Airborne particulate matter selectively activates endoplasmic reticulum stress response in the lung and liver tissues. Am J Physiol Cell Physiol 2010 Oct;299(4):C736-49
Date
06/18/2010Pubmed ID
20554909Pubmed Central ID
PMC2957267DOI
10.1152/ajpcell.00529.2009Scopus ID
2-s2.0-77957673495 (requires institutional sign-in at Scopus site) 180 CitationsAbstract
Recent studies have suggested a link between inhaled particulate matter (PM) exposure and increased mortality and morbidity associated with pulmonary and cardiovascular diseases. However, a precise understanding of the biological mechanism underlying PM-associated toxicity and pathogenesis remains elusive. Here, we investigated the impact of PM exposure in intracellular stress signaling pathways with animal models and cultured cells. Inhalation exposure of the mice to environmentally relevant fine particulate matter (aerodynamic diameter < 2.5 μm, PM(2.5)) induces endoplasmic reticulum (ER) stress and activation of unfolded protein response (UPR) in the lung and liver tissues as well as in the mouse macrophage cell line RAW264.7. Ambient PM(2.5) exposure activates double-strand RNA-activated protein kinase-like ER kinase (PERK), leading to phosphorylation of translation initiation factor eIF2α and induction of C/EBP homologous transcription factor CHOP/GADD153. Activation of PERK-mediated UPR pathway relies on the production of reactive oxygen species (ROS) and is critical for PM(2.5)-induced apoptosis. Furthermore, PM(2.5) exposure can activate ER stress sensor IRE1α, but it decreases the activity of IRE1α in splicing the mRNA encoding the UPR trans-activator X-box binding protein 1 (XBP1). Together, our study suggests that PM(2.5) exposure differentially activates the UPR branches, leading to ER stress-induced apoptosis through the PERK-eIF2α-CHOP UPR branch. This work provides novel insights into the cellular and molecular basis by which ambient PM(2.5) exposure elicits its cytotoxic effects that may be related to air pollution-associated pathogenesis.
Author List
Laing S, Wang G, Briazova T, Zhang C, Wang A, Zheng Z, Gow A, Chen AF, Rajagopalan S, Chen LC, Sun Q, Zhang KAuthor
Ze Zheng PhD Assistant Professor in the Medicine department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
Administration, InhalationAir Pollutants
Animals
Apoptosis
Cells, Cultured
DNA-Binding Proteins
Endoplasmic Reticulum
Eukaryotic Initiation Factor-2
Humans
Liver
Lung
Macrophages
Male
Mice
Mice, Inbred C57BL
Particle Size
Particulate Matter
Reactive Oxygen Species
Regulatory Factor X Transcription Factors
Signal Transduction
Transcription Factor CHOP
Transcription Factors
Unfolded Protein Response
X-Box Binding Protein 1
eIF-2 Kinase