Cellular and molecular characterization of ozone-induced pulmonary inflammation in the Cynomolgus monkey.
We investigated the cellular and molecular effects of ozone exposure in Cynomolgus monkeys. Thirty-six Cynomolgus monkeys were exposed to single or repeat ozone challenge. Pulmonary inflammation was assessed using bronchoalveolar lavage fluid (BAL) and histology. Gene expression profiling in lung and blood was performed. Ozone challenge evoked BAL cellular inflammation and increases in total protein, alkaline phosphatase and cytokines. Lung histology revealed cellular inflammation and epithelial necrosis. Gene expression profiling identified oxidative phosphorylation, immune response and cell adhesion pathways altered in response to ozone, with common and unique profiles in lung and blood. Lipocalin 2, CD177, the FK-506 and S100A8 binding proteins and ST-2 represent novel peripheral biomarkers of ozone toxicity. Repeat ozone challenge evoked reproducible inflammation but attenuated cell damage. These studies provide data on the molecular mechanisms and biomarker identification of ozone-evoked toxicity, and support the use of the Cynomolgus monkey as a model of human ozone challenge.
Hicks
Alexandra
A
RNA Therapeutics, Roche, Nutley, NJ 07110, USA. alexandra.hicks@roche.com
Kourteva
Galina
G
Hilton
Holly
H
Li
Hongli
H
Lin
Tai-An
TA
Liao
Will
W
Li
Ying
Y
Wei
Xin
X
March
Thomas
T
Benson
Janet
J
Renzetti
Louis M
LM
D000469:Alkaline Phosphatase / Q000097:blood; D000818:Animals; D001798:Blood Proteins / Q000378:metabolism; D055745:Bronchioles / Q000473:pathology; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D016207:Cytokines / Q000097:blood; D020869:Gene Expression Profiling; D008252:Macaca fascicularis; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis; D010083:Oxidants, Photochemical / Q000633:toxicity*; D010126:Ozone / Q000633:toxicity*; D011014:Pneumonia / Q000139:chemically induced / Q000235:genetics / Q000473:pathology; D029424:Pulmonary Disease, Chronic Obstructive / Q000139:chemically induced / Q000235:genetics / Q000473:pathology; D020545:Respiratory Mucosa / Q000473:pathology
D001798:Blood Proteins; D016207:Cytokines; D010083:Oxidants, Photochemical; D010126:Ozone; D000469:Alkaline Phosphatase