Male Fischer 344 rats, from 19 to 32 weeks old

SIGNALMENT: (age, breed, sex, species, and scientific name) 

Male Fischer 344 rats, from 19 to 32 weeks old.

HISTORY:
The rats were part of a study to assess toxic effects and carcinogenesis mechanisms of inhaled nickel subsulfide (Ni3S2). The rats were exposed, whole-body, to aerosols of Ni3S2 at 0.6 mg/m3 for 6 hours/day, 5 days/week, and 13 weeks. After the exposure period, one group of animals was held to recover for an additional 13 weeks prior to necropsy.

GROSS PATHOLOGY:
none provided

LABORATORY RESULTS:
none provided.

MORPHOLOGIC DIAGNOSI(E)S AND ETIOLOGY:
• Lung: Moderate to marked chronic alveolitis with alveolar proteinosis, histiocytosis, and type II epithelial hyperplasia.

CONTRIBUTOR:
Anonymous

CONTRIBUTOR'S COMMENTS:
Epidemiologic and experimental evidence suggest that inhaled insoluble nickel compounds are respiratory tract carcinogens, yet the carcinogenic mechanism of these non-mutagenic but genotoxic compounds remains to be elucidated. A hyperplastic response of injured epithelium likely plays a role, and oxidants may be responsible for genetic damage.

In these studies, lesions consisted primarily of alveolar macrophage hyperplasia. Affected foci were not limited to centriacinar zones but appeared scattered throughout the parenchyma. Macrophages within alveoli of the affected foci were sometimes aggregated closely and often were enlarged with abundant finely vacuolated or foamy cytoplasm. Very often, macrophages were either necrotic or degenerated with condensed nuclei and variably sized cytoplasmic vacuoles. Alveolitis was present along with the macrophage hyperplasia and was characterized by small numbers of neutrophils and cell debris mixed with degenerated or necrotic macrophages within alveolar lumina. Wispy, granular, and amorphous eosinophilic material, sometimes with resemblance to degenerated macrophage cytoplasm, accumulated in and sometimes completely filled alveolar lumina in some of these foci.

Type II epithelial cells were hyperplastic and sometimes mildly to moderately vacuolated. The perivascular interstitium, particularly of venules deep in the parenchyma, was variably infiltrated by macrophages, lymphocytes, and fewer numbers of neutrophils. Inflammation of and around the conducting airways was generally not a feature. However, scattered apoptosis and vacuolar degeneration of bronchiolar epithelial cells was noted.

In lungs of animals that were exposed for 13 weeks and then were allowed a 13 week-period of recovery, the inflammatory lesions resolved somewhat but persisted. The character of the inflammation had progressed from that of alveolar macrophage hyperplasia to alveolar histiocytosis. This lesion consisted of chronic, often times granulomatous inflammation where enlarged, foamy, and frequently degenerated macrophages were mixed with varying numbers of neutrophils, granules and wisps of eosinophilic protein, and cholesterol clefts within alveolar lumina. Type II epithelial hyperplasia was often pronounced in these foci, and alveolar septa were sometimes infiltrated by macrophages and neutrophils or widened by small amounts of fibrous tissue.

The lesions were multifocal and occurred both centrally, often juxtaposed to terminal bronchioles, and peripherally in the subpleural parenchyma. These lesions are essentially the same as those described previously in the lungs of rats exposed for 13 weeks to Ni3S2 (Benson et al., 1990), although alveolar proteinosis was not specifically mentioned. Proteinosis has been described in the lungs of rats (Takenaka et al., 1985) and hamsters (Takenaka et al., 1988) exposed to a variety of insoluble nickel compounds. Further, electron micrographic and lipid analyses of rabbit lungs exposed to metallic nickel have demonstrated accumulation of lamellar bodies and phospholipids within alveolar lumina and alveolar macrophage cytoplasm (Johansson, et al., 1983), in consistency with the relative misnomer of proteinosis. Pulmonary alveolar proteinosis may also accompany the relatively common lesion of alveolar histiocytosis. These lesions may reflect some defect in surfactant metabolism by alveolar macrophages.

REFERENCES:
1. Benson, J. M., Burt, D. G., Cheng, Y. S., Eidson, A. F., Gulati, D. K., Hahn, F. F., Hobbs, C. H., Pickrell, J. A. Subchronic inhalation toxicity of nickel subsulfide to rats and mice. Inhal. Toxicol. 2:1-19, 1990.

2. Johansson, A., Camner, P., Jarstrand, C., Wiernik, A. Rabbit lungs after long-term exposure to low nickel dust concentration. II. Effects on morphology and function. Environ. Res. 30:142-151, 1983.

3. Takenaka, S., Hochrainer, D., Oldiges, H. Alveolar proteinosis induced in rats by long-term inhalation of nickel oxide. In: Progress in Nickel Toxicology. Proceedings of the Third International Conference on Nickel Metabolism and Toxicology. Brown, S. S. and Sunderman, Jr., F. W., eds. Blackwell Scientific Publications Inc.; Palo Alto, CA; pp. 89-92; 1985.

4. Takenaka, S., Muhle, H., Bellmann, B., Creutzenberg, O., Mohr, U. Morphological effect of nickel powders on the lung of Syrian golden hamsters. J. Aerosol. Sci. 19(7):1149-1152, 1988.

 

r084a.jpg

4x, H&E. Low magnification photomicrograph of lung from a control rat exposed to filtered air for 13 weeks.


r084b.jpg

4x, H&E. . Low magnification photomicrograph of lung from a rat exposed to Ni3S2 for 13 weeks. Note filling of alveolar airspaces with proteinaceous material, cell debris, and inflammatory cells.


 
r084c.jpg

10x, H&E. Lung from rat exposed to Ni3S2 for 13 weeks. Alveolar macrophages, many of which are degenerated or necrotic, comprise most of the inflammatory cells within alveolar air spaces. Much of the proteinaceous material in alveolar air spaces is remnants of macrophage cytoplasm. Type II epithelial hyperplasia is evident in this focus. 


 
r084d.jpg

20x, H&E. Lung from rat exposed to Ni3S2 for 13 weeks. Alveolar macrophages are enlarged with finely vacuolated cytoplasm. Exudates containing neutrophils are evident in some inflammatory foci. Airway epithelium is unaffected. 
 

r084e.jpg

10x, H&E. Lung from rat exposed to Ni3S2 for 13 weeks then allowed to recover for an additional 13 weeks. Lesions persisted with recovery and organized into granulomatous foci containing cholesterol clefts, macrophages, proteinaceous material, and occasional neutrophils (alveolar histiocytosis).


 
r084f.jpg

20x, H&E. Lung from rat exposed to Ni3S2 for 13 weeks then allowed to recover for an additional 13 weeks. Type II epithelial hyperplasia is evident in this focus of alveolar histiocytosis.


 

 

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