Relationship of cytochrome P-450 activity to Clara cell cytotoxicity. III. Morphometric comparison of changes in the epithelial populations of terminal bronchioles and lobar bronchi in mice, hamsters, and rats after parenteral administration of naphthalene

Abstract

Background: The purpose of this study was to define, in quantitative terms, epithelial alterations produced by the cytochrome P-450-activated Clara cell cytotoxicant, naphthalene, in lobar bronchi and terminal bronchioles of three species with differing sensitivity: mouse, rat, and hamster.

Experimental design: Adult mice, hamsters, and rats were treated intraperitoneally with a single dose of naphthalene ranging from 0 mg/kg up to the approximate LD50. The animals were killed 24 hours postinjection and the changes in airway epithelium characterized by light microscopic morphometry.

Results: In mouse, bronchiolar epithelial thickness was significantly elevated by low, but not high, doses; ciliated cell number increased and Clara cell number decreased in a dose-dependent fashion. Vacuolated Clara cell number increased in all treated mice. In rat and hamster, bronchiolar epithelial thickness or cell number did not change. In mice, bronchial epithelial thickness was unchanged except at high doses, but both ciliated and Clara cell number was decreased. In bronchi of rats, epithelial thickness and numbers of nonciliated, ciliated, and basal cells were unchanged. In bronchi of hamsters, both ciliated and nonciliated cell number were decreased.

Conclusions: (a) In mice, naphthalene-induced acute bronchiolar toxicity involves not only Clara cells, but also affects the purported nontarget cell type (ciliated cells). (b) In rats and hamsters, bronchiolar epithelium is insensitive to naphthalene injury. (c) In mice, injury to bronchi occurs at higher doses than in bronchioles and involves both ciliated and nonciliated cells. (d) In rats, bronchi are insensitive. (e) In hamsters, bronchi are more sensitive than bronchioles. This study emphasizes the variability of response by species, airway and epithelial cell type to cytochrome P-450-mediated pulmonary toxicants and the need for precise quantitative methods of defining both cytotoxic and metabolic events.