OxyFile #140

Endotoxin or cytokines attenuate ozone-induced DNA synthesis in 
rat nasal transitional epithelium. 

Author:  Hotchkiss JA; Harkema JR 

Address: Inhalation Toxicology Research Institute, 
         Albuquerque, New Mexico 87185. 

Source:  Toxicol Appl Pharmacol, 1992 Jun, 114:2, 182-7 


Pretreatment of rats with endotoxin (E), a potent inducer of tumor 
necrosis factor alpha (TNF), and interleukin 1 beta (IL 1), or a 
combination of TNF and IL1, has been shown to increase levels of 
lung antioxidant enzymes and protect against pulmonary toxicity 
associated with hyperoxia. Inhalation of ozone (O3) induces cell 
injury, followed by increased DNA synthesis, cell proliferation, 
and secretory cell metaplasia in rat nasal transitional epithelium 
(NTE). This study was designed to test the effects of E, TNF, and 
IL1 pretreatment on acute O3-induced NTE cell injury as measured 
by changes in NTE cell DNA synthesis. Rats were exposed to either 
0.8 ppm O3 or air for 6 hr in whole-body inhalation chambers. 
Immediately before exposure, rats in each group were injected 
intraperitoneally (ip) with either saline alone or saline 
containing E (1 microgram/g body wt), TNF (10 micrograms), IL1 (10 
micrograms), or both TNF and IL1 (TNF/IL1; 10 micrograms each). 
Eighteen hours postexposure, rats were injected ip with 
bromodeoxyuridine (BrdU; 50 micrograms/g body wt) to label cells 
undergoing DNA synthesis and were euthanized 2 hr later. NTE was 
processed for light microscopy and immunochemically stained to 
identify cells that had incorporated BrdU into nuclear DNA. The 
number of BrdU-labeled NTE nuclei per millimeter of basal lamina 
was quantitated. There were no significant differences in the 
number of BrdU-labeled NTE nuclei in air-exposed rats that were 
injected with E, TNF, IL1, or TNF/IL1 compared with those in 
saline-injected, air-exposed controls. Rats that were injected 
with saline and exposed to O3 had approximately 10 times the 
number of BrdU-labeled NTE nuclei than saline-injected, air-
exposed control rats. O3 exposure also induced a significant 
increase in labeled nuclei in rats that were pretreated with TNF 
alone. In contrast, pretreatment with E, IL1, or TNF/IL1 
attenuated the O3-induced increase in NTE DNA synthesis. These 
results indicate that both E and the cytokines TNF and IL1 have 
physiologic effects that can attenuate O3-induced injury or modify 
the response to NTE cells to O3 exposure.