title: Airborne particulate matter selectively activates endoplasmic reticulum stress response in the lung and liver tissues.
abstract: 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.
authors.affiliation: Center for Molecular Medicine and Genetics, The Wayne State University School of Medicine, Detroit, MI 48201, USA.
authors.forename: Suzette
authors.initials: S
authors.lastname: Laing
authors.forename: Guohui
authors.initials: G
authors.lastname: Wang
authors.forename: Tamara
authors.initials: T
authors.lastname: Briazova
authors.forename: Chunbin
authors.initials: C
authors.lastname: Zhang
authors.forename: Aixia
authors.initials: A
authors.lastname: Wang
authors.forename: Ze
authors.initials: Z
authors.lastname: Zheng
authors.forename: Alexander
authors.initials: A
authors.lastname: Gow
authors.forename: Alex F
authors.initials: AF
authors.lastname: Chen
authors.forename: Sanjay
authors.initials: S
authors.lastname: Rajagopalan
authors.forename: Lung Chi
authors.initials: LC
authors.lastname: Chen
authors.forename: Qinghua
authors.initials: Q
authors.lastname: Sun
authors.forename: Kezhong
authors.initials: K
authors.lastname: Zhang
mesh_terms: D000280:Administration, Inhalation; D000393:Air Pollutants / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000502:physiology; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008168:Lung / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010316:Particle Size; D052638:Particulate Matter / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D000071701:Regulatory Factor X Transcription Factors; D015398:Signal Transduction / Q000502:physiology; D051742:Transcription Factor CHOP / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D056811:Unfolded Protein Response / Q000187:drug effects*; D000071717:X-Box Binding Protein 1; D019892:eIF-2 Kinase / Q000378:metabolism
chemical_list: D000393:Air Pollutants; D004268:DNA-Binding Proteins; D015852:Eukaryotic Initiation Factor-2; D052638:Particulate Matter; D017382:Reactive Oxygen Species; D000071701:Regulatory Factor X Transcription Factors; D051742:Transcription Factor CHOP; D014157:Transcription Factors; D000071717:X-Box Binding Protein 1; D019892:eIF-2 Kinase; C497250:Ddit3 protein, mouse; C000605543:XBP1 protein, human; C000605544:Xbp1 protein, mouse