Single-cell RNA-seq analysis reveals lung epithelial cell-specific contributions of Tet1 to allergic inflammation

Background: Tet1 protects against house dust mite (HDM)-induced lung inflammation in mice and alters the lung methylome and transcriptome. We explored the role of Tet1 in individual lung epithelial cell types in HDM-induced inflammation. Methods: A model of HDM-induced lung inflammation was established in Tet1 knockout and littermate wildtype mice. EpCAM+ lung epithelial cells were isolated. Libraries were generated using the 10X Chromium workflow and sequenced. ScRNA-seq analysis was performed using Cell Ranger, scAlign, and Seurat. Cell types were labeled using known markers. Enriched pathways were identified using Ingenuity Pathway Analysis. Transcription factor (TF) activity was analyzed by DoRothEA. Single-cell trajectory analysis was performed with Monocle to explore Alveolar type 2 (AT2) cell differentiation. Results: AT2 cells were the most abundant among the eight EpCAM+ lung epithelial cell types. HDM challenge increased the percentage of alveolar progenitor cells (AP), broncho alveolar stem cells (BAS), and goblet cells, and decreased the percentage of AT2 and ciliated cells. Bulk and cell-type-specific analysis identified genes subject to Tet1 regulation and linked to augmented lung inflammation, including alarms, detoxification enzymes and oxidative stress response genes, and gene in tissue repair. The transcriptomic regulation was accompanied by alterations in TF activities. Trajectory analysis supports that HDM may enhance the differentiation of AP and BAS cells into AT2 cells, independent of Tet1. Conclusions: Collectively, lung epithelial cells had common and unique transcriptomic signatures of allergic lung inflammation. Tet1 deletion altered transcriptomic networks in various lung epithelial cells, with an overall effect of promoting allergen-induced lung inflammation.

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Regulated in Development and DNA Damage Response 1 Knockdown Alleviates Lipopolysaccharide-Induced Acute Lung Injury

Journal of Biomaterials and Tissue Engineering ◽

10.1166/jbt.2021.2691 ◽

2021 ◽

Vol 11 (7) ◽

pp. 1333-1338

Author(s):

Han Han ◽

Zhenxi Yu ◽

Mei Feng

Keyword(s):

Acute Lung Injury ◽

Epithelial Cell ◽

Epithelial Cells ◽

Lung Injury ◽

Cell Activity ◽

Lung Epithelial Cells ◽

Lung Epithelial Cell ◽

Inflammatory Factors ◽

Lung Epithelial ◽

Damage Response

Regulated in Development and DNA Damage Response 1 (REDD1) knockdown can reduce the endoplasmic reticulum stress response in liver injury. However, its role on lipopolysaccharide (LPS)-induced acute lung injury (ALI) has not been explored. This study aimed to evaluate the effect of REDD1 on lung epithelial cells induced by LPS. Rt-qPCR and Western blot were used to detect REDD1 expression in 16HBE cells induced by LPS. The interfering REDD1 plasmid was constructed, and CCK8 was used to detect the effect of interference with REDD1 on LPS-induced lung epithelial cell activity. The expression of inflammatory factors was detected by ELISA and the apoptotic level was detected by TUNEL staining. String database was used to predict the combination of REDD1 and EP300 in lung epithelial cells, which was verified by CoIP experiment. An overexpressed plasmid of EP300 was constructed to detect the effects of EP300 on inflammatory factors and apoptosis in REDD1 lung epithelial cells. LPS-induced increased REDD1 expression in lung epithelial cells. Interference with REDD1 inhibits LPS-induced lung epithelial cell activity injury and inflammatory factor expression and inhibits LPS-induced lung epithelial cell apoptosis. After interference with REDD1, the expression of EP300 in LPS-induced lung epithelial cells was inhibited, and the overexpression of EP300 was reversed to promote the production of inflammatory factors and apoptosis. In conclusion, these results demonstrate that REDD1 knockdown alleviates LPS-induced acute lung injury.

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TNF Family Cytokines Induce Distinct Cell Death Modalities in the A549 Human Lung Epithelial Cell Line when Administered in Combination with Ricin Toxin

Toxins ◽

10.3390/toxins11080450 ◽

2019 ◽

Vol 11 (8) ◽

pp. 450 ◽

Cited By ~ 5

Author(s):

Hodges ◽

Kempen ◽

McCaig ◽

Parker ◽

Mantis ◽

...

Keyword(s):

Cell Death ◽

Epithelial Cell ◽

Epithelial Cells ◽

Human Lung ◽

Lung Epithelial Cells ◽

Lung Epithelial Cell ◽

Distinct Cell ◽

Tnf Α ◽

Lung Epithelial ◽

Human Lung Epithelial Cells

Ricin is a member of the ribosome-inactivating protein (RIP) family of toxins and is classified as a biothreat agent by the Centers for Disease Control and Prevention (CDC). Inhalation, the most potent route of toxicity, triggers an acute respiratory distress-like syndrome that coincides with near complete destruction of the lung epithelium. We previously demonstrated that the TNF-related apoptosis-inducing ligand (TRAIL; CD253) sensitizes human lung epithelial cells to ricin-induced death. Here, we report that ricin/TRAIL-mediated cell death occurs via apoptosis and involves caspases -3, -7, -8, and -9, but not caspase-6. In addition, we show that two other TNF family members, TNF-α and Fas ligand (FasL), also sensitize human lung epithelial cells to ricin-induced death. While ricin/TNF-α- and ricin/FasL-mediated killing of A549 cells was inhibited by the pan-caspase inhibitor, zVAD-fmk, evidence suggests that these pathways were not caspase-dependent apoptosis. We also ruled out necroptosis and pyroptosis. Rather, the combination of ricin plus TNF-α or FasL induced cathepsin-dependent cell death, as evidenced by the use of several pharmacologic inhibitors. We postulate that the effects of zVAD-fmk were due to the molecule’s known off-target effects on cathepsin activity. This work demonstrates that ricin-induced lung epithelial cell killing occurs by distinct cell death pathways dependent on the presence of different sensitizing cytokines, TRAIL, TNF-α, or FasL.

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Lung epithelial cell-derived extracellular vesicles activate macrophage-mediated inflammatory responses via ROCK1 pathway

Cell Death and Disease ◽

10.1038/cddis.2015.282 ◽

2015 ◽

Vol 6 (12) ◽

pp. e2016-e2016 ◽

Cited By ~ 49

Author(s):

H-G Moon ◽

Y Cao ◽

J Yang ◽

J H Lee ◽

H S Choi ◽

...

Keyword(s):

Epithelial Cell ◽

Epithelial Cells ◽

Extracellular Vesicles ◽

Caspase 3 ◽

Inflammatory Responses ◽

Lung Epithelial Cells ◽

Lung Epithelial Cell ◽

Apoptotic Bodies ◽

Protein Markers ◽

Lung Epithelial

Abstract Despite decades of research, the pathogenesis of acute respiratory distress syndrome (ARDS) remains poorly understood, thus impeding the development of effective treatment. Diffuse alveolar damage (DAD) and lung epithelial cell death are prominent features of ARDS. Lung epithelial cells are the first line of defense after inhaled stimuli, such as in the case of hyperoxia. We hypothesized that lung epithelial cells release ‘messenger’ or signaling molecules to adjacent or distant macrophages, thereby initiating or propagating inflammatory responses after noxious insult. We found that, after hyperoxia, a large amount of extracellular vesicles (EVs) were generated and released into bronchoalveolar lavage fluid (BALF). These hyperoxia-induced EVs were mainly derived from live lung epithelial cells as the result of hyperoxia-associated endoplasmic reticulum (ER) stress. These EVs were remarkably different from epithelial ‘apoptotic bodies’, as reflected by the significantly smaller size and differentially expressed protein markers. These EVs fall mainly in the size range of the exosomes and smaller microvesicles (MVs) (50–120 nm). The commonly featured protein markers of apoptotic bodies were not found in these EVs. Treating alveolar macrophages with hyperoxia-induced, epithelial cell-derived EVs led to an increased secretion of pro-inflammatory cytokines and macrophage inflammatory protein 2 (MIP-2). Robustly increased macrophage and neutrophil influx was found in the lung tissue of the mice intranasally treated with hyperoxia-induced EVs. It was determined that EV-encapsulated caspase-3 was largely responsible for the alveolar macrophage activation via the ROCK1 pathway. Caspase-3-deficient EVs induced less cytokine/MIP-2 release, reduced cell counts in BALF, less neutrophil infiltration and less inflammation in lung parenchyma, both in vitro and in vivo. Furthermore, the serum circulating EVs were increased and mainly derived from lung epithelial cells after hyperoxia exposure. These circulating EVs also activated systemic macrophages other than the alveolar ones. Collectively, the results show that hyperoxia-induced, lung epithelial cell-derived and caspase-3 enriched EVs activate macrophages and mediate the inflammatory lung responses involved in lung injury.

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The fibrinolytic system and the regulation of lung epithelial cell proteolysis, signaling, and cellular viability

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.90349.2008 ◽

2008 ◽

Vol 295 (6) ◽

pp. L967-L975 ◽

Cited By ~ 46

Author(s):

Sreerama Shetty ◽

Joseph Padijnayayveetil ◽

Torry Tucker ◽

Dorota Stankowska ◽

Steven Idell

Keyword(s):

Epithelial Cell ◽

Epithelial Cells ◽

Plasminogen Activator ◽

Mrna Stability ◽

Fibrinolytic System ◽

Lung Epithelial Cells ◽

Lung Epithelial Cell ◽

Plasminogen Activator Inhibitor 1 ◽

Lung Epithelial ◽

Pai 1

The urokinase-type plasminogen activator (uPA), its receptor (uPAR), and plasminogen activator inhibitor-1 (PAI-1) are key components of the fibrinolytic system and are expressed by lung epithelial cells. uPA, uPAR, and PAI-1 have been strongly implicated in the pathogenesis of acute lung injury (ALI) and pulmonary fibrosis. Recently, it has become clear that regulation of uPA, uPAR, and PAI-1 occurs at the posttranscriptional level of mRNA stability in lung epithelial cells. uPA further mediates its own expression in these cells as well as that of uPAR and PAI-1 through induction of changes in mRNA stability. In addition, uPA-mediated signaling controls the expression of the tumor suppressor protein p53 in lung epithelial cells at the posttranslational level. p53 has recently been shown to be a trans-acting uPA, uPAR, and PAI-1 mRNA-binding protein that regulates the stability of these mRNAs. It is now clear that signaling initiated by uPA mediates dose-dependent regulation of lung epithelial cell apoptosis and likewise involves changes in p53, uPA, uPAR, and PAI-1 expression. These findings demonstrate that the uPA-uPAR-PAI-1 system of lung epithelial cells mediates a broad repertoire of responses that encompass but extend well beyond traditional fibrinolysis, involve newly recognized interactions with p53 that influence the viability of the lung epithelium, and are thereby implicated in the pathogenesis of ALI and its repair.

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SARS-CoV-2 ORF8 Forms Intracellular Aggregates and Inhibits IFNγ-Induced Antiviral Gene Expression in Human Lung Epithelial Cells

Frontiers in Immunology ◽

10.3389/fimmu.2021.679482 ◽

2021 ◽

Vol 12 ◽

Author(s):

Hua Geng ◽

Saravanan Subramanian ◽

Longtao Wu ◽

Heng-Fu Bu ◽

Xiao Wang ◽

...

Keyword(s):

Cell Proliferation ◽

Epithelial Cell ◽

Epithelial Cells ◽

Viral Infection ◽

Human Lung ◽

Lung Epithelial Cells ◽

Lung Epithelial Cell ◽

Accessory Protein ◽

Epithelial Cell Proliferation ◽

Lung Epithelial

Infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes COVID-19, a disease that involves significant lung tissue damage. How SARS-CoV-2 infection leads to lung injury remains elusive. The open reading frame 8 (ORF8) protein of SARS-CoV-2 (ORF8SARS-CoV-2) is a unique accessory protein, yet little is known about its cellular function. We examined the cellular distribution of ORF8SARS-CoV-2 and its role in the regulation of human lung epithelial cell proliferation and antiviral immunity. Using live imaging and immunofluorescent staining analyses, we found that ectopically expressed ORF8SARS-CoV-2 forms aggregates in the cytosol and nuclear compartments of lung epithelial cells. Using in silico bioinformatic analysis, we found that ORF8SARS-CoV-2 possesses an intrinsic aggregation characteristic at its N-terminal residues 1-18. Cell culture did not reveal any effects of ORF8SARS-CoV-2 expression on lung epithelial cell proliferation and cell cycle progression, suggesting that ORF8SARS-CoV-2 aggregates do not affect these cellular processes. Interestingly, ectopic expression of ORF8SARS-CoV-2 in lung epithelial cells suppressed basal expression of several antiviral molecules, including DHX58, ZBP1, MX1, and MX2. In addition, expression of ORF8SARS-CoV-2 attenuated the induction of antiviral molecules by IFNγ but not by IFNβ in lung epithelial cells. Taken together, ORF8SARS-CoV-2 is a unique viral accessory protein that forms aggregates when expressing in lung epithelial cells. It potently inhibits the expression of lung cellular anti-viral proteins at baseline and in response to IFNγ in lung epithelial cells, which may facilitate SARS-CoV-2 escape from the host antiviral innate immune response during early viral infection. In addition, it seems that formation of ORF8SARS-CoV-2 aggregate is independent from the viral infection. Thus, it would be interesting to examine whether any COVID-19 patients exhibit persistent ORF8 SARS-CoV-2 expression after recovering from SARS-CoV-2 infection. If so, the pathogenic effect of prolonged ORF8SARS-CoV-2 expression and its association with post-COVID symptoms warrant investigation in the future.

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SARS-CoV-2 activates lung epithelia cell proinflammatory signaling and leads to immune dysregulation in COVID-19 patients by single-cell sequencing

10.1101/2020.05.08.20096024 ◽

2020 ◽

Cited By ~ 1

Author(s):

Huarong Chen ◽

Weixin Liu ◽

Dabin Liu ◽

Liuyang Zhao ◽

Jun Yu

Keyword(s):

Immune Response ◽

Epithelial Cells ◽

Nk Cells ◽

Single Cell ◽

Immune Cells ◽

Cell Types ◽

Lung Epithelial Cells ◽

Healthy Controls ◽

Inflammatory Signaling ◽

Lung Epithelial

Objective: The outbreak of Coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 infection has become a global health emergency. We aim to decipher SARS-CoV-2 infected cell types, the consequent host immune response and their interplay in the lung of COVID-19 patients. Design: We analyzed single-cell RNA sequencing (scRNA-seq) data of lung samples from 17 subjects (6 severe COVID-19 patients, 3 mild patients who recovered and 8 healthy controls). The expression of SARS-CoV-2 receptors (ACE2 and TMPRSS2) was examined among different cell types in the lung. The immune cells infiltration patterns, their gene expression profiles, and the interplay of immune cells and SARS-CoV-2 target cells were further investigated. Results: Compared to healthy controls, the overall ACE2 (receptor of SARS-CoV-2) expression was significantly higher in lung epithelial cells of COVID-19 patients, in particular in ciliated cell, club cell and basal cell. Comparative transcriptome analysis of these lung epithelial cells of COVID-19 patients and healthy controls identified that SARS-CoV-2 infection activated pro-inflammatory signaling including interferon pathway and cytokine signaling. Moreover, we identified dysregulation of immune response in patients with COVID-19. In severe COVID-19 patients, significantly higher neutrophil, but lower T and NK cells in lung were observed along with markedly increased cytokines (CCL2, CCL3, CCL4, CCL7, CCL3L1 and CCL4L2) compared with healthy controls as well as mild patients who recovered. The cytotoxic phenotypes were shown in lung T and NK cells of severe patients as evidenced by enhanced IFNγ, Granulysin, Granzyme B and Perforin expression. Moreover, SARS-CoV-2 infection altered the community interplay of lung epithelial cells and immune cells: the interaction between epithelial cells with macrophage, T and NK cell was stronger, but their interaction with neutrophils was lost in COVID-19 patients compared to healthy controls. Conclusions: SARS-CoV-2 infection activates pro-inflammatory signaling in lung epithelial cells expressing ACE2 and causes dysregulation of immune response to release more pro-inflammatory cytokines. Moreover, SARS-CoV-2 infection breaks the interplay of lung epithelial cells and immune cells.

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Single-cell analysis of human lung epithelia reveals concomitant expression of the SARS-CoV-2 receptor ACE2 with multiple virus receptors and scavengers in alveolar type II cells

10.1101/2020.04.16.045617 ◽

2020 ◽

Author(s):

Guangchun Han ◽

Ansam Sinjab ◽

Warapen Treekitkarnmongkol ◽

Patrick Brennan ◽

Kieko Hara ◽

...

Keyword(s):

Epithelial Cells ◽

Single Cell ◽

Expression Patterns ◽

Severe Pneumonia ◽

Lung Epithelial Cells ◽

Chronic Obstructive ◽

Alveolar Type ◽

Type I ◽

Type Ii ◽

Lung Epithelial

ABSTRACTThe novel coronavirus SARS-CoV-2 was identified as the causative agent of the ongoing pandemic COVID 19. COVID-19-associated deaths are mainly attributed to severe pneumonia and respiratory failure. Recent work demonstrated that SARS-CoV-2 binds to angiotensin converting enzyme 2 (ACE2) in the lung. To better understand ACE2 abundance and expression patterns in the lung we interrogated our in-house single-cell RNA-sequencing dataset containing 70,085 EPCAM+ lung epithelial cells from paired normal and lung adenocarcinoma tissues. Transcriptomic analysis revealed a diverse repertoire of airway lineages that included alveolar type I and II, bronchioalveolar, club/secretory, quiescent and proliferating basal, ciliated and malignant cells as well as rare populations such as ionocytes. While the fraction of lung epithelial cells expressing ACE2 was low (1.7% overall), alveolar type II (AT2, 2.2% ACE2+) cells exhibited highest levels of ACE2 expression among all cell subsets. Further analysis of the AT2 compartment (n = 27,235 cells) revealed a number of genes co-expressed with ACE2 that are important for lung pathobiology including those associated with chronic obstructive pulmonary disease (COPD; HHIP), pneumonia and infection (FGG and C4BPA) as well as malarial/bacterial (CD36) and viral (DMBT1) scavenging which, for the most part, were increased in smoker versus light or non-smoker cells. Notably, DMBT1 was highly expressed in AT2 cells relative to other lung epithelial subsets and its expression positively correlated with ACE2. We describe a population of ACE2-positive AT2 cells that co-express pathogen (including viral) receptors (e.g. DMBT1) with crucial roles in host defense thus comprising plausible phenotypic targets for treatment of COVID-19.

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Single-Cell Transcriptomics Identifies Dysregulated Metabolic Programs of Aging Alveolar Progenitor Cells in Lung Fibrosis

10.1101/2020.07.30.227892 ◽

2020 ◽

Author(s):

Jiurong Liang ◽

Guanling Huang ◽

Xue Liu ◽

Forough Taghavifar ◽

Ningshan Liu ◽

...

Keyword(s):

Lipid Metabolism ◽

Epithelial Cells ◽

Lung Injury ◽

Single Cell ◽

Cell Types ◽

Alveolar Epithelial Cells ◽

Lung Epithelial Cells ◽

Alveolar Epithelial ◽

Metabolic Defects ◽

Lung Epithelial

ABSTRACTAging is a critical risk factor in progressive lung fibrotic diseases such as idiopathic pulmonary fibrosis (IPF). Loss of integrity of type 2 alveolar epithelial cells (AEC2s) is the main causal event in the pathogenesis of IPF. To systematically examine the genomic program changes of AEC2s with aging and lung injury, we performed unbiased single cell RNA-seq analyses of lung epithelial cells from either uninjured or bleomycin-injured young and old mice. Major lung epithelial cell types were readily identified with canonical cell markers in our dataset. Heterogenecity of AEC2s was apparent, and AEC2s were then classified into three subsets according to their gene signatures. Genes related to lipid metabolism and glycolysis were significantly altered within these three clusters of AEC2s, and also affected by aging and lung injury. Importantly, IPF AEC2s showed similar genomic programming and metabolic changes as that of AEC2s from bleomycin injured old mouse lungs relative to controls. Furthermore, perturbation of both lipid metabolism and glycolysis significantly changed progenitor renewal capacity in 3-Demensional organoid culture of AEC2s. Taken togather, this work identified metabolic defects of AEC2s in aging and during lung injury. Strategies to rectify these altered programs would promote AEC2 renewal which in turn improves lung repair.One sentence summaryMetabolic defects of alveolar progenitors in aging and during lung injury impair their renewal.

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miR-185 mediates lung epithelial cell death after oxidative stress

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00392.2015 ◽

2016 ◽

Vol 310 (7) ◽

pp. L700-L710 ◽

Cited By ~ 22

Author(s):

Duo Zhang ◽

Heedoo Lee ◽

Yong Cao ◽

Charles S. Dela Cruz ◽

Yang Jin

Keyword(s):

Cell Death ◽

Epithelial Cell ◽

Epithelial Cells ◽

Lung Epithelial Cells ◽

Lung Epithelial Cell ◽

Time Dependent ◽

Dependent Manner ◽

Lung Epithelial ◽

Class Iia Hdacs ◽

Epithelial Cell Death

Lung epithelial cell death is a prominent feature involved in the development of acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). Hyperoxia-induced ALI is an established animal model mimicking human ARDS. Small noncoding RNAs such as microRNAs (miRNAs) have potent physiological and pathological functions involving multiple disease processes. Emerging interests focus on the potential of miRNAs to serve as novel therapeutic targets and diagnostic biomarkers. We found that hyperoxia highly induces miR-185 and its precursor in human lung epithelial cells in a time-dependent manner, and this observation is confirmed using mouse primary lung epithelial cells. The hyperoxia-induced miR-185 is mediated by reactive oxygen species. Furthermore, histone deacetylase 4 (HDAC4) locates in the promoter region of miR-185. We found that hyperoxia suppresses HDAC4 specifically in a time-dependent manner and subsequently affects histone deacetylation, resulting in an elevated miR-185 transcription. Using MC1586, an inhibitor of class IIa HDACs, we showed that inhibition of class IIa HDACs upregulates the expression of miR-185, mimicking the effects of hyperoxia. Functionally, miR-185 promotes hyperoxia-induced lung epithelial cell death through inducing DNA damage. We confirmed functional roles of miR-185 using both the loss- and gain-of-function approaches. Moreover, multiple 14-3-3δ pathway proteins are highly attenuated by miR-185 in the presence of hyperoxia. Taken together, hyperoxia-induced miR-185 in lung epithelial cells contributes to oxidative stress-associated epithelial cell death through enhanced DNA damage and modulation of 14-3-3δ pathways.

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Carbon nanoparticle-induced lung epithelial cell proliferation is mediated by receptor-dependent Akt activation

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00323.2007 ◽

2008 ◽

Vol 294 (2) ◽

pp. L358-L367 ◽

Cited By ~ 50

Author(s):

Klaus Unfried ◽

Ulrich Sydlik ◽

Katrin Bierhals ◽

Alexander Weissenberg ◽

Josef Abel

Keyword(s):

Cell Proliferation ◽

Epithelial Cells ◽

Carbon Nanoparticles ◽

Growth Factor Receptor ◽

Lung Epithelial Cells ◽

Alveolar Type ◽

Specific Cell ◽

Akt Inhibitor ◽

Signaling Mechanism ◽

Lung Epithelial

Treatment of lung epithelial cells with different kinds of nano-sized particles leads to cell proliferation. Because bigger particles fail to induce this reaction, it is suggested that the special surface properties, due to the extremely small size of these kinds of materials, is the common principle responsible for this specific cell reaction. Here the activation of the protein kinase B (Akt) signaling cascade by carbon nanoparticles was investigated with regard to its relevance for proliferation. Kinetics and dose-response experiments demonstrated that Akt is specifically activated by nanoparticulate carbon particles in rat alveolar type II epithelial cells as well as in human bronchial epithelial cells. This pathway appeared to be dependent on epidermal growth factor receptor and β1-integrins. The activation of Akt by these receptors is known to be a feature of adhesion-dependent signaling. However, intracellular proteins described in this context (focal adhesion kinase pp125FAK and integrin-linked kinase) were not activated, indicating a specific signaling mechanism. Inhibitor studies demonstrate that nanoparticle-induced proliferation is mediated by phosphoinositide 3-kinases and Akt. Moreover, overexpression of mutant Akt, as well as pretreatment with an Akt inhibitor, reduced nanoparticle-specific ERK1/2 phosphorylation, which is decisive for nanoparticle-induced proliferation. With this report, we describe the activation of a pathway by carbon nanoparticles that was so far known to be triggered by ligand receptor binding or on cell adhesion to extracellular matrix proteins.

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