Doctoral Dissertations

Date of Award

8-1985

Degree Type

Dissertation

Degree Name

Doctor of Philosophy

Major

Biomedical Sciences

Major Professor

Hanspeter Witschi

Committee Members

K. Berry Jacobson, R. Ullrich, Stephen K. Kennel

Abstract

The effect of lung injury, in rats and mice, exposed to an aerosol of beryllium sulfate (BE) for one hour, through nose-only inhalation, was evaluated by the methods of bronchoalveolar lavage (BAL) and lung cell kinetics. The BAL in rats, sacrificed over a 21 day period following exposure, showed lactate dehydrogenase (LDH) and alkaline phosphatase (Alk Pase) activities as the most sensitive indicators of lung damage. LDH activity peaked at day 8 while Alk Pase activity peaked at day 5, both being 30 times greater than comparable control values. Acid phosphatase activity and albumin levels were also increased, but not to the same extent as LDH and Alk Pase. The BAL of mice showed LDH activity as the most sensitive indicator of lung damage, with a maximum response 3 times greater than controls at day 5.

Lung cell kinetics in rats showed a maximum value at day 8. Cell labeling was predominated by interstitial cell replication. Cell turnover in mice, reduced in comparison to rats, peaked at day 5 with interstitial cell replication predominating. A second rise in labeling was seen at 21 days, consisting of endothelial cell turnover. Differences in response of the two species to toxicity was best explained by the differences in initial dose received to the lung. Comparison of lung lavage parameters and cell kinetics showed a high correlation between the two methods.

In another series of experiments, animals were treated with a known immunosuppressant, Cyclosporin A (Cy A), to deplete T cell dependent responses during the development of lung fibrosis. Rats and mice were treated with three agents capable of inducing fibrosis: beryllium sulfate, bleomycin, and butylated hydroxytoluene (BHT). Cy A completely inhibited the fibrogenic effects of BHT in mice, as measured through total lung hydroxyproline content. Bleomycin-induced fibrosis was significantly reduced by Cy A treatment in rats, but showed no effect in mice.

Additionally, the effect of iron salt administration to rats decreased the intravenous LD50 dose, and significantly reduced the inhalation toxicity, of beryllium sulfate. The protective mechanism of iron salt administration, through the induction of ferritin synthesis, is postulated.

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