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PM2.5 induces Nrf2-mediated defense mechanisms against oxidative stress by activating PIK3/AKT signaling pathway in human lung alveolar epithelial A549 cells.
Cell Biol Toxicol. 2013 Jun; 29(3):143-57.CB

Abstract

It has been well documented in in vitro studies that ambient airborne particulate matter (PM) with an aerodynamic diameter less than 2.5 μm (PM(2.5)) is capable of inducing oxidative stress, which plays a key role in PM(2.5)-mediated cytotoxicity. Although nuclear factor erythroid-2-related factor 2 (Nrf2) has been shown to regulate the intracellular defense mechanisms against oxidative stress, a potential of the Nrf2-mediated cellular defense against oxidative stress induced by PM(2.5) remains to be determined. This study was aimed to explore the potential signaling pathway of Nrf2-mediated defense mechanisms against PM(2.5)-induced oxidative stress in human type II alveolar epithelial A549 cells. We exposed A549 cells to PM(2.5) particles collected from Beijing at a concentration of 16 μg/cm(2). We observed that PM(2.5) triggered an increase of intracellular reactive oxygen species (ROS) in a time-dependent manner during a period of 2 h exposure. We also found that Nrf2 overexpression suppressed and Nrf2 knockdown increased PM(2.5)-induced ROS generation. Using Western blot and confocal microscopy, we found that PM(2.5) exposure triggered significant translocation of Nrf2 into nucleus, resulting in AKT phosphorylation and significant transcription of ARE-driven phases II enzyme genes, such as NAD(P)H:quinone oxidoreductase (NQO-1), heme oxygenase-1 (HO-1), and glutamate-cysteine ligase catalytic subunit (GCLC) in A549 cells. Evaluation of signaling pathways showed that a phosphatidylinositol 3-kinase (PI3K) inhibitor (LY294002), but not an ERK 1/2 inhibitor (PD98059) or a p38 MAPK (SB203580), significantly down-regulated PM(2.5)-induced Nrf2 nuclear translocation and HO-1 mRNA expression, indicating PI3K/AKT is involved in the signaling pathway leads to the PM(2.5)-induced nuclear translocation of Nrf2 and subsequent Nrf2-mediated HO-1 transcription. Taken together, our results suggest that PM(2.5)-induced ROS may function as signaling molecules to activate Nrf2-mediated defenses, such as HO-1 expression, against oxidative stress induced by PM(2.5) through the PI3K/AKT signaling pathway.

Authors+Show Affiliations

Laboratory of Environment and Health, College of Life Sciences, University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing, 100049, China.No affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

23525690

Citation

Deng, Xiaobei, et al. "PM2.5 Induces Nrf2-mediated Defense Mechanisms Against Oxidative Stress By Activating PIK3/AKT Signaling Pathway in Human Lung Alveolar Epithelial A549 Cells." Cell Biology and Toxicology, vol. 29, no. 3, 2013, pp. 143-57.
Deng X, Rui W, Zhang F, et al. PM2.5 induces Nrf2-mediated defense mechanisms against oxidative stress by activating PIK3/AKT signaling pathway in human lung alveolar epithelial A549 cells. Cell Biol Toxicol. 2013;29(3):143-57.
Deng, X., Rui, W., Zhang, F., & Ding, W. (2013). PM2.5 induces Nrf2-mediated defense mechanisms against oxidative stress by activating PIK3/AKT signaling pathway in human lung alveolar epithelial A549 cells. Cell Biology and Toxicology, 29(3), 143-57. https://doi.org/10.1007/s10565-013-9242-5
Deng X, et al. PM2.5 Induces Nrf2-mediated Defense Mechanisms Against Oxidative Stress By Activating PIK3/AKT Signaling Pathway in Human Lung Alveolar Epithelial A549 Cells. Cell Biol Toxicol. 2013;29(3):143-57. PubMed PMID: 23525690.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - PM2.5 induces Nrf2-mediated defense mechanisms against oxidative stress by activating PIK3/AKT signaling pathway in human lung alveolar epithelial A549 cells. AU - Deng,Xiaobei, AU - Rui,Wei, AU - Zhang,Fang, AU - Ding,Wenjun, Y1 - 2013/03/24/ PY - 2012/11/22/received PY - 2013/02/25/accepted PY - 2013/3/26/entrez PY - 2013/3/26/pubmed PY - 2013/11/19/medline SP - 143 EP - 57 JF - Cell biology and toxicology JO - Cell Biol Toxicol VL - 29 IS - 3 N2 - It has been well documented in in vitro studies that ambient airborne particulate matter (PM) with an aerodynamic diameter less than 2.5 μm (PM(2.5)) is capable of inducing oxidative stress, which plays a key role in PM(2.5)-mediated cytotoxicity. Although nuclear factor erythroid-2-related factor 2 (Nrf2) has been shown to regulate the intracellular defense mechanisms against oxidative stress, a potential of the Nrf2-mediated cellular defense against oxidative stress induced by PM(2.5) remains to be determined. This study was aimed to explore the potential signaling pathway of Nrf2-mediated defense mechanisms against PM(2.5)-induced oxidative stress in human type II alveolar epithelial A549 cells. We exposed A549 cells to PM(2.5) particles collected from Beijing at a concentration of 16 μg/cm(2). We observed that PM(2.5) triggered an increase of intracellular reactive oxygen species (ROS) in a time-dependent manner during a period of 2 h exposure. We also found that Nrf2 overexpression suppressed and Nrf2 knockdown increased PM(2.5)-induced ROS generation. Using Western blot and confocal microscopy, we found that PM(2.5) exposure triggered significant translocation of Nrf2 into nucleus, resulting in AKT phosphorylation and significant transcription of ARE-driven phases II enzyme genes, such as NAD(P)H:quinone oxidoreductase (NQO-1), heme oxygenase-1 (HO-1), and glutamate-cysteine ligase catalytic subunit (GCLC) in A549 cells. Evaluation of signaling pathways showed that a phosphatidylinositol 3-kinase (PI3K) inhibitor (LY294002), but not an ERK 1/2 inhibitor (PD98059) or a p38 MAPK (SB203580), significantly down-regulated PM(2.5)-induced Nrf2 nuclear translocation and HO-1 mRNA expression, indicating PI3K/AKT is involved in the signaling pathway leads to the PM(2.5)-induced nuclear translocation of Nrf2 and subsequent Nrf2-mediated HO-1 transcription. Taken together, our results suggest that PM(2.5)-induced ROS may function as signaling molecules to activate Nrf2-mediated defenses, such as HO-1 expression, against oxidative stress induced by PM(2.5) through the PI3K/AKT signaling pathway. SN - 1573-6822 UR - https://www.unboundmedicine.com/medline/citation/23525690/PM2_5_induces_Nrf2_mediated_defense_mechanisms_against_oxidative_stress_by_activating_PIK3/AKT_signaling_pathway_in_human_lung_alveolar_epithelial_A549_cells_ L2 - https://doi.org/10.1007/s10565-013-9242-5 DB - PRIME DP - Unbound Medicine ER -