Clara Cell Necrosis Research Articles

Elf3 plays a role in regulating bronchiolar epithelial repair kinetics following Clara cell-specific injury

E74-like transcription factor-3 (Elf3), a member of the E26 transformation-specific transcription factor family, is strongly expressed in epithelial-rich tissues, such as small intestine, fetal lung, and various lung cancers. Although previous studies have shown a defect in terminal differentiation of the small intestinal epithelium of Elf3-deficient (Elf3−/−) mice during embryonic development, very little is known about the role Elf3 may play in repair of the airway epithelium after injury. In order to investigate whether Elf3 is involved in regeneration of the bronchiolar epithelium after Clara cell-specific injury, we administered naphthalene to both wild-type (Elf3+/+) and Elf3−/− mice. Histopathological analysis revealed no significant difference in the extent of naphthalene-induced Clara cell necrosis between Elf3+/+ mice and Elf3−/− mice. In the bronchiolar epithelium of Elf3−/− mice, there was a substantial delay in the kinetics of cell proliferation and mitosis along with Clara cell renewal, whereas in the peribronchiolar interstitium, there was a significantly greater level of cell proliferation and mitosis in Elf3−/− mice than in Elf3+/+ mice. Last, the intensity of immunopositive signal for transforming growth factor-β type II receptor, which is a well-known transcriptional target gene of Elf3 and involved in the induction of epithelial cell differentiation, was significantly lower in the bronchiolar epithelium of Elf3−/− mice when compared with Elf3+/+ mice. Taken together, our results suggest that Elf3 plays an important role in the regulation of lung cell proliferation and differentiation during repair of the injured bronchiolar airway epithelium.

Gender differences in pulmonary regenerative response to naphthalene‐induced bronchiolar epithelial cell injury

Accumulating evidence suggests that gender affects the incidence and severity of several pulmonary diseases. Previous studies on mice have shown gender differences in susceptibility to naphthalene-induced lung injury, where Clara cell damage was found to occur earlier and to be more extensive in females than in males. However, very little is known about whether there are any gender differences in subsequent lung repair responses. The aim of this study was to investigate whether gender plays an important role in pulmonary regenerative response to naphthalene-induced Clara cell ablation. Adult male and female mice were injected with a low, medium, or high dose of naphthalene, and lung tissue regeneration was examined by immunohistochemical staining for cell proliferation marker (Ki-67) and mitosis marker (phosphohistone-3). Histopathological analysis showed that naphthalene-induced Clara cell necrosis was more prominent in the lungs of female mice as compared to male mice. Cell proliferation and mitosis in both the distal bronchiolar airway epithelium and peribronchiolar interstitium of female mice was significantly greater than that of male mice after treatment with the low and medium doses. However, after treatment with high dose of naphthalene, lung regeneration was delayed in female mice, while male mice mounted a timely regenerative response. These findings show that there are clear gender differences in naphthalene-induced lung injury and repair.

Development of tolerance to Clara cell necrosis with repeat administration of coumarin.

Coumarin was identified as a mouse-lung carcinogen following oral gavage administration in a chronic bioassay, and was shown to cause the selective necrosis of terminal bronchiolar Clara (non-ciliated bronchiolar epithelial) cells in the mouse lung after acute administration. After oral gavage, a similar effect was not observed in the terminal bronchioles of rats, suggesting that coumarin-mediated Clara cell toxicity is a species-specific effect. Using coumarin dosages (50 and 200 mg/kg) and a dosing schedule modeled after the chronic bioassay, the current study examined the effects of repeated coumarin administration in mouse lung. A single dosage of coumarin (200 mg/kg) caused swelling of Clara cells and necrosis in mouse-lung terminal bronchioles. However, after 5 consecutive oral doses of coumarin (200 mg/kg), the mouse lung became tolerant to coumarin, and although areas of bronchiolar epithelial flattening and hyperplasia were noted, Clara cell necrosis was not observed. After 10 doses of coumarin, mouse lungs appeared nearly normal. Coumarin-mediated Clara cell injury is thought to result from the cytochrome P450-catalyzed formation of coumarin 3,4-epoxide and Western analysis of whole mouse lung microsomal P450 content indicated that, commensurate with Clara cell necrosis, many P450s were decreased. However, P450 levels appeared qualitatively normal in lung microsomes from tolerant mice. Similarly, coumarin epoxidation and 7-hydroxylation rates in whole lung microsomes from tolerant animals were similar to controls. To determine if animals tolerant to coumarin were tolerant to other Clara cell toxicants, a single toxic dose of naphthalene (200 mg/kg) was administered to coumarin-tolerant mice. Coumarin pretreatment reduced naphthalene-mediated Clara cell toxicity, supporting the hypothesis that tolerance may result from general biochemical and molecular changes and not exclusively from alterations in chemical metabolism.

1,1-Dichloroethylene-induced alterations in glutathione and covalent binding in murine lung: morphological, histochemical, and biochemical studies.

Non-ciliated Clara cells of the pulmonary bronchiolar epithelium are preferentially damaged by administration of 1,1-dichloroethylene (1,1-DCE) to mice. In this study, an in vivo system was utilized to investigate the dose-dependent effects of 1,1-DCE (75, 125, 175, and 225 mg/kg) on covalent binding and on reduced glutathione (GSH) in murine lung. Treatment of mice with each dose level of 1,1-DCE elicited significant decreases in GSH content and resulted in covalent binding of [14C]1,1-DCE in a dose-dependent manner. Histochemical staining for GSH in lungs of control mice revealed positive cellular sites in alveolar septa and bronchiolar epithelium, with the highest staining intensities in Clara cells. Staining was reduced after exposure to 75 and 125 mg/kg 1,1-DCE, and at higher doses it was abolished in alveolar septa and retained in bronchiolar epithelium, albeit at considerably reduced intensities. Heterogeneity with respect to staining intensities was consistently observed in the Clara cell population in both control and 1,1-DCE-treated mice. Progressive increases in covalent binding and decreases in GSH content correlated with increasing severities of Clara cell injury. These results show a dose dependence in regard to the magnitudes of [14C]1,1-DCE binding, the alterations in cellular GSH, and the severities of Clara cell necrosis.

Pulmonary toxicity of naphthalene derivatives in the rat.

The intraperitoneal administration of naphthalene (N) or N-derivatives damages the bronchiolar epithelium of mice (Rasmussen et al. 1986). The bronchiolar epithelium of rats is unaffected by naphthalene (O’Brien et al. 1985), but Clara cell necrosis has been described after administration of 1-nitronaphthalene (INN; 100 mg/kg) to Sprague-Dawley rats (Johnson et al. 1984).KeywordsCiliated CellPulmonary ToxicityClara CellArch ToxicolNaphthalene DerivativeThese keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

The effect of 3-methylfuran inhalation exposure on the rat nasal cavity

The acute inhalation toxicity of 3-methylfuran (3MF) was investigated in female CD/CR rats. Animals were killed 1,3,6,9,12,15 and 30 days following a 1-h exposure to 148 μmol 3MF/l. Relatively selective 3MF-induced necrosis of the olfactory epithelium was seen at day 1 post exposure. Subsequent resolution of the acute olfactory necrosis was not complete and resulted in partial occlusive fibrosis of the nasal cavity as at 30 days. Pretreatment of the animals with piperonyl butoxide (PB) did not block 3MF-induced olfactory epithelial necrosis although it prevented Clara cell necrosis when given at a dose of 800 mg/kg intraperitoneally 1 h before exposure to 3MF.

Nonciliated bronchiolar epithelial (Clara) cell necrosis induced by organometallic carbonyl compounds

The administration of transition metal organometallic compounds such as manganese, chromium, and iron carbonyls by the i.p. route, and nickel by inhalation (mice) or intravenously (rats), resulted in selective necrosis of the noneiliated bronehiolar epithelial (Clara) cells and variable pulmonary parenchymal damage in BALB/c mice and Fischer-derived rats within 24 h of administration. The pulmonary toxicity of methylcyclopentadienyl manganese tricarbonyl (MMT), a representative of this group of compounds, was enhanced by pretreatment with piperonyl butoxide (PB), an inhibitor of the mixed-function oxidase system. This finding suggests that Clara cell necrosis can result from direct toxicity and that the specificity of toxic agents for Clara cells may not be related solely to the presence of the mixed-function oxidase system.

Pulmonary toxicity of methylcyclopentadienyl manganese tricarbonyl: Nonciliated bronchiolar epithelial (Clara) cell necrosis and alveolar damage in the mouse, rat, and hamster

Methylcyclopentadienyl manganese tricarbonyl (MMT) was administered ip to young female BALB c mice (120 mg MMT/kg), S A albino rats (5 mg MMT/kg), or LV 6 LAK Syrian hamsters (180 mg MMT/kg). This administration resulted in lung cell damage followed by cellular proliferation, which was quantified by measuring increases in thymidine incorporation into DNA (mouse, rat, and hamster) and by labeling indices (LI) determined from cell kinetic studies (mouse and rat). Thymidine incorporation into pulmonary DNA was significantly elevated within 1 to 2 days following MMT treatment in all three species, with peak incorporation occurring on Day 2 in the rat and hamster, and Day 4 in the mouse. Both bronchiolar and parenchymal LI were elevated at this time. Alveolar damage and nonciliated bronchiolar epithelial (Clara) cell necrosis were evident within 1 day of injection. This finding was followed by type II epithelial and Clara cell proliferation. Ultrastructurally, in the mouse, mitochondrial swelling and degeneration preceded Clara cell necrosis. Bronchiolar damage was most severe in the mouse, whereas parenchymal damage was most severe in the rat. These results suggest that the mouse, rat, and hamster have different susceptibilities to MMT-induced injury.