls were recruited to explore the possible mechanism of particulate matter (PM) on the epigenetic regulation of CD4+T IFN-γ and IL-4 promoter genes. Daily average PM10 and PM2.5 were obtained from five state-controlled monitoring stations, and activity-based dynamic exposure and personal exposure data were collected. DNA methylation patterns of IFN-γ and IL-4 promoter regions were analyzed using bisulfite sequencing. mRNA levels were detected by real-time quantitative reverse transcription polymerase chain reaction. We found that the methylation rate in IFN-γ was higher in AR CD4+T cells than in the controls. IFN-γ mRNA expression was significantly decreased in CD4+T cells, and negatively correlated with the mean methylation level of IFN-γ. However, no correlation between IL-4 methylation and IL-4 mRNA expression was found. After adjusting for age, gender, exclusive breastfeeding within 4 months after birth and parental history of allergic disease, out data showed that PM2.5 exposure level was positively correlated with methylation level in IFN-γ promoter region and decreased cytokine expression. We conclude that the effect of PM2.5 on pediatric AR may be mediated through epigenetic modification of IFN-γ promoter region.

Cardiotoxicity and Mechanism of Particulate Matter 2.5 (PM2.5) Exposure in Offspring Rats During Pregnancy

BackgroundThe aim of this study was to investigate the cardiotoxicity and mechanism of particulate matter 2.5 (PM2.5) exposure on offspring rats during pregnancy.Material/MethodsWistar rats were used to establish a PM2.5 exposure animal model during pregnancy, and they were divided into a control group, a low-dose group, a middle-dose group, and a high-dose group according to PM2.5 exposure dose. The pathological changes of heart tissue, the rate of myocardial cell apoptosis, the levels of LDH, AST, and CM-KB in serum, and the difference in mitochondrial fusion genes (OPA1 and Mfn1) and mitochondrial genes (Drp1 and Fis1) were compared among groups.ResultsThe arrangement of myocardial fibers in offspring mice of PM2.5 exposure groups became disordered, the shape of some cardiomyocytes became irregular, and some staining darker nuclei appeared. The apoptotic rates of myocardium in offspring rats exposed to PM2.5 were (12.61±0.93)% in the low-dose group, (25.14±1.53)% in the middle-dose group, and (30.13±1.50)% in the high-dose group, which were all significantly higher than in the control group (9.12±0.80)% (P<0.05). The levels of LDH, AST, and CM-KB and the expression of OPA1, Mfn1, Drp1, and Fis1 in offspring mice of PM2.5 exposure groups increased with the increase of PM2.5 exposure dose, and were significantly higher than that of the control group (P<0.05).ConclusionsThe mitochondria of the offspring mice were damaged due to the abnormal expression of mitochondrial fusion/splicing gene by PM2.5 exposure during pregnancy, and the hearts of offspring mice were damaged due to damaged mitochondria.

Epidermal growth factor receptor (EGFR)-MAPK-nuclear factor(NF)-κB-IL8: A possible mechanism of particulate matter(PM) 2.5-induced lung toxicity.

Airway inflammation plays a central role in the pathophysiology of diverse pulmonary diseases. In this study, we investigated whether exposure to particulate matter (PM) 2.5, a PM with an aerodynamic diameter of less than 2.5 µm, enhances inflammation-related toxicity in the human respiratory system through activation of the epidermal growth factor receptor (EGFR) signaling pathway. Through cytokine antibody array analysis of two extracts of PM2.5 [water (W-PM2.5 ) and organic (O-PM2.5 ) soluble extracts] exposed to A549 (human alveolar epithelial cell), we identified eight cytokines changed their expression with W-PM2.5 and three cytokines with O-PM2.5 . Among them, epidermal growth factor (EGF) was commonly up-regulated by W-PM2.5 and O-PM2.5 . Then, in both groups, we can identify the increase in EGF receptor protein levels. Likewise, increases in the phosphorylation of ERK1/2 MAP kinase and acetylation of nuclear factor(NF)-κB were detected. We also detected an increase in IL-8 that was related to inflammatory response. And using the erlotinib as an inhibitor of EGFR, we identified the erlotinib impaired the phosphorylation of EGFR, ERK1/2, acetylation of NF-κB proteins and decreased IL-8. Furthermore, at in vivo model, we were able to identify similar patterns. These results suggest that PM2.5 may contribute to an abnormality in the human respiratory system through EGFR, MAP kinase, NF-κB, and IL-8 induced toxicity signaling. © 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 1628-1636, 2017.

Effect of particulate matter 2.5 on acute lung injury fibrosis in rats

Objective To investigate the effect and mechanism of particulate matter 2.5 (PM2.5) on acute lung injury and pulmonary fibrosis in healthy rats. Methods Sixty healthy Sprague-Dawley (SD) rats were instilled into trachea with two different solutions twice per week for four weeks: Control group with saline and experimental group with PM2.5 60 mg/kg. Experimental subgroup d5 rats were killed 5 days later and subgroup d28 rats 28 days later, respectively. Bronchoalveolar lavage fluid (BALF) were left for measurement of interleukin(IL)-6, tumor necrosis factor-α (TNF-α), type Ⅰ procollagen N-terminal propeptide (PⅠNP) and PⅢNP concentration, right lungs were left for hematoxylin eosin(HE) and Masson dyeing to observe the degree of inflammatory cell infiltration and collagenous fiber distribution, respectively. Results Compared to the control group, the concentration of IL-6 and TNF-α in two experimental groups were significantly higher(P<0.01 or P<0.05); While the level of IL-6 and TNF-α in subgroup d28 was significantly lower than that in subgroup d5(P<0.01 and P<0.05, respectively). The concentration of PⅠNP and PⅢNP in subgroup d5 was significantly higher than that in control group(P<0.05). The levels of PⅠNP and PⅢNP in subgroup d28 were significantly higher than that in the other two groups (P<0.01). Light microscope showed the apparent inflammatory cell infiltration in the lungs of subgroup d5, which was also appeared in subgroup d28. Beyond that, collagenous fiber deposition and pulmonary interstitial fibrosis was also found in subgroup d28. Conclusions PM2.5 inhalation can induce the increase of concentration of inflammatory factors and fibrosis indicators in healthy rats, which leads to the acute lung injury and pulmonary fibrosis. Key words: Particulate matter/AE; Respiratory distress syndrome, adult/ET; Pulmonary fibrosis/ET

EGF-MAPK-NF-kB cascade signaling pathway: Possible mechanism of particulate matter (PM) 2.5 -induced lung inflammatory responses

Different cubic Co-based Heusler alloys — Co 2FeAl (CFA), Co 2FeSi (CFS), Co 2MnAl (CMA), and Co 2MnSi (CMS) — were grown epitaxially on tetragonal Heusler-like D0 22–MnGa at different annealing temperatures (Ta) in the form of Heusler (20 nm)/MnGa (30 nm) bilayers. The CMA/MnGa bilayer showed the largest critical temperature (450 ∘ C), indicating good structural stability against interdiffusion. The experimental results showed an easier interdiffusion of the Fe and Si elements than of Mn and Al. An inverted hysteresis loop was observed in a polar magneto-optical Kerr effect (P-MOKE) measurement for the CFS/MnGa, CMA/MnGa, and CMS/MnGa bilayers. This is one piece of evidence for the existence of the antiferromagnetic (AFM) interfacial exchange coupling (J ex). We evaluated J ex for the Heusler/MnGa bilayers annealed at different temperatures. J ex changed from ferromagnetic (FM) to AFM after annealing at 300 ∘ C for the CFA/MnGa bilayer. Other bilayers showed only AFM coupling. The strongest J ex value of approximately − 3.2 erg/cm 2 was obtained for the CMS/MnGa bilayer annealed at 400 ∘ C. It was found that the tendency of the Mn and Si elements to make AFM J ex in the Heusler/MnGa bilayers interfaces is larger than that of Fe and Al.

Systemic translocation of 70Zinc: Kinetics following intratracheal instillation in rats

Mechanisms of particulate matter (PM)-induced cardiotoxicity are not fully understood. Direct translocation of PM-associated metals, including zinc, may mediate this effect. We hypothesized that following a single intratracheal instillation (IT), zinc directly translocates outside of the lungs, reaching the heart. To test this, we used high resolution magnetic sector field inductively coupled plasma mass spectrometry to measure levels of five stable isotopes of zinc ( 64Zn, 66Zn, 67Zn, 68Zn, 70Zn), and copper in lungs, plasma, heart, liver, spleen, and kidney of male Wistar Kyoto rats (13 weeks old, 250–300 g), 1, 4, 24, and 48 h following a single IT or oral gavage of saline or 0.7 μmol/rat 70Zn, using a solution enriched with 76.6% 70Zn. Natural abundance of 70Zn is 0.62%, making it an easily detectable tracer following exposure. In IT rats, lung 70Zn was highest 1 h post IT and declined by 48 h. Liver endogenous zinc was increased 24 and 48 h post IT. 70Zn was detected in all extrapulmonary organs, with levels higher following IT than following gavage. Heart 70Zn was highest 48 h post IT. Liver, spleen and kidney 70Zn peaked 4 h following gavage, and 24 h following IT. 70Zn IT exposure elicited changes in copper homeostasis in all tissues. IT instilled 70Zn translocates from lungs into systemic circulation. Route of exposure affects 70Zn translocation kinetics. Our data suggests that following pulmonary exposure, zinc accumulation and subsequent changes in normal metal homeostasis in the heart and other organs could induce cardiovascular injury.

Ultrafine Carbon Black Particles Cause Early Airway Inflammation and Have Adjuvant Activity in a Mouse Allergic Airway Disease Model

To gain more insight into the mechanisms of particulate matter (PM)-induced adjuvant activity, we studied the kinetics of airway toxicity/inflammation and allergic sensitization to ovalbumin (OVA) in response to ultrafine carbon black particles (CBP). Mice were exposed intranasally to OVA alone or in combination with different concentrations of CBP. Airway toxicity and inflammation were assessed at days 4 and 8. Immune adjuvant effects were studied in the lung draining peribronchial lymph nodes (PBLN) at day 8. Antigen-specific IgE was measured at days 21 and 28, whereas allergic airway inflammation was studied after OVA challenges (day 28). Results show that a total dose of 200 microg CBP per mouse, but not 20 microg or 2 microg, induced immediate airway inflammation. This 200 microg CBP was the only dose that had immune adjuvant activity, by inducing enlargement of the PBLN and increasing OVA-specific production of Th2 cytokines (IL-4, IL-5, and IL-10). The immune adjuvant activity of 200 microg CBP dosing was further examined. Whereas increased OVA-specific IgE levels in serum on day 21 confirms systemic sensitization, this was further supported by allergic airway inflammation after challenges with OVA. Our data show a link between early airway toxicity and adjuvant effects of CBP. In addition, results indicate that local cytokine production early after exposure to CBP is predictive of allergic airway inflammation. In addition this model appears suitable for studying the role of airway toxicity, inflammation and other mechanisms of particle adjuvant activity, and predicting the adjuvant potential of different particles.