Toxicological Sciences 60, 338-347 (2001)
Copyright © 2001 by the Society of Toxicology
RESPIRATORY TOXICOLOGY |
Endotoxin Enhancement of Ozone-Induced Mucous Cell Metaplasia Is Neutrophil-Dependent in Rat Nasal Epithelium
Department of Veterinary Pathology, College of Veterinary Medicine, Michigan State University, East Lansing, Michigan 48824
Ozone, the primary oxidant gas in photochemical smog, causes neutrophilic inflammation and mucous cell metaplasia (MCM) in the nasal transitional epithelium (NTE) of rats and monkeys. Bacterial endotoxin is another common airborne agent that induces acute neutrophilic inflammation, but not MCM, in NTE. It does, however, enhance ozone-induced MCM in rat nasal airways (Fanucchi et al., 1998, Toxicol. Appl. Pharmacol. 152, 1–9). In the present study, F344 rats exposed to filtered air or 0.5 ppm ozone (8 h/day for 3 days) were intranasally instilled with sterile saline or 100 µg endotoxin 24 h and 48 h after the third ozone exposure. To determine the role of neutrophilic inflammation in endotoxin-induced potentiation of the MCM caused by ozone, half of the rats were depleted of circulating neutrophils prior to saline or endotoxin instillations. Rats were killed 6 h or 3 days after the last intranasal instillation, and nasal tissues were processed for (1) light microscopy and morphometric analysis to determine the number of infiltrating neutrophils and the volume amount (density) of stored mucosubstances in the NTE, and (2) quantitative RT-PCR analysis of steady-state mucin gene (rMuc-5AC) mRNA levels in the NTE. Endotoxin induced a transient influx of neutrophils in both air- and ozone-exposed rats that was completely blocked by neutrophil depletion. Endotoxin increased rMuc-5AC mRNA levels in the NTE of ozone-exposed rats. Neutrophil depletion, however, had no effect on endotoxin-induced upregulation of mucin gene mRNA levels. Endotoxin enhanced the ozone-induced increase in stored mucosubstances (4-fold increase), but only in neutrophil-sufficient rats. These data indicate that endotoxin enhancement of ozone-induced upregulation of rMuc-5AC mRNA levels is neutrophil-independent, while its effects on intraepithelial production and storage of mucus glycoproteins is dependent on the presence of neutrophils.
Key Words: ozone; endotoxin; mucous cell metaplasia; neutrophils; nasal epithelium.
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