HMGB1 inhibition reduces TDI-induced occupational asthma through ROS/AMPK/autophagy pathway.

Exposure to toluene diisocyanate (TDI) can cause pulmonary diseases such as asthma. Inhibition of high mobility group box 1 protein (HMGB1) has been found to be protective against the toxic effects of TDI on human bronchial epithelial (HBE) cells. Here, we evaluated the in vivo positive roles of HMGB1 in the TDI-caused asthma mice and explored its underlying mechanisms in HBE cells. We found that suppression of HMGB1 obviously alleviated airway inflammation, airway hyperresponsiveness, and airway remodeling in the lung tissue of the asthma mice. The in vitro results showed that inhibition of HMGB1 ameliorated TDI-induced reactive oxygen species (ROS) release, inflammatory response, and activation of autophagy in HBE cells. At the molecular level, inhibition of HMGB1 decreased the expressions of HMGB1, Toll-like receptor 4, Vimentin and matrix metalloproteinase-9 proteins, activated NF-κB and NOD-like receptor protein 3 (NLRP3) inflammasome, and increased E-cadherin expression. Importantly, activation of autophagy could lead to the overactivation of NLRP3 inflammasome in TDI-induced asthma. These results suggest that inhibition of HMGB1 can alleviate TDI-induced asthma through ROS/AMPK/autophagy pathways, which may provide valuable evidence for the pathogenesis and therapeutic targets of TDI-induced asthma.

Microcrystalline silica particles induce inflammatory response via pyroptosis in primary human respiratory epithelial cells.

The mechanism of the sterile inflammatory response in the respiratory tract induced by exposure to sterile particles has not been fully elucidated. The aim of our study is to explore the earlier events in initiating inflammatory response at molecular and cellular level in primary cultured human airway epithelial cells (AEC) exposed to silica particles in order to provide information for earlier diagnosis and prevention of silica particle-induced toxicity as well as possible information on the genesis of silicosis. We isolated primary AEC from three healthy adults and treated them with silica particles at different concentrations for 48 h. We found evidence for silica-induced inflammasome activation by the co-localization of Caspase-1 and NLRP3, as well as increased levels of IL-1ß and IL-18. Lactate dehydrogenase and NucGreen analysis proved the occurrence of pyroptosis. High throughput mRNA sequencing showed that the inflammatory response and NF-κB signaling pathways were significantly enriched in gene ontology and Kyoto encyclopedia of genes and genomes analysis, and pyroptosis-related genes were up-regulated. The miR-455-3p and five lncRNAs (LOC105375913, NEAT1, LOC105375181, LOC100506098, and LOC105369370) were verified as key factors related to the mechanism by ceRNA network analysis. LOC105375913 was first discovered to be associated with inflammation in AEC. These data suggest that microcrystalline silica can induce significant inflammation and pyroptosis in human primary AEC through NLRP3 inflammasome pathway and NF-κB signaling pathway at both the gene and protein levels, and the possible mechanism could be miR-455-3p mediated ceRNA hypothesis. Our data provide a method for the studies of the respiratory toxicity of fine particulate matter and the pathogenesis of early silicosis. The miR-455-3p and five lncRNAs related ceRNA network might be the toxicity mechanism of microcrystalline silica particles to AEC.

Oxidative stress-mediated mitochondrial pathway-dependent apoptosis is induced by silica nanoparticles in H9c2 cardiomyocytes.

The use of silica nanoparticles (SiNPs) is increasing in popularity; however, the emissions released during manufacturing, use and during the disposal stages potentially harm the environment. SiNPs can enter the body and cause cardiac toxicity indirectly or directly. However, toxicological data on SiNPs in cardiac cells in vitro, and the detailed molecular mechanisms by which damage is caused remain unclear. In the present study, oxidative stress-mediated apoptosis and cytotoxicity induced by SiNPs in H9c2 cells were examined. H9c2 cells were used to explore the mechanisms of toxicity by treating cells with 0, 25, 50, 100, and 200 µg/ml SiNPs, with and without 3 mM of the reactive oxygen species (ROS) scavenger, N-acetyl-l-cysteine (NAC), for 24 h. The results showed that SiNPs decreased cell viability and proliferation by increasing the release of lactate dehydrogenase (LDH) and inducing apoptosis in H9c2 cells. ROS levels were significantly increased in a dose-dependent manner. Additionally, the levels of superoxide dismutase (SOD), glutathione (GSH), and GSH-peroxidase (Px) were significantly decreased following exposure to SiNPs. Treatment with NAC attenuated LDH release; the levels of ROS, SOD, GSH, and GSH-Px production were increased, and SiNPs-induced mitochondrial pathway-dependent apoptosis was reduced. These results demonstrate that apoptosis and cytotoxicity induced by SiNPs in H9c2 cells are a result of ROS-mediated oxidative stress. These data suggest that exposure to SiNPs is a potential risk factor for cardiovascular disease.

Immune-related adverse events associated with programmed cell death protein-1 and programmed cell death ligand 1 inhibitors for non-small cell lung cancer: a PRISMA systematic review and meta-analysis.

BACKGROUND: Programmed cell death protein-1 (PD-1) and programmed cell death ligand 1 (PD-L1) inhibitors have remarkable clinical efficacy in the treatment of non-small cell lung cancer (NSCLC); however, the breakdown of immune escape causes a variety of immune-related adverse events (irAEs). With the increasing use of PD-1/PD-L1 inhibitors alone or in combination with other therapies, awareness and management of irAEs have become more important. We aimed to assess the incidence and nature of irAEs associated with PD-1 and PD-L1 inhibitors for NSCLC. METHODS: Articles from the MEDLINE, EMBASE, and Cochrane databases were searched through December 2017. The incidence of overall and organ-specific irAEs was investigated in all clinical trials with nivolumab, pembrolizumab, atezolimumab, durvalumab, and avelumab as single agents for treatment of NSCLC. We calculated the pooled incidence using R software with package Meta. RESULTS: Sixteen trials were included in the meta-analysis: 10 trials with PD-1 inhibitors (3734 patients) and 6 trials with PD-L1 inhibitors (2474 patients). The overall incidence of irAEs was 22% (95% confidence interval [CI], 17-28) for all grades and 4% (95% CI, 2-6) for high-grade irAEs. The frequency of irAEs varied based on drug type and organ, and patients treated with PD-1 inhibitors had an increased rate of any grade and high-grade irAEs compared with patients who received PD-L1 inhibitors. Organ-specific irAEs were most frequently observed in, in decreasing order, the endocrine system, skin, pulmonary tract, and gastrointestinal tract. The total number of patients whose death was attributed to irAEs was 14 (0.34%), and most (79%) of these patients died because of pneumonitis. The median time to the onset of irAEs after the initiation of treatment was 10 weeks (interquartile range, 6-19.5 weeks) and varied depending on the organ system involved. CONCLUSIONS: The specificity of irAEs was closely associated with the mechanism of PD-1/PD-L1 antibodies involved in restarting anticancer immune attacks. Comprehensive understanding, timely detection, and effective management could improve the compliance of patients and guide the interruption of treatment.

Efficacy of bone marrow mesenchymal stem cell transplantation in animal models of pulmonary fibrosis after exposure to bleomycin: A meta-analysis.

Previous studies have demonstrated that bone marrow mesenchymal stem cell (BMSC) transplantation is a promising treatment strategy for pulmonary fibrosis. Although encouraging results have been obtained using animal models of bleomycin (BLM)-induced pulmonary fibrosis, it is evident that transplantation of BMSCs at various time-points after BLM administration has produced different results in terms of treatment efficacy. To shed light on the potential utility of BMSCs for the treatment of lung disease, the present study performed a meta-analysis to estimate the efficacy of BMSCs in animal models of BLM-induced pulmonary fibrosis, and compare early transplantation (BMSCs injected on the same day after administration of BLM) with late transplantation (BMSCs injected on the 14th day after administration of BLM). Relevant studies were retrieved from the MEDLINE, PubMed, Chinese Knowledge Infrastructure and WanFang databases using a comprehensive search approach. A total of 6 studies involving 228 model rats were included. Meta-analysis indicated that early BMSC transplantation was able to prevent or reduce BLM-induced alveolitis and pulmonary fibrosis, while late BMSC transplantation was able to reduce alveolitis, but there was no significant evidence regarding improvement of pulmonary fibrosis. Although BMSC therapy was identified to be generally beneficial in rodent models of BLM-induced pulmonary fibrosis, the efficacy of early transplantation appears to be more satisfactory; overall, the efficacy of transplantation of BMSCs at the acute inflammatory phase was more effective compared with that at the chronic fibrosis stage. Of note, regarding alveolitis and pulmonary fibrosis scores after late transplantation of BMSCs, the sensitivity analysis revealed that the scores were less stable; thus, this result must be interpreted with caution. Furthermore, the quality and methodology of the included studies was comparatively low. Therefore, higher-quality and more rigorous studies are required to validate the results of the present meta-analysis in the future.

Silica nanoparticles induce cardiomyocyte apoptosis via the mitochondrial pathway in rats following intratracheal instillation.

Diseases of the cardiac system caused by silicon dioxide exposure have captured wide public attention. Upon entering the blood circulation, ultrafine particles have the potential to influence cardiomyocytes, leading to myocardial ischemia or even cardiac failure, and the molecular mechanisms remain to be completely elucidated. In this study, the toxicity of ultrafine particles on cardiomyocytes from rats exposed to silica nanoparticles was observed. Rats were randomly divided into a normal saline control group and three exposure groups (2, 5 and 10 mg/kg·body weight) that were intratracheally treated with 60­nm silica nanoparticles. Alterations in body weight, routine blood factors and myocardial enzymes, histopathological and microstructural alterations, apoptosis and the expression of apoptosis­associated proteins were assessed at the end of the exposure period. The silicon levels in the heart and serum, and myocardial enzymes in exposed rats were significantly increased in a dose­dependent manner. In addition, exposure to the silica nanoparticles caused notable histological and ultrastructural alterations in the hearts of these animals. Furthermore, a significant apoptotic effect was observed in the exposure groups. The present data suggest that silica nanoparticles may enter the circulatory system through the lungs, and are distributed to the heart causing cardiovascular injury. Silica nanoparticle­induced apoptosis via the mitochondrial pathway may serve an important role in observed cardiac damage.

Bone marrow mesenchymal stromal cells attenuate silica-induced pulmonary fibrosis potentially by attenuating Wnt/ß-catenin signaling in rats.

BACKGROUND: Pulmonary fibrosis induced by silica dust is an irreversible, chronic, and fibroproliferative lung disease with no effective treatment at present. Previous studies have shown that early intervention with bone marrow mesenchymal stem/stromal cells (BMSCs) has positive effect on anti-pulmonary fibrosis caused by silica dust. However, early intervention using BMSCs is not practical, and the therapeutic effects of BMSCs advanced intervention on pulmonary fibrosis have rarely been reported. In this study, we investigated the effects of advanced transplantation (on the 28th day after exposure to silica suspension) of BMSCs on an established rat model of pulmonary fibrosis. METHODS: Sprague Dawley (SD) rats were randomly divided into four groups including (1) control group (n = 6) which were normally fed, (2) silica model group (n = 6) which were exposed to silica suspension (1 mL of 50 mg/mL/rat), (3) BMSC transplantation group (n = 6) which received 1 mL BMSC suspension (2 × 106 cells/mL) by tail vein injection on the 28th day after exposure to silica suspension, and (4) BMSC-CM (conditioned medium) transplantation group (n = 6) which received CM from the same cell number by tail vein injection on the 28th day after exposure to silica suspension. On the 56th day after exposure to silica suspension, we used computed tomography (CT), hematoxylin and eosin (H&E), and Masson's trichrome staining to evaluate the changes in lung tissue. We examined the expression of epithelial-mesenchymal transition (EMT) and Wnt/ß-catenin pathway-related proteins in lung tissue using immunohistochemistry and western blotting. RESULTS: Successful construction of a pulmonary fibrosis model was confirmed by H&E and Masson's trichrome staining on the 28th day after exposure to silica suspension. On the 56th day after exposure, pulmonary CT examination showed a relieving effect of BMSCs on silica-induced pulmonary fibrosis which was confirmed by H&E and Masson's trichrome staining. Treatment of BMSCs increased the expression of epithelial marker proteins including E-cadherin (E-cad) and cytokeratin19 (CK19) and reduced the expression of fibrosis marker proteins including Vimentin (Vim) and α-Smooth actin (α-SMA) after exposure to silica suspension. Furthermore, we found that Wnt/ß-catenin signaling pathway is abnormally activated in silica-induced pulmonary fibrosis, and exogenous transplantation of BMSCs may attenuate their expression. CONCLUSIONS: BMSC transplantation inhibits the EMT to alleviate silica-induced pulmonary fibrosis in rats and the anti-fibrotic effect potentially by attenuating Wnt/ß-catenin signaling. ᅟ: ᅟ.

Relationship between occupational noise exposure and the risk factors of cardiovascular disease in China: A meta-analysis.

BACKGROUND: At present, occupational noise exposure has become one of the risk factors of occupational workers and attracted serious concerned of most of occupational disease researchers. To assess associations of occupational noise exposure and cardiovascular disease by meta-analysis. METHODS AND ANALYSIS: Results from primary studies about occupational noise and cardiovascular disease (2000-2017) were retrieved from literatures, which were conducted in China only. Both random and fixed effect model were used to calculate pooled odds ratio (OR) and their corresponding 95% confidence interval (CI). Review Manager and Stata software were used to perform data analysis. This study followed the Preferred Reporting Items for Systematic Reviews and Meta-Analysis statements. RESULTS: After applying stringent inclusion and exclusion criteria, 4771 exposures and 3068 controls from 11 primary studies were used to analyze the relationship between occupational noise exposure and cardiovascular disease. The risk of developing high blood pressure for workers exposed to noise is 2.55 times higher than the controls (I = 52%, 95% CI: 1.94-3.36), and electrocardiograph (ECG) abnormality is 2.27 times higher than the control groups (I = 22%, 95% CI: 1.96-2.62). The bias analysis suggested that there is publication bias, but it didn't affect the conclusions from trim test. CONCLUSION: The impact of high-intensity noise exposure on the worker's cardiovascular system is much greater than that of the unexposed control group, and the effect on hypertension of the exposed group is greater than that of the ECG.

Transplantation of adipose-derived mesenchymal stem cells attenuates pulmonary fibrosis of silicosis via anti-inflammatory and anti-apoptosis effects in rats.

BACKGROUND: Silicosis has been topping the list of high-incidence occupational diseases in developing countries and cannot be completely cured. Recent advances in stem cell research have made possible the treatment of various diseases including lung fibrosis. The application of stem cell therapy in occupational diseases, in particular the use of adipose-derived mesenchymal stem cells (AD-MSCs) in treatment of silicosis, has not yet been reported. The aim of the study is to explore the intervening effect of silica-induced lung fibrosis in rats. METHODS: In this study, we investigated the anti-pulmonary fibrosis effects of the transplantation of AD-MSCs in rats in which lung fibrosis was induced by oral tracheal intubation with silica suspension. Twenty rats were divided into four groups: control group (n = 5), exposure group (n = 5), vehicle group (n = 5) and treatment group (n = 5). AD-MSCs were given to rats after exposure to silica for 24 h. Twenty-eight days after AD-MSC transplantation, we examined the organ coefficient, inflammatory cytokines, apoptosis, pathological and fibrotic changes in lung tissue. RESULTS: Results showed that exposure to silica for 28 days induced an increase of the lung coefficient with significant pulmonary fibrosis. Treatment with AD-MSC transplantation led to a remissive effect on pulmonary fibrosis. We found that after AD-MSC transplantation the inflammatory response decreased and Caspase-3 protein expression significantly decreased with a significant increase of the Bcl-2/Bax ratio. CONCLUSIONS: Anti-inflammatory and anti-apoptosis of AD-MSCs may play important roles in their anti-pulmonary fibrosis effect. Our data suggest that transplantation of AD-MSCs holds promise for potential interference in the formation of silicosis through regulating inflammatory and apoptotic processes.

Immune-related adverse events associated with PD-1 and PD-L1 inhibitors for nonsmall cell lung cancer: Protocol for a systematic review and meta-analysis.

INTRODUCTION: Nonsmall cell lung cancer accounts for approximately 80% of all lung cancers, and approximately 75% of cases are diagnosed in the middle and late stages of disease. Unfortunately, limited treatment does not improve the prognosis of advanced disease. Monoclonal antibodies targeting programmed cell death protein-1 (PD-1) and programmed death-ligand 1 (PD-L1) represent a new treatment paradigm for nonsmall cell lung cancer. Nevertheless, the immune-related adverse events (irAEs) associated with PD-1 and PD-L1 inhibitors are unique, and early recognition and treatment of these events are essential. METHODS AND ANALYSIS: A systematic literature search will be performed using the EMBASE, MEDLINE, and Cochrane databases to identify relevant articles published in any language. Randomized clinical trials, case series, and case reports of PD-1 and PD-L1 inhibitors in the treatment of nonsmall cell lung cancer will be included. All meta-analyses will be performed using RevMan software. The quality of the studies will be evaluated using the guidelines listed in the Cochrane Handbook. If the necessary data are available, then subgroup analyses will be performed for high-, median-, and low-dose cohorts. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses statements will be followed until the findings of the systematic review and meta-analysis are reported. CONCLUSIONS: This will be the first systematic review and meta-analysis to describe previously reported irAEs related to PD-1 and PD-L1 inhibitors in the treatment of nonsmall cell lung cancer.