title: Type I interferon and pattern recognition receptor signaling following particulate matter inhalation.
abstract: BACKGROUND
  Welding, a process that generates an aerosol containing gases and metal-rich particulates, induces adverse physiological effects including inflammation, immunosuppression and cardiovascular dysfunction. This study utilized microarray technology and subsequent pathway analysis as an exploratory search for markers/mechanisms of in vivo systemic effects following inhalation. Mice were exposed by inhalation to gas metal arc - stainless steel (GMA-SS) welding fume at 40 mg/m3 for 3 hr/d for 10 d and sacrificed 4 hr, 14 d and 28 d post-exposure. Whole blood cells, aorta and lung were harvested for global gene expression analysis with subsequent Ingenuity Pathway Analysis and confirmatory qRT-PCR. Serum was collected for protein profiling.
  
  
  RESULTS
  The novel finding was a dominant type I interferon signaling network with the transcription factor Irf7 as a central component maintained through 28 d. Remarkably, these effects showed consistency across all tissues indicating a systemic type I interferon response that was complemented by changes in serum proteins (decreased MMP-9, CRP and increased VCAM1, oncostatin M, IP-10). In addition, pulmonary expression of interferon α and β and Irf7 specific pattern recognition receptors (PRR) and signaling molecules (Ddx58, Ifih1, Dhx58, ISGF3) were induced, an effect that showed specificity when compared to other inflammatory exposures. Also, a canonical pathway indicated a coordinated response of multiple PRR and associated signaling molecules (Tlr7, Tlr2, Clec7a, Nlrp3, Myd88) to inhalation of GMA-SS.
  
  
  CONCLUSIONS
  This methodological approach has the potential to identify consistent, prominent and/or novel pathways and provides insight into mechanisms that contribute to pulmonary and systemic effects following toxicant exposure.
authors: Pathology and Physiology Research Branch, Health Effects Laboratory Division, National Institute for Occupational Safety and Health, Morgantown, WV, USA. efi4@cdc.gov
authors: Aaron
authors: A
authors: Erdely
authors: James M
authors: JM
authors: Antonini
authors: Rebecca
authors: R
authors: Salmen-Muniz
authors: Angie
authors: A
authors: Liston
authors: Tracy
authors: T
authors: Hulderman
authors: Petia P
authors: PP
authors: Simeonova
authors: Michael L
authors: ML
authors: Kashon
authors: Shengqiao
authors: S
authors: Li
authors: Ja K
authors: JK
authors: Gu
authors: Samuel
authors: S
authors: Stone
authors: Bean T
authors: BT
authors: Chen
authors: David G
authors: DG
authors: Frazer
authors: Patti C
authors: PC
authors: Zeidler-Erdely
mesh_terms: D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000378:metabolism; D001773:Blood Cells / Q000187:drug effects / Q000378:metabolism; D001798:Blood Proteins / Q000235:genetics / Q000378:metabolism; D016000:Cluster Analysis; D003627:Data Interpretation, Statistical; D019570:Inhalation Exposure / Q000009:adverse effects* / Q000032:analysis; D050839:Interferon Regulatory Factor-7 / Q000235:genetics; D007370:Interferon Type I / Q000097:blood* / Q000235:genetics; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D052638:Particulate Matter / Q000633:toxicity*; D060888:Real-Time Polymerase Chain Reaction; D051192:Receptors, Pattern Recognition / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects*; D018675:Toxicity Tests / Q000295:instrumentation / Q000379:methods; D059467:Transcriptome; D014896:Welding
chemical_list: D001798:Blood Proteins; D050839:Interferon Regulatory Factor-7; D007370:Interferon Type I; C494235:Irf7 protein, mouse; D052638:Particulate Matter; D051192:Receptors, Pattern Recognition