title: Particulate matter air pollution causes oxidant-mediated increase in gut permeability in mice.
abstract: BACKGROUND
  Exposure to particulate matter (PM) air pollution may be an important environmental factor leading to exacerbations of inflammatory illnesses in the GI tract. PM can gain access to the gastrointestinal (GI) tract via swallowing of air or secretions from the upper airways or mucociliary clearance of inhaled particles.
  
  
  METHODS
  We measured PM-induced cell death and mitochondrial ROS generation in Caco-2 cells stably expressing oxidant sensitive GFP localized to mitochondria in the absence or presence of an antioxidant. C57BL/6 mice were exposed to a very high dose of urban PM from Washington, DC (200 μg/mouse) or saline via gastric gavage and small bowel and colonic tissue were harvested for histologic evaluation, and RNA isolation up to 48 hours. Permeability to 4 kD dextran was measured at 48 hours.
  
  
  RESULTS
  PM induced mitochondrial ROS generation and cell death in Caco-2 cells. PM also caused oxidant-dependent NF-κB activation, disruption of tight junctions and increased permeability of Caco-2 monolayers. Mice exposed to PM had increased intestinal permeability compared with PBS treated mice. In the small bowel, colocalization of the tight junction protein, ZO-1 was lower in the PM treated animals. In the small bowel and colon, PM exposed mice had higher levels of IL-6 mRNA and reduced levels of ZO-1 mRNA. Increased apoptosis was observed in the colon of PM exposed mice.
  
  
  CONCLUSIONS
  Exposure to high doses of urban PM causes oxidant dependent GI epithelial cell death, disruption of tight junction proteins, inflammation and increased permeability in the gut in vitro and in vivo. These PM-induced changes may contribute to exacerbations of inflammatory disorders of the gut.
authors.affiliation: Department of Medicine, Section of Gastroenterology and Nutrition Rush University Medical College, 1725 W Harrison Street, Chicago, IL 60612, USA. Ece_Mutlu@rush.edu
authors.forename: Ece A
authors.initials: EA
authors.lastname: Mutlu
authors.forename: Phillip A
authors.initials: PA
authors.lastname: Engen
authors.forename: Saul
authors.initials: S
authors.lastname: Soberanes
authors.forename: Daniela
authors.initials: D
authors.lastname: Urich
authors.forename: Christopher B
authors.initials: CB
authors.lastname: Forsyth
authors.forename: Recep
authors.initials: R
authors.lastname: Nigdelioglu
authors.forename: Sergio E
authors.initials: SE
authors.lastname: Chiarella
authors.forename: Kathryn A
authors.initials: KA
authors.lastname: Radigan
authors.forename: Angel
authors.initials: A
authors.lastname: Gonzalez
authors.forename: Shriram
authors.initials: S
authors.lastname: Jakate
authors.forename: Ali
authors.initials: A
authors.lastname: Keshavarzian
authors.forename: G R Scott
authors.initials: GR
authors.lastname: Budinger
authors.forename: Gökhan M
authors.initials: GM
authors.lastname: Mutlu
mesh_terms: D000397:Air Pollution; D000818:Animals; D018938:Caco-2 Cells / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D016923:Cell Death / Q000187:drug effects; D002463:Cell Membrane Permeability / Q000187:drug effects*; D004219:District of Columbia; D017097:Electric Impedance; D041981:Gastrointestinal Tract / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008928:Mitochondria / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D062793:Occludin; D016877:Oxidants / Q000494:pharmacology*; D010316:Particle Size; D052638:Particulate Matter / Q000008:administration & dosage / Q000494:pharmacology*; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D019108:Tight Junctions / Q000378:metabolism / Q000648:ultrastructure; D062826:Zonula Occludens-1 Protein
chemical_list: D015850:Interleukin-6; D008565:Membrane Proteins; D016328:NF-kappa B; C568985:OCLN protein, human; D062793:Occludin; C568986:Ocln protein, mouse; D016877:Oxidants; D052638:Particulate Matter; D010750:Phosphoproteins; D017382:Reactive Oxygen Species; C569042:TJP1 protein, human; C569043:Tjp1 protein, mouse; D062826:Zonula Occludens-1 Protein