title: Endotoxin or cytokines attenuate ozone-induced DNA synthesis in rat nasal transitional epithelium.
abstract: 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.
authors.affiliation: Inhalation Toxicology Research Institute, Albuquerque, New Mexico 87185.
authors.forename: J A
authors.initials: JA
authors.lastname: Hotchkiss
authors.forename: J R
authors.initials: JR
authors.lastname: Harkema
mesh_terms: D000818:Animals; D004247:DNA / Q000096:biosynthesis*; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D004731:Endotoxins / Q000627:therapeutic use*; D004848:Epithelium / Q000187:drug effects / Q000378:metabolism; D005260:Female; D007375:Interleukin-1 / Q000627:therapeutic use*; D009296:Nasal Cavity / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009297:Nasal Mucosa / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D009336:Necrosis; D010126:Ozone / Q000633:toxicity*; D051381:Rats; D011916:Rats, Inbred F344; D012220:Rhinitis / Q000139:chemically induced / Q000517:prevention & control; D014409:Tumor Necrosis Factor-alpha / Q000627:therapeutic use*
chemical_list: D004731:Endotoxins; D007375:Interleukin-1; D014409:Tumor Necrosis Factor-alpha; D010126:Ozone; D004247:DNA