title: Novel Roles for Notch3 and Notch4 Receptors in Gene Expression and Susceptibility to Ozone-Induced Lung Inflammation in Mice.
abstract: BACKGROUND
  Ozone is a highly toxic air pollutant and global health concern. Mechanisms of genetic susceptibility to ozone-induced lung inflammation are not completely understood. We hypothesized that Notch3 and Notch4 are important determinants of susceptibility to ozone-induced lung inflammation.
  
  
  METHODS
  Wild-type (WT), Notch3 (Notch3-/-), and Notch4 (Notch4-/-) knockout mice were exposed to ozone (0.3 ppm) or filtered air for 6-72 hr.
  
  
  RESULTS
  Relative to air-exposed controls, ozone increased bronchoalveolar lavage fluid (BALF) protein, a marker of lung permeability, in all genotypes, but significantly greater concentrations were found in Notch4-/- compared with WT and Notch3-/- mice. Significantly greater mean numbers of BALF neutrophils were found in Notch3-/- and Notch4-/- mice compared with WT mice after ozone exposure. Expression of whole lung Tnf was significantly increased after ozone in Notch3-/- and Notch4-/- mice, and was significantly greater in Notch3-/- compared with WT mice. Statistical analyses of the transcriptome identified differentially expressed gene networks between WT and knockout mice basally and after ozone, and included Trim30, a member of the inflammasome pathway, and Traf6, an inflammatory signaling member.
  
  
  CONCLUSIONS
  These novel findings are consistent with Notch3 and Notch4 as susceptibility genes for ozone-induced lung injury, and suggest that Notch receptors protect against innate immune inflammation.
authors: Laboratory of Respiratory Biology, National Institute of Environmental Health Sciences (NIEHS), National Institutes of Health (NIH), Department of Health and Human Resources (DHHS), Research Triangle Park, North Carolina, USA.
authors: Kirsten C
authors: KC
authors: Verhein
authors: Zachary
authors: Z
authors: McCaw
authors: Wesley
authors: W
authors: Gladwell
authors: Shweta
authors: S
authors: Trivedi
authors: Pierre R
authors: PR
authors: Bushel
authors: Steven R
authors: SR
authors: Kleeberger
mesh_terms: D000393:Air Pollutants / Q000633:toxicity*; D000818:Animals; D001992:Bronchoalveolar Lavage Fluid; D004198:Disease Susceptibility / Q000276:immunology; D015870:Gene Expression / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010126:Ozone / Q000633:toxicity*; D011014:Pneumonia / Q000139:chemically induced*; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D000071656:Receptor, Notch3; D000074562:Receptor, Notch4; D051880:Receptors, Notch / Q000235:genetics* / Q000378:metabolism
chemical_list: D000393:Air Pollutants; C499373:Notch3 protein, mouse; D011518:Proto-Oncogene Proteins; D000071656:Receptor, Notch3; D000074562:Receptor, Notch4; D051880:Receptors, Notch; C073572:Notch4 protein, mouse; D010126:Ozone