scholarly journals Diesel exhaust particulates induce neutrophilic lung inflammation by modulating endoplasmic reticulum stress-mediated CXCL1/KC expression in alveolar macrophages

2020 ◽  
Author(s):  
Dong Im Kim ◽  
Mi-Kyung Song ◽  
Kyuhong Lee
Keyword(s):  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Alveolar Macrophages ◽  
Diesel Exhaust ◽  
Lung Inflammation ◽  
Inflammatory Responses ◽  
Cell Damage ◽  
Interferon Γ ◽  
Mouse Lung ◽  
Lung Weight

Abstract Background Exposure to particular matter (PM)2.5, including diesel exhaust particulates (DEP), has adverse effects on the respiratory system. Endoplasmic reticulum (ER) abnormalities contribute to respiratory disease pathogenesis such as lung inflammation. However, there is little published research on the relationship between DEP exposure and ER stress in the respiratory immune system and especially the alveolar macrophages (AM). Here, we examined ER stress and inflammatory responses in a DEP-induced murine lung inflammation model and in DEP-stimulated AM.Results DEP treatment increased relative lung weight and the number of total cells, neutrophils, and lymphocytes in mouse BALF. Histological examinations also showed that DEP exposure induced neutrophilic lung inflammation and increased the number of DEP-pigmented AM. Western blot analysis showed that BiP and CHOP were relatively upregulated in DEP-induced mouse lung tissues. DEP caused cell damage, increased intracellular reactive oxygen species (ROS), and upregulated the genes associated with inflammation (tumor necrosis factor-α, interleukin [IL]-1β, IL-6, interferon-γ, and toll-like receptor 4) and with ER stress (bound immunoglobulin protein [BiP], CCAAT/enhancer binding protein-homologous protein [CHOP], sXBP-1, and activating transcription factor 4) in AM. Furthermore, DEP stimulation upregulated the gene encoding the chemokine CXCL1/KC in AM.Conclusions DEP may contribute to neutrophilic lung inflammation pathogenesis by modulating ER stress-mediated CXCL1/KC expression in alveolar macrophages.

scholarly journals Diesel Exhaust Particulates Induce Neutrophilic Lung Inflammation by Modulating Endoplasmic Reticulum Stress-Mediated CXCL1/KC Expression in Alveolar Macrophages

Molecules ◽  
2020 ◽  
Vol 25 (24) ◽  
pp. 6046 ◽  
Author(s):  
Dong Im Kim ◽  
Mi-Kyung Song ◽  
Hye-In Kim ◽  
Kang Min Han ◽  
Kyuhong Lee
Keyword(s):  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Alveolar Macrophages ◽  
Diesel Exhaust ◽  
Lung Inflammation ◽  
Binding Protein ◽  
In Vitro Study ◽  
Vitro Study

Diesel exhaust particulates (DEP) have adverse effects on the respiratory system. Endoplasmic reticulum (ER) abnormalities contribute to lung inflammation. However, the relationship between DEP exposure and ER stress in the respiratory immune system and especially the alveolar macrophages (AM) is poorly understood. Here, we examined ER stress and inflammatory responses using both in vivo and in vitro study. For in vivo study, mice were intratracheally instilled with 25, 50, and 100 μg DEP and in vitro AM were stimulated with DEP at 1, 2, and 3 mg/mL. DEP increased lung weight and the number of inflammatory cells, especially neutrophils, and inflammatory cytokines in bronchoalveolar lavage fluid of mice. DEP also increased the number of DEP-pigmented AM and ER stress markers including bound immunoglobulin protein (BiP) and CCAAT/enhancer binding protein-homologous protein (CHOP) were upregulated in the lungs of DEP-treated mice. In an in vitro study, DEP caused cell damage, increased intracellular reactive oxygen species, and upregulated inflammatory genes and ER stress-related BiP, CHOP, splicing X-box binding protein 1, and activating transcription factor 4 expressions in AM. Furthermore, DEP released the C-X-C Motif Chemokine Ligand 1 (CXCL1/KC) in AM. In conclusion, DEP may contribute to neutrophilic lung inflammation pathogenesis by modulating ER stress-mediated CXCL1/KC expression in AM.

Inhibition of Autophagy Potentiated Hippocampal Cell Death Induced by Endoplasmic Reticulum Stress and its Activation by Trehalose Failed to be Neuroprotective

2019 ◽  
Vol 16 (1) ◽  
pp. 3-11
Author(s):  
Luisa Halbe ◽  
Abdelhaq Rami
Keyword(s):  
Endoplasmic Reticulum ◽  
Cell Death ◽  
Er Stress ◽  
Cell Damage ◽  
Protective Mechanism ◽  
Unfolded Proteins ◽  
Neuronal Viability ◽  
Hippocampal Cell ◽  
Trigger Cell Death ◽  
Autophagy Inhibition

Introduction: Endoplasmic reticulum (ER) stress induced the mobilization of two protein breakdown routes, the proteasomal- and autophagy-associated degradation. During ERassociated degradation, unfolded ER proteins are translocated to the cytosol where they are cleaved by the proteasome. When the accumulation of misfolded or unfolded proteins excels the ER capacity, autophagy can be activated in order to undertake the degradative machinery and to attenuate the ER stress. Autophagy is a mechanism by which macromolecules and defective organelles are included in autophagosomes and delivered to lysosomes for degradation and recycling of bioenergetics substrate. Materials and Methods: Autophagy upon ER stress serves initially as a protective mechanism, however when the stress is more pronounced the autophagic response will trigger cell death. Because autophagy could function as a double edged sword in cell viability, we examined the effects autophagy modulation on ER stress-induced cell death in HT22 murine hippocampal neuronal cells. We investigated the effects of both autophagy-inhibition by 3-methyladenine (3-MA) and autophagy-activation by trehalose on ER-stress induced damage in hippocampal HT22 neurons. We evaluated the expression of ER stress- and autophagy-sensors as well as the neuronal viability. Results and Conclusion: Based on our findings, we conclude that under ER-stress conditions, inhibition of autophagy exacerbates cell damage and induction of autophagy by trehalose failed to be neuroprotective.

scholarly journals Coptisine Attenuates Diabetes—Associated Endothelial Dysfunction through Inhibition of Endoplasmic Reticulum Stress and Oxidative Stress

Molecules ◽  
2021 ◽  
Vol 26 (14) ◽  
pp. 4210
Author(s):  
Yan Zhou ◽  
Chunxiu Zhou ◽  
Xutao Zhang ◽  
Chi Teng Vong ◽  
Yitao Wang ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Risk Factors ◽  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Vascular Function ◽  
Inflammatory Responses ◽  
Therapeutic Potential ◽  
Ex Vivo ◽  
Diabetic Mice ◽  
And Oxidative Stress

Coptisine is the major bioactive protoberberine alkaloid found in Rhizoma Coptidis. Coptisine reduces inflammatory responses and improves glucose tolerance; nevertheless, whether coptisine has vasoprotective effect in diabetes is not fully characterized. Conduit arteries including aortas and carotid arteries were obtained from male C57BL/6J mice for ex vivo treatment with risk factors (high glucose or tunicamycin) and coptisine. Some arterial rings were obtained from diabetic mice, which were induced by high-fat diet (45% kcal% fat) feeding for 6 weeks combined with a low-dose intraperitoneal injection of streptozotocin (120 mg/kg). Functional studies showed that coptisine protected endothelium-dependent relaxation in aortas against risk factors and from diabetic mice. Coptisine increased phosphorylations of AMPK and eNOS and downregulated the endoplasmic reticulum (ER) stress markers as determined by Western blotting. Coptisine elevates NO bioavailability and decreases reactive oxygen species level. The results indicate that coptisine improves vascular function in diabetes through suppression of ER stress and oxidative stress, implying the therapeutic potential of coptisine to treat diabetic vasculopathy.

EPA and DHA confer protection against DON-induced endoplasmic reticulum stress and iron imbalance in IPEC-1 cells

2021 ◽  
pp. 1-29
Author(s):  
Jia Lin ◽  
Feifei Huang ◽  
Tianzeng Liang ◽  
Qin Qin ◽  
Qiao Xu ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Rna Sequencing ◽  
Cell Injury ◽  
Cell Damage ◽  
Binding Protein ◽  
Sequencing Analysis ◽  
Epa And Dha ◽  
Expression Of Genes ◽  
Transferrin Receptor 1

Abstract This study assessed the molecular mechanism of eicosapentaenoic acid (EPA) or docosahexaenoic acid (DHA) protection against IPEC-1 cell damage induced by deoxynivalenol (DON). The cells were divided into six groups, including the CON group, the EPA group, the DHA group, the DON group, the EPA+DON group, and the DHA+DON group. RNA sequencing was used to investigate the potential mechanism, and qRT-PCR was employed to verify the expression of selected genes. Changes in ultrastructure were used to estimate pathological changes and endoplasmic reticulum (ER) injury in IPEC-1 cells. Transferrin receptor 1 (TFR1) was tested by ELISA. Fe2+ and malondialdehyde (MDA) contents were estimated by spectrophotometry, and reactive oxygen species (ROS) was assayed by fluorospectrophotometry. RNA sequencing analysis showed that EPA and DHA had a significant effect on the expression of genes involved in ER stress and iron balance during DON-induced cell injury. The results showed that DON increased ER damage, the content of MDA and ROS, the ratio of X-box binding protein 1s (XBP-1s)/X-box binding protein 1u (XBP-1u), the concentration of Fe2+, and the activity of TFR1. However, the results also showed that EPA and DHA decreased the ratio of XBP-1s/XBP-1u to relieve DON-induced ER damage of IPEC-1 cells. Moreover, EPA and DHA (especially DHA) reversed the factors related to iron balance. It can be concluded that EPA and DHA reversed IPEC-1 cell damage induced by DON. DHA has the potential to protect IPEC-1 cells from DON-induced iron imbalance by inhibiting ER stress.

Enteroids Derived From Inflammatory Bowel Disease Patients Display Dysregulated Endoplasmic Reticulum Stress Pathways, Leading to Differential Inflammatory Responses and Dendritic Cell Maturation

2019 ◽  
Vol 14 (7) ◽  
pp. 948-961 ◽  
Author(s):  
William D Rees ◽  
Martin Stahl ◽  
Kevan Jacobson ◽  
Brian Bressler ◽  
Laura M Sly ◽  
...  
Keyword(s):  
Inflammatory Bowel Disease ◽  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Bowel Disease ◽  
Inflammatory Responses ◽  
Human Colon ◽  
Intestinal Epithelial ◽  
Stress Changes ◽  
Inflammatory Bowel ◽  
Stress Pathway

Abstract Background and Aims Endoplasmic reticulum [ER] stress in intestinal epithelial cells [IECs] contributes to the pathogenesis of inflammatory bowel disease [IBD]. We hypothesized that ER stress changes innate signalling in human IECs, augmenting toll-like receptor [TLR] responses and inducing pro-inflammatory changes in underlying dendritic cells [DCs]. Methods Caco-2 cells and primary human colon-derived enteroid monolayers were exposed to ATP [control stressor] or thapsigargin [Tg] [ER stress inducer], and were stimulated with the TLR5 agonist flagellin. Cytokine release was measured by an enzyme immunoassay. ER stress markers CHOP, GRP78 and XBP1s/u were measured via quantitative PCR and Western blot. Monocyte-derived DCs [moDCs] were cultured with the IEC supernatants and their activation state was measured. Responses from enteroids derived from IBD patients and healthy control participants were compared. Results ER stress enhanced flagellin-induced IL-8 release from Caco-2 cells and enteroids. Moreover, conditioned media activated DCs to become pro-inflammatory, with increased expression of CD80, CD86, MHCII, IL-6, IL-15 and IL-12p70 and decreased expression of CD103 and IL-10. Flagellin-induced IL-8 production correlated with DC activation, suggesting a common stress pathway. Moreover, there were distinct differences in cytokine expression and basal ER stress between IBD and healthy subject-derived enteroid monolayers, suggesting a dysregulated ER stress pathway in IBD-derived enteroids. Conclusions Cellular stress enhances TLR5 responses in IECs, leading to increased DC activation, indicating a previously unknown mechanistic link between epithelial ER stress and immune activation in IBD. Furthermore, dysregulated ER stress may be propagated from the intestinal epithelial stem cell niche in IBD patients.

The role of endoplasmic reticulum stress in lead (Pb)-induced mitophagy of HEK293 cells

2020 ◽  
Vol 36 (12) ◽  
pp. 1002-1009
Author(s):  
Ke Gao ◽  
Chengfei Zhang ◽  
Yihong Tian ◽  
Sajid Naeem ◽  
Yingmei Zhang ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Cell Damage ◽  
Hek293 Cells ◽  
Dependent Manner ◽  
Pb Toxicity ◽  
Hsp60 Expression ◽  
Living Organisms ◽  
Almost All

It is well-documented that lead (Pb) toxicity can affect almost all systems in living organisms. It can induce selective autophagy of mitochondria (mitophagy) by triggering reactive oxygen species production. Emerging evidence has suggested that Pb-induced autophagy can also be activated by the endoplasmic reticulum (ER) stress pathway. However, the interplay between ER stress and mitophagy remains to be elucidated. In this study, human embryonic kidney HEK293 cells were employed to investigate the role of ER stress in Pb-induced mitophagy. The results showed that the cell viability was decreased and cell damage was induced after exposure to Pb (0, 0.5, 1, 2, and 4 mM) for 24 h in a dose-dependent manner. Moreover, the expression of LC3-Ⅱ was significantly increased, and the expression of HSP60 was dramatically decreased after exposure to 1 mM and 2 mM Pb, indicating the induction of mitophagy following Pb exposure. Meanwhile, the expressions of activating transcription factor 6, inositol-requiring protein-1α, CCAAT/enhancer binding protein homologous protein, and glucose-regulated protein 78 were dramatically increased after Pb treatment, signifying the initiation of ER stress. Notably, the mitophagic effect was significantly compromised when ER stress was inhibited by 0.5 mM 4-phenylbutyrate, which was evidenced by lesser decreases in HSP60 expression and level of LC3-Ⅱ, suggesting Pb-induced mitophagy may be activated by the ER stress. Taken together, these findings provide a better understanding of Pb toxicity and suggest that Pb-induced ER stress may play a regulatory role in the upstream of mitophagy.

Tauroursodeoxycholic acid reduces endoplasmic reticulum stress, acinar cell damage, and systemic inflammation in acute pancreatitis

2011 ◽  
Vol 301 (5) ◽  
pp. G773-G782 ◽  
Author(s):  
Ersin Seyhun ◽  
Antje Malo ◽  
Claus Schäfer ◽  
Christopher A. Moskaluk ◽  
Ralf-Thorsten Hoffmann ◽  
...  
Keyword(s):  
Acute Pancreatitis ◽  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Stress Responses ◽  
Cell Damage ◽  
Binding Protein ◽  
Edema Formation ◽  
Tauroursodeoxycholic Acid ◽  
Caspase 12

In acute pancreatitis, endoplasmic reticulum (ER) stress prompts an accumulation of malfolded proteins inside the ER, initiating the unfolded protein response (UPR). Because the ER chaperone tauroursodeoxycholic acid (TUDCA) is known to inhibit the UPR in vitro, this study examined the in vivo effects of TUDCA in an acute experimental pancreatitis model. Acute pancreatitis was induced in Wistar rats using caerulein, with or without prior TUDCA treatment. UPR components were analyzed, including chaperone binding protein (BiP), phosphorylated protein kinase-like ER kinase (pPERK), X-box binding protein (XBP)-1, phosphorylated c-Jun NH2-terminal kinase (pJNK), CCAAT/enhancer binding protein homologues protein, and caspase 12 and 3 activation. In addition, pancreatitis biomarkers were measured, such as serum amylase, trypsin activation, edema formation, histology, and the inflammatory reaction in pancreatic and lung tissue. TUDCA treatment reduced intracellular trypsin activation, edema formation, and cell damage, while leaving amylase levels unaltered. The activation of myeloperoxidase was clearly reduced in pancreas and lung. Furthermore, TUDCA prevented caerulein-induced BiP upregulation, reduced XBP-1 splicing, and caspase 12 and 3 activation. It accelerated the downregulation of pJNK. In controls without pancreatitis, TUDCA showed cytoprotective effects including pPERK signaling and activation of downstream targets. We concluded that ER stress responses activated in acute pancreatitis are grossly attenuated by TUDCA. The chaperone reduced the UPR and inhibited ER stress-associated proapoptotic pathways. TUDCA has a cytoprotective potential in the exocrine pancreas. These data hint at new perspectives for an employment of chemical chaperones, such as TUDCA, in prevention of acute pancreatitis.

scholarly journals Ginsenoside Rg1 Regulates SIRT1 to Ameliorate Sepsis-Induced Lung Inflammation and Injury via Inhibiting Endoplasmic Reticulum Stress and Inflammation

2019 ◽  
Vol 2019 ◽  
pp. 1-10 ◽  
Author(s):  
Qian-Lu Wang ◽  
Lei Yang ◽  
Yue Peng ◽  
Min Gao ◽  
Ming-Shi Yang ◽  
...  
Keyword(s):  
Lung Injury ◽  
Er Stress ◽  
Inflammatory Cytokines ◽  
Lung Inflammation ◽  
A549 Cells ◽  
Mouse Lung ◽  
Ginsenoside Rg1 ◽  
Marker Proteins

Objectives. To investigate the protective effect of ginsenoside Rg1 on relieving sepsis-induced lung inflammation and injury in vivo and in vitro. Methods. Cultured human pulmonary epithelial cell line A549 was challenged with LPS to induce cell injury, and CLP mouse model was generated to mimic clinical condition of systemic sepsis. Rg1 was applied to cells or animals at indicated dosage. Apoptosis of cultured cells was quantified by flow cytometry, along with ELISA for inflammatory cytokines in supernatant. For septic mice, lung tissue pathology was examined, plus ELISA assay for serum cytokines. Western blotting was used to examine the activation of inflammatory pathways and ER stress marker proteins in both cells and mouse lung tissues. Reactive oxygen species (ROS) level was quantified by DCFDA kit. Results. Ginsenoside Rg1 treatment remarkably suppressed apoptosis rate of LPS-induced A549 cells, relieved mouse lung tissue damage, and elevated survival rate. Rg1 treatment also rescued cells from LPS-induced intracellular ROS. In both A549 cells and mouse lung tissues, further study showed that Rg1 perfusion significantly suppressed the secretion of inflammatory cytokines including tumor necrosis factor- (TNF-) alpha and interleukin- (IL-) 6 and relieved cells from ER stress as supported by decreased expression of marker proteins via upregulating sirtuin 1 (SIRT1). Conclusion. Our results showed that ginsenoside Rg1 treatment effectively relieved sepsis-induced lung injury in vitro and in vivo, mainly via upregulating SIRT1 to relieve ER stress and inflammation. These findings provide new insights for unrevealing potential candidate for severe sepsis accompanied with lung injury.

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