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《Inhalation toxicology》2013,25(6):313-323
Complexation of host iron (Fe) on the surface of inhaled asbestos fibers has been postulated to cause oxidative stress contributing to in vivo pulmonary injury and inflammation. We examined the role of Fe in Libby amphibole (LA; mean length 4.99?µm ± 4.53 and width 0.28?µm ± 0.19) asbestos-induced inflammogenic effects in vitro and in vivo. LA contained acid-leachable Fe and silicon. In a cell-free media containing FeCl3, LA bound #17 µg of Fe/mg of fiber and increased reactive oxygen species generation #3.5 fold, which was reduced by deferoxamine (DEF) treatment. In BEAS-2B cells exposure to LA, LA loaded with Fe (FeLA), or LA with DEF did not increase HO-1 or ferritin mRNA expression. LA increased IL-8 expression, which was reduced by Fe loading but increased by DEF. To determine the role of Fe in LA-induced lung injury in vivo, spontaneously hypertensive rats were exposed intratracheally to either saline (300 µL), DEF (1?mg), FeCl3 (21 µg), LA (0.5?mg), FeLA (0.5?mg), or LA + DEF (0.5?mg). LA caused BALF neutrophils to increase 24?h post-exposure. Loading of Fe on LA but not chelation slightly decreased neutrophilic influx (LA + DEF > LA > FeLA). At 4?h post-exposure, LA-induced lung expression of MIP-2 was reduced in rats exposed to FeLA but increased by LA + DEF (LA + DEF > LA > FeLA). Ferritin mRNA was elevated in rats exposed to FeLA compared to LA. In conclusion, the acute inflammatory response to respirable fibers and particles may be inhibited in the presence of surface-complexed or cellular bioavailable Fe. Cell and tissue Fe-overload conditions may influence the pulmonary injury and inflammation caused by fibers. 相似文献
3.
Internalization of Libby amphibole asbestos and induction of oxidative stress in murine macrophages.
David J Blake Celeste M Bolin David P Cox Fernando Cardozo-Pelaez Jean C Pfau 《Toxicological sciences》2007,99(1):277-288
The community members of Libby, MT, have experienced significant asbestos exposure and developed numerous asbestos-related diseases including fibrosis and lung cancer due to an asbestos-contaminated vermiculite mine near the community. The form of asbestos in the contaminated vermiculite has been characterized in the amphibole family of fibers. However, the pathogenic effects of these fibers have not been previously characterized. The purpose of this study is to determine the cellular consequences of Libby amphibole exposure in macrophages compared to another well-characterized amphibole fiber; crocidolite asbestos. Our results indicate that Libby asbestos fibers are internalized by macrophages and localize to the cytoplasm and cytoplasmic vacuoles similar to crocidolite fibers. Libby asbestos fiber internalization generates a significant increase in intracellular reactive oxygen species (ROS) as determined by dichlorofluorescein diacetate and dihydroethidine fluorescence indicating that the superoxide anion is the major contributing ROS generated by Libby asbestos. Elevated superoxide levels in macrophages exposed to Libby asbestos coincide with a significant suppression of total superoxide dismutase activity. Both Libby and crocidolite asbestos generate oxidative stress in exposed macrophages by decreasing intracellular glutathione levels. Interestingly crocidolite asbestos, but not Libby asbestos, induces significant DNA damage in macrophages. This study provides evidence that the difference in the level of DNA damage observed between Libby and crocidolite asbestos may be a combined consequence of the distinct chemical compositions of each fiber as well as the activation of separate cellular pathways during asbestos exposure. 相似文献
4.
《Inhalation toxicology》2013,25(3):129-141
Pulmonary toxicity induced by asbestos is thought to be mediated through redox-cycling of fiber-bound and bioavailable iron (Fe). We hypothesized that Libby amphibole (LA)-induced cute lung injury will be exacerbated in rat models of cardiovascular disease (CVD)-associated Fe-overload and oxidative stress. Healthy male Wistar Kyoto (WKY), spontaneously hypertensive (SH) and SH heart failure (SHHF) rats were intratracheally instilled with 0.0, 0.25 or 1.0?mg/rat LA and examined at 1 day, 1 week or 1 month. Although histologically it was not possible to distinguish severity differences between strains in LA-induced initial inflammation and later fibrosis, quantitative assessment of biomarkers showed strain-related differences. LA-induced neutrophilic inflammation was reversible in WKY but persisted more in SH and SHHF. Lung MIP-2 mRNA increased only in WKY at 1 day in response to LA but not in SH and SHHF. Bronchoalveolar lavage fluid (BALF) protein increased in SH but not WKY at 1 week and 1 month, while γ-glutamyltransferase and N-acetyl-β-D-glucosaminidase activities increased in all strains (WKY>SH=SHHF). BALF ferritin levels were high at baseline and increased following LA exposure only in SH and SHHF. Ferritin heavy chain mRNA increased only in SHHF at 1 day. At 1 month ferritin light chain mRNA declined from already high baseline levels in SHHF but increased in WKY and SH suggesting its differential involvement in LA-induced injury in Fe-overload. Unlike WKY, both SHHF and SH failed to increase the lung lining antioxidant, ascorbate, in response to LA. We conclude that underlying CVD-associated Fe-overload is likely linked to persistent lung injury, inflammation and antioxidant decompensation following LA exposure in rats. 相似文献
5.
Shannahan JH Alzate O Winnik WM Andrews D Schladweiler MC Ghio AJ Gavett SH Kodavanti UP 《Toxicology and applied pharmacology》2012,260(2):105-114
Identification of biomarkers assists in the diagnosis of disease and the assessment of health risks from environmental exposures. We hypothesized that rats exposed to Libby amphibole (LA) would present with a unique serum proteomic profile which could help elucidate epidemiologically-relevant biomarkers. In four experiments spanning varied protocols and temporality, healthy (Wistar Kyoto, WKY; and F344) and cardiovascular compromised (CVD) rat models (spontaneously hypertensive, SH; and SH heart failure, SHHF) were intratracheally instilled with saline (control) or LA. Serum biomarkers of cancer, inflammation, metabolic syndrome (MetS), and the acute phase response (APR) were analyzed. All rat strains exhibited acute increases in α-2-macroglobulin, and α1-acid glycoprotein. Among markers of inflammation, lipocalin-2 was induced in WKY, SH and SHHF and osteopontin only in WKY after LA exposure. While rat strain- and age-related changes were apparent in MetS biomarkers, no LA effects were evident. The cancer marker mesothelin was increased only slightly at 1 month in WKY in one of the studies. Quantitative Intact Proteomic profiling of WKY serum at 1 day or 4 weeks after 4 weekly LA instillations indicated no oxidative protein modifications, however APR proteins were significantly increased. Those included serine protease inhibitor, apolipoprotein E, α-2-HS-glycoprotein, t-kininogen 1 and 2, ceruloplasmin, vitamin D binding protein, serum amyloid P, and more 1 day after last LA exposure. All changes were reversible after a short recovery regardless of the acute or long-term exposures. Thus, LA exposure induces an APR and systemic inflammatory biomarkers that could have implications in systemic and pulmonary disease in individuals exposed to LA. 相似文献
6.
Brad Black Ronald F. Dodson James R. Bruce Lee W. Poye Claudia Henschke Gregory Loewen 《Inhalation toxicology》2017,29(9):404-413
During its days of operation (1920s–1990), the world’s largest source of vermiculite was extracted from a mine located near Libby, Montana. The material mined at this site was shipped for various commercial applications to numerous sites in the United States. There was a “fibrous” component with toxic potential within the vermiculite deposit that has resulted in “asbestos-like” diseases/deaths being reported in numerous studies involving miners as well as residents of the town of Libby. The present case involves the clinical assessments of an individual who worked at the mine from 1969 to 1990. He had no other known occupational exposures to fibrous materials. He developed a clinical picture that included “asbestos-like” pathological features and eventually an adenocarcinoma. The clinical assessment including radiographic features will be presented. The evaluation will also include the analytical evaluation of the fibrous/ferruginous body composition of the lung tissue. This is to our knowledge the first time such an extensive evaluation has been conducted in a vermiculite miner from Libby, Montana. 相似文献
7.
Hua Shao Li Huang Shuyin Duan Min Gao Jiacheng Zhu Xiaohui Chen Yajuan Zhu Wenhan Wang Zengwen Yang Xinyu Wang Zhen Wang Zhimin Wang Yue Ba Ruiqin Zhang Chunyang Li Qiao Zhang Jing Wang Hong Liu Weidong Wu Feifei Feng 《Environmental toxicology》2020,35(8):831-839
Glyburide is a classic antidiabetic drug that is dominant in inflammation regulation, but its specific role in ozone‐induced lung inflammation and injury remains unclear. In order to investigate whether glyburide prevents ozone‐induced pulmonary inflammation and its mechanism, C57BL/6 mice were intratracheally pre‐instilled with glyburide or the vehicle 1 hour before ozone (1 ppm, 3 hours) or filtered air exposure. After 24 hours, the total inflammatory cells and total protein in bronchoalveolar lavage fluid (BALF) were detected. The pathological alternations in lung tissues were evaluated by HE staining. The expression of NLRP3, interleukin‐1β (IL‐1β), and IL‐18 protein in lung tissues was detected by immunohistochemistry. Western blotting was used to examine the levels of caspase‐1 p10 and active IL‐1β protein. Levels of IL‐1β and IL‐18 in BALF were measured using ELISA kits. Glyburide treatment decreased the total cells in BALF, the inflammatory score, and the mean linear intercept induced by ozone in lung tissues. In addition, glyburide inhibited the expression of NLRP3, IL‐18, and IL‐1β protein in lung tissues, and also suppressed NLRP3 inflammasome activation, including caspase‐1 p10, active IL‐1β protein in lung tissues, IL‐1β, and IL‐18 in BALF. These results demonstrate that glyburide effectively attenuates ozone‐induced pulmonary inflammation and injury via blocking the NLRP3 inflammasome. 相似文献
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Background: In the 2014 Integrated Risk Information System (IRIS) assessment for Libby amphibole asbestos (LAA), US EPA calculated a reference concentration (RfC) based on the prevalence of pleural plaques in a group of vermiculite workers in Marysville, Ohio. This RfC is based on the assumption that pleural plaques are associated with adverse lung function. In this study, we evaluated the association between pleural plaques and lung function in the Marysville worker cohort to determine whether they are associated with adverse effects or, rather, are more likely a biomarker of cumulative exposure to LAA.Methods: We obtained the dataset on the Marysville worker cohort from University of Cincinnati, which included information on demographics, occupational exposures and results of chest high-resolution computed tomography (HRCT)/computed tomography (CT) scans and pulmonary function tests (PFTs). We used multivariate linear regression to estimate mean differences in several lung function parameters, and logistic regression to evaluate the odds of abnormal ventilatory patterns, among men with different pulmonary findings on HRCT/CT scans.Results: No statistically significant differences in FEV1, FVC, FEV1/FVC, TLC, RV or DLCO were observed between workers with normal scans and those with pleural plaques but no other abnormalities. In contrast, workers with other abnormal findings had statistically significant lower FEV1, FVC, TLC and DLCO, compared with those with normal scans.Conclusions: This study does not indicate that pleural plaques have a significant effect on lung function when past asbestos exposure is accounted for. 相似文献
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Apolipoprotein E (ApoE) has been reported as a steroid unresponsive gene and functions as a negative regulator of airway hyperreactivity (AHR) and goblet cell hyperplasia in house dust mite (HDM)-challenged mice. However, the role of ApoE in Ovalbumin (OVA)-induced allergic airway inflammation disease and the underlying mechanism are still unknown. In the present study, murine allergic airway inflammation was induced by inhaled OVA for consecutive 7 days in wild type (WT) and ApoE−/− mice. In the OVA-induced model, the ApoE level in the bronchoalveolar lavage fluid (BALF) and lung tissues was significantly higher than that of control mice. And ApoE deficiency aggravated airway inflammation including leukocytes infiltration, goblet cell hyperplasia and IgE production as compared to those of WT mice after OVA- challenged, suggesting ApoE servers as an endogenous negative regulator of airway inflammation. Furthermore, OVA challenge elevated the activation of NLRP3 inflammasome with higher protein expression of NLRP3, caspase1 and IL-1β, enhanced oxidative stress with higher expression of 8-OHdG, nitrotyrosine and SOD2, increased the expression of mitochondrial fusion/fission markers including Optic Atrophy 1 (OPA1), Mitofusion 2 (Mfn2), dynamin-related protein 1 (DRP1) and Fission 1 (Fis1). However, these OVA-induced changes were augmented in ApoE−/− mice. Collectively, our results demonstrated that the OVA-induced airway inflammation was aggravated in ApoE−/− mice, and suggested that the underlying mechanism may be associated with the augmented activation of NLRP3 inflammasome and oxidative stress in ApoE−/− mice, therefore targeting ApoE pathway might be a novel therapy approach for allergic airway diseases such as asthma. 相似文献
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Shuyin Duan Na Wang Li Huang Ying Zhao Hua Shao Yuefei Jin Ruiqin Zhang Chunyang Li Weidong Wu Jing Wang Feifei Feng 《Environmental toxicology》2019,34(11):1246-1254
Growing evidences indicate that inflammation induced by PM2.5 exposure has been considered as a major driving force for the development of cardiovascular diseases. However, the mechanisms underlying PM2.5‐induced cardiac injury remain unclear. This study aims to investigate the role of NLRP3 inflammasome in PM2.5‐induced cardiac functional and pathological injury in mice. In this study, BALB/c mice were intratracheally instilled with PM2.5 suspension (4.0 mg/kg BW) for 5 days to set up a cardiac injury model, which was evaluated by electrocardiogram monitoring, HE and Masson staining. Then, the effects of PM2.5 on the expression of α‐SMA, NLRP3, IL‐1β, and IL‐18 proteins and the activation of caspase‐1 and IL‐1β were investigated. The results showed that PM2.5 exposure induced characteristic abnormal ECG changes such as the abnormality of heart rhythm, tachycardia, and T‐wave reduction. Inflammatory cell infiltration and fibrosis were observed in the heart tissues of PM2.5‐exposed mice. Meanwhile, PM2.5 exposure increased the expression of α‐SMA. And, NLRP3 activation‐associated proteins of NLRP3, IL‐1β, IL‐18, Cleaved caspase‐1 p10, and Cleaved IL‐1β were upregulated in heart tissue of PM2.5‐induced mice. In summary, PM2.5 exposure could induce cardiac functional and pathological injury, which may be associated with the activation of NLRP3 inflammasome. 相似文献
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Dexamethasone (DEX) is the mainstay treatment for asthma, which is a common chronic airway inflammation disease. However, the mechanism of DEX resolute symptoms of asthma is not completely clear. Here, we aimed to analyze the effect of DEX on airway inflammation in OVA-induced mice and whether this effect is related to the inhibition of the activation of NLRP3 inflammasome. Female (C57BL/6) mice were used to establish the allergic airway inflammation model by inhalation OVA. The number of inflammatory cells in the bronchi alveolar lavage fluid (BALF) was counted by Swiss-Giemsa staining, and the contents of IL-1β, IL-18, IL-5 and IL-17 were detected by ELISA. The degree of inflammatory cells infiltration and mucous cells proliferation in lung tissue were separately observed by H&E and PAS staining. The proteins expression of NLRP3, pro-caspase-1, caspase-1, IL-1β, IL-6 and IL-17 in lung tissue were detected by Western blotting. We found that DEX significantly inhibited OVA-induced inflammatory cells infiltration, airway mucus secretion and goblet cell proliferation in mice. The total and classified numbers of inflammatory cells and the levels of IL-1β, IL-18, IL-5 and IL-17 in the BALF of the experimental group were significantly lower than those of the model group after DEX treatment. DEX also significantly inhibited the activity of NLRP3 inflammasome and reduced the protein contents of Pro-Caspase-1, Caspase-1, Capase-1/Pro-Caspase-1, IL-1β, IL-6 and IL-17 in lung tissues. Our study suggested that DEX alleviates allergic airway inflammation by inhibiting the activity of NLRP3 inflammasome and the levels of IL-1β and IL-18. 相似文献
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Alessandra Bitto Domenica Altavilla Gabriele Pizzino Natasha Irrera Giovanni Pallio Michele R Colonna Francesco Squadrito 《British journal of pharmacology》2014,171(9):2300-2307
Background and Purpose
Type 2 diabetes impairs the healing process because of an exaggerated and persistent inflammatory response, and an altered expression pattern of angiogenic molecules. We investigated the effects of inflammasome blockade in diabetes-related wound-healings defects, in genetically diabetic mice.Experimental Approach
An incisional skin wound model was produced on the back of female diabetic C57BL/KsJ-m +/+ Leptdb mice (db+/db+) and their normal littermates (db+/m+). Animals were treated daily with two inflammasome blocking agents, BAY 11-7082 (20 mg·kg−1 i.p.), or Brilliant Blue G (BBG, 45.5 mg·kg−1 i.p.), or vehicle. Mice were killed on 3, 6 and 12 days after skin injury to measure expression of the NOD-like receptor NLRP3, caspase-1, VEGF, the inflammasome adapter protein apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) and the chemokine CXCL12. Wound levels of IL-1β and IL-18 were also measured, along with histological assessments of wound tissue and the time to complete wound closure.Key Results
During healing, the diabetic mice exhibited increased activation of NLRP3, caspase-1, ASC, IL-1β and IL-18. They also showed a reduced expression of VEGF and CXCL12.Treatment with BAY 11-7082 or BBG, to block activation of the inflammasome, decreased the levels of pro-inflammatory molecules. Histological evaluation indicated that inflammasome blockade improved the impaired healing pattern, at day 12 in diabetic mice, along with a decreased time to complete skin healing.Conclusions and Implications
These data strongly suggest that activation of the NLRP3 inflammasome is one of the key contributors to the delayed healing of wounds in diabetic mice. 相似文献13.
Objective: Angiopoietin-1 (Ang1) is reported to have the ability to attenuate endothelial permeability and inflammation during the stress condition and is considered to play a critical role in vascular stabilization. The aim of this study was to investigate the mechanisms involved in the protective effects of adenovirus-delivered Ang1 in phosgene-induced acute lung injury (ALI).Methods: ALI was induced in rats by phosgene exposure at 8.33?g/m3 for 5?min, followed by an intravenous injection of adenovirus-Ang1 (Ad/Ang1). The histologic changes of the lung were evaluated with H&;E staining. The levels of cytokines in the serum and bronchoalveolar lavage fluid (BALF) were determined by ELISA. NLRP3 inflammasome activation was assessed with immunohistochemistry, RT-PCR, Western blotting and TUNEL staining.Results: Histologic analyses suggested that reduced severity in phosgene-induced ALI with Ad/Ang1 treatment. Reduced levels of IL-1β, IL-18 and IL-33 were found in both serum and BALF samples from Ad/Ang1-treated ALI rats induced by phosgene. Moreover, immunohistochemistry analysis revealed that Ad/Ang1 treatment inhibited the NLRP3 inflammasome activation. Decreased mRNA and protein levels of NLRP3 and caspase-1 were found in phosgene-exposed rats treated with Ad/Ang1. In addition, TUNEL staining indicated a decrease in pyroptosis in phosgene-exposed rats treated with Ad/Ang1.Conclusions: Ang1 exerts beneficial effects on phosgene-induced lung injury via inhibition of NLRP3 inflammasome activation. Disruption of NLRP3 inflammasome activation might be served as therapeutic modality for the treatment of phosgene-induced ALI. 相似文献
14.
Li-hong Ding Dan Liu Min Xu Hong Liu Min Wu Ri-ning Tang Lin-li Lv Kun-ling Ma Bi-cheng Liu 《Acta pharmacologica Sinica》2014,35(10):1293-1301
Aim:
Proteinuria is not only a common marker of renal disease, but also involved in renal tubulointerstitial inflammation and fibrosis. The aim of this study was to investigate the mechanisms underlying the protective effects of enalapril, an ACEI, against nephropathy in rats.Methods:
Wistar rats underwent unilateral right nephrectomy, and then were treated with BSA (5 g·kg−1·d−1, ip), or BSA plus enalapril (0.5 g·kg−1·d−1, po) for 9 weeks. The renal lesions were evaluated using histology and immunohistochemistry. The expression of NLRP3, caspase-1, IL-1β and IL-18 was analyzed using immunohistochemistry, RT-PCR and Western blot.Results:
BSA-overload resulted in severe proteinuria, which peaked at week 7, and interstitial inflammation with prominent infiltration of CD68+ cells (macrophages) and CD3+ cells (T lymphocytes), particularly of CD20+ cells (B lymphocytes). BSA-overload markedly increased the expression of NLRP3, caspase-1, IL-1β and IL-18 in the proximal tubular epithelial cells, and in inflammatory cells as well. Furthermore, the expression of IL-1β or IL-18 was significantly correlated with proteinuria (IL-1β: r=0.757; IL-18: r=0.834). These abnormalities in BSA-overload rats were significantly attenuated by concurrent administration of enalapril.Conclusion:
Enalapril exerts protective effects against BSA-overload nephropathy in rats via suppressing NLRP3 inflammasome expression and tubulointerstitial inflammation. 相似文献15.
Aberrant activation of Nod-like receptor family pyrin domain-containing-3 (NLRP3) inflammasome is implicated in a variety of inflammatory diseases. Targeting NLRP3 inflammasome represents a promising therapy to cure such diseases. We and others recently demonstrated that acetylation of NLRP3 promotes the inflammasome activity and also suggested lysine acetyltransferases inhibitors could be a kind of promising agents for treating NLRP3 associated disorders. In this study, by searching for kinds of lysine acetyltransferases inhibitors, we showed that SI-2 hydrochloride (SI-2), a specific inhibitor of lysine acetyltransferase KAT13B (lysine acetyltransferases 13B), specifically blocks NLRP3 inflammasome activation both in mice in vivo and in human cells ex vivo. Intriguingly, SI-2 does not affect the acetylation of NLRP3. Instead, it disrupts the interaction between NLRP3 and adaptor apoptosis-associated speck-like protein containing CARD (ASC), then blocks the formation of ASC speck. Thus, our study identified a specific inhibitor for NLRP3 inflammasome and suggested SI-2 as a potential inhibitory agent for the therapy of NLRP3-driven diseases. 相似文献
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Tina M. Sager Michael Wolfarth Stephen S. Leonard Anna M. Morris Dale W. Porter Vincent Castranova 《Inhalation toxicology》2016,28(14):686-697
Incomplete understanding of the contributions of dispersants and engineered nanoparticles/materials (ENM) agglomeration state to biological outcomes presents an obstacle for toxicological studies. Although reactive oxygen species (ROS) production is often regarded as the primary indicator of ENM bioactivity and toxicity, it remains unclear whether ENM produce ROS or whether ROS is an outcome of ENM-induced cell injury. Phagolysosomal disruption and cathepsin B release also promote bioactivity through inflammasome activation. Therefore, specific particle parameters, i.e. preexposure dispersion status and particle surface area, of two ENM (NiO and CeO2) were used to evaluate the role of ROS generation and cathepsin B release during ENM-induced toxicity. Male C57BL/6J mice were exposed to 0, 20, 40, or 80?μg of poorly or well-dispersed NiO-NP or CeO2-NP in four types of dispersion media. At 1- and 7-day postexposure, lung lavage fluid was collected to assess inflammation, cytotoxicity, and inflammasome activation. Results showed that preexposure dispersion status correlated with postexposure pulmonary bioactivity. The differences in bioactivity of NiO-NP and CeO2-NP are likely due to NiO-NP facilitating the release of cathepsin B and in turn inflammasome activation generating proinflammatory cytokines. Further, both metal oxides acted as free radical scavengers. Depending on the pH, CeO2-NP acted as a free radical scavenger in an acidic environment (an environment mimicking the lysosome) while the NiO-NP acted as a scavenger in a physiological pH (an environment that mimics the cytosol of the cell). Therefore, results from this study suggest that ENM-induced ROS is not likely a mechanism of inflammasome activation. 相似文献
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Involvement of EGF receptor signaling and NLRP12 inflammasome in fine particulate matter‐induced lung inflammation in mice
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Yuefei Jin Weidong Wu Weiguo Zhang Yang Zhao Yongjun Wu Guoyin Ge Yue Ba Qiang Guo Tianyu Gao Xuejing Chi Huiyun Hao Jing Wang Feifei Feng 《Environmental toxicology》2017,32(4):1121-1134
Epidemiological studies have shown that exposure to ambient fine particulate matter (PM2.5) is associated with respiratory diseases. Lung inflammation is a central feature of many pulmonary diseases, which can be induced by PM2.5 exposure. However, the mechanisms underlying PM2.5‐induced lung inflammation remain unclear. To characterize the role of epidermal growth factor receptor (EGFR) and inflammasome in PM2.5‐induced lung inflammation in mice, 30 BALB/c mice were intrabroncheally instilled with saline and PM2.5 suspension (4.0 mg/kg b.w.) for 5 consecutive days, respectively. Bronchoalveolar lavage (BAL) was conducted and BAL fluid (BALF) was collected. The levels of reactive oxygen species (ROS), inducible nitric oxide synthase (iNOS), epidermal growth factor (EGF), CXCL1, interleukin (IL)?1β, and IL‐18 in BALF were determined using ELISA. mRNA levels of IL‐6, IL‐1β, IL‐18, CXCL1, IL‐10, NLRP3, Caspase‐1, and NLRP12 in lung tissues were determined by RT‐PCR. Phospho‐EGFR (Tyr1068) and phospho‐Akt (Thr308) in lung tissues were examined using immunohistochemical staining and Western blotting, respectively. Protein levels of Caspase‐1, NLRP3, NF‐κB‐p52/p100, and NF‐κB‐p65 in bronchial epithelium were examined using immunohistochemical staining. It was shown that PM2.5 exposure induced lung inflammation. Levels of total protein, ROS, iNOS, EGF, and CXCL1 and cell number in the BALF of mice exposed to PM2.5 were markedly elevated relative to the control. mRNA levels of CXCL1, IL‐1β, and IL‐18 in lung tissues of PM2.5‐exposed mice were increased in comparison with the control. However, level of NLRP12 mRNA in lung tissues of PM2.5‐exposed mice was reduced. Phospho‐EGFR (Tyr1068) and phospho‐Akt (Thr308) levels in the lungs of PM2.5‐instilled mice were higher than those in the lungs of the control. The protein levels of NF‐κB‐p52/p100 and NF‐κB‐p65 in bronchial epithelium of PM2.5‐exposed mice were also increased compared with the control. This study suggests that EGF‐EGFR‐Akt‐NF‐κB signaling and NLRP12 inflammasome may be associated with PM2.5‐induced lung inflammation in mice. © 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 1121–1134, 2017. 相似文献
19.
Shannahan JH Ghio AJ Schladweiler MC McGee JK Richards JH Gavett SH Kodavanti UP 《Inhalation toxicology》2011,23(6):313-323
Complexation of host iron (Fe) on the surface of inhaled asbestos fibers has been postulated to cause oxidative stress contributing to in vivo pulmonary injury and inflammation. We examined the role of Fe in Libby amphibole (LA; mean length 4.99 μm ± 4.53 and width 0.28 μm ± 0.19) asbestos-induced inflammogenic effects in vitro and in vivo. LA contained acid-leachable Fe and silicon. In a cell-free media containing FeCl(3), LA bound #17 μg of Fe/mg of fiber and increased reactive oxygen species generation #3.5 fold, which was reduced by deferoxamine (DEF) treatment. In BEAS-2B cells exposure to LA, LA loaded with Fe (FeLA), or LA with DEF did not increase HO-1 or ferritin mRNA expression. LA increased IL-8 expression, which was reduced by Fe loading but increased by DEF. To determine the role of Fe in LA-induced lung injury in vivo, spontaneously hypertensive rats were exposed intratracheally to either saline (300 μL), DEF (1 mg), FeCl(3) (21 μg), LA (0.5 mg), FeLA (0.5 mg), or LA + DEF (0.5 mg). LA caused BALF neutrophils to increase 24 h post-exposure. Loading of Fe on LA but not chelation slightly decreased neutrophilic influx (LA + DEF > LA > FeLA). At 4 h post-exposure, LA-induced lung expression of MIP-2 was reduced in rats exposed to FeLA but increased by LA + DEF (LA + DEF > LA > FeLA). Ferritin mRNA was elevated in rats exposed to FeLA compared to LA. In conclusion, the acute inflammatory response to respirable fibers and particles may be inhibited in the presence of surface-complexed or cellular bioavailable Fe. Cell and tissue Fe-overload conditions may influence the pulmonary injury and inflammation caused by fibers. 相似文献
20.
Qun Zhao Yun Bi Jian Guo Ying-xiang Liu Jing Zhong Long-rui Pan Yan Tan Xian-jun Yu 《Acta pharmacologica Sinica》2021,42(6):975-986
Excessive activation of NLRP3 inflammasome is associated with the pathogenesis of inflammatory diseases. Pristimerin (Pri) is a quinonoid triterpene derived from traditional Chinese medical herb Celastraceae and Hippocrateaceae. Pri has shown antifungal, antibacterial, antioxidant, and anticancer activities. In this study we investigated whether NLRP3 inflammasome was associated with the anti-inflammatory activity of Pri. We showed that Pri (0.1−0.4 μM) dose-dependently blocked caspase-1 activation and IL-1β maturation in LPS-primed mouse bone-marrow-derived macrophages (BMDMs). Pri specifically inhibited NLRP3 inflammasome activation, had no visible effects on NLRC4 and AIM2 inflammasome activation. Furthermore, we demonstrated that Pri blocked the assembly of the NLRP3 inflammasome via disturbing the interaction between NEK7 and NLRP3; the α, β-unsaturated carbonyl moiety of Pri was essential for NLRP3 inflammasome inactivation. In LPS-induced systemic inflammation mouse model and MSU-induced mouse peritonitis model, preinjection of Pri (500 μg/kg, ip) produced remarkable therapeutic effects via inhibition of NLRP3 inflammasome in vivo. In HFD-induced diabetic mouse model, administration of Pri (100 μg· kg−1 ·d−1, ip, for 6 weeks) reversed HFD-induced metabolic disorders via suppression of NLRP3 inflammasome activation. Taken together, our results demonstrate that Pri acts as a NLRP3 inhibitor, suggesting that Pri might be useful for the treatment of NLRP3-associated diseases. 相似文献