Novel Roles for Notch3 and Notch4 Receptors in Gene Expression and Susceptibility to Ozone-Induced Lung Inflammation in Mice

• Published in: Environmental health perspectives 2015-08, Vol.123 (8), p.799-799
• Main Authors: Verhein, Kirsten C, McCaw, Zachary, Gladwell, Wesley, Trivedi, Shweta, Bushel, Pierre R, Kleeberger, Steven R
• Format: Article
• Language: English
• Subjects: Air Pollutants - toxicity; Air pollution; Animals; Asthma; Bronchoalveolar Lavage Fluid; Causes of; Cell receptors; Cytokines; Disease Susceptibility - immunology; Environmental aspects; Exposure; Gene expression; Gene Expression - drug effects; Gene Expression Regulation - drug effects; Genes; Genetic aspects; Genotype & phenotype; Genotypes; Global health; Health; Health aspects; Inflammation; Kinases; Laboratories; Lung diseases; Lungs; Male; Males; Mice; Mice, Knockout; Ozone; Ozone - toxicity; Pneumonia - chemically induced; Proteins; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins - metabolism; Receptor, Notch3; Receptor, Notch4; Receptors; Receptors, Notch - genetics; Receptors, Notch - metabolism; Rodents; Statistical analysis; Tumor necrosis factor-TNF; Variance analysis
• ISSN: 0091-6765; 1552-9924
• DOI: 10.1289/ehp.1408852

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. Wild-type (WT), Notch3 (Notch3-/-), and Notch4 (Notch4-/-) knockout mice were exposed to ozone (0.3 ppm) or filtered air for 6-72 hr. 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. 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.