Pulmonary tissue which has received an acute toxic insult may either repair itself normally or develop a chronic fibrotic lesion characterized by the deposition of excess collagen. Treatment of patients with acute lung damage often involves the use of corticosteroids because of their anti-inflammatory activity and ability to decrease collagen synthesis in some in vitro and in vivo systems. Corticosteroid therapy of acute lung damage is controversial, however, because of reports it may be detrimental in some situations. The effects of corticosteroids in animal models of lung damage, as in humans, has been conflicting. It is not clear whether these differences are related to the species, type of lung damage, or steroid dosage regimen employed. Previous work has demonstrated that corticosteroids will enhance the development of fibrosis in mice with acute alveolar damage induced by butylated hydroxytoluene (BHT). This project will continue to investigate the effects of corticosteroids on collagen synthesis and degradation in this model system. However, BHT only damages lung tissue in mice. Therefore, potential differences in species responsiveness to corticosteroids will be studied using O,S,S-trimethyl phosphorodithioate (OSS), a chemical which produces a lung lesion much like BHT in rats, mice, and hamsters following intraperitoneal administration. Collagen synthesis in OSS- and BHT-damaged lung tissue will be assessed by measuring the conversion of (3H)proline to (3H)hydroxyproline and by the specific digestion of labeled collagen by collagenase. Additional experiments will determine the role of degradation of newly synthesized and established collagen in collagen homeostasis and pulmonary repair processes after the induction of acute damage and corticosteroid therapy. The degradation of newly synthesized collagen will be determined by measuring acid-soluble (3H)hydroxyproline after the administration of (3H)proline in vitro. The degradation of established collagen will be determined by measuring the rate at which (3H)hydroxyproline, deposited following the intratracheal administration of (3H)proline, is lost from lung tissue. The types of collagen synthesized at various times after the induction of lung damage and corticosteroid therapy will be determined by using a high performance liquid chromatographic technique to separate collagen peptides following cyanogen bromide digestion. The data obtained in mice, rats, and hamsters with OSS-induced lung damage will be compared to each other and to mice with BHT-induced lung damage.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Modified Research Career Development Award (K04)
Project #
5K04HL001435-05
Application #
3073777
Study Section
Toxicology Study Section (TOX)
Project Start
1984-09-01
Project End
1989-08-31
Budget Start
1988-09-01
Budget End
1989-08-31
Support Year
5
Fiscal Year
1988
Total Cost
Indirect Cost
Name
University of Texas Austin
Department
Type
Schools of Pharmacy
DUNS #
City
Austin
State
TX
Country
United States
Zip Code
78713
Kehrer, J P; DiGiovanni, J (1990) Comparison of lung injury induced in 4 strains of mice by butylated hydroxytoluene. Toxicol Lett 52:55-61
Park, Y; Bowles, D K; Kehrer, J P (1990) Protection against hypoxic injury in isolated-perfused rat heart by ruthenium red. J Pharmacol Exp Ther 253:628-35
Kehrer, J P (1989) Bleomycin and cyclophosphamide toxicity in mice with damaged lung tissue. Toxicology 57:69-82
Kehrer, J P; Starnes, J W (1989) Models and markers used to study cardiac reperfusion injury. Pharmacol Ther 44:123-45
Murphy, M E; Kehrer, J P (1989) Lipid peroxidation inhibitory factors in liver and muscle of rat, mouse, and chicken. Arch Biochem Biophys 268:585-93
Murphy, M E; Kehrer, J P (1989) Altered contents of tocopherols in chickens with inherited muscular dystrophy. Biochem Med Metab Biol 41:234-45
Murphy, M E; Kehrer, J P (1989) Oxidation state of tissue thiol groups and content of protein carbonyl groups in chickens with inherited muscular dystrophy. Biochem J 260:359-64
Kehrer, J P (1989) Concepts related to the study of reactive oxygen and cardiac reperfusion injury. Free Radic Res Commun 5:305-14
Murphy, M E; Kehrer, J P (1988) Increased oxidation of tocopherols in chickens with inherited muscular dystrophy. Basic Life Sci 49:611-4
Kehrer, J P; Mossman, B T; Sevanian, A et al. (1988) Free radical mechanisms in chemical pathogenesis. Summary of the symposium presented at the 1988 annual meeting of the Society of Toxicology. Toxicol Appl Pharmacol 95:349-62

Showing the most recent 10 out of 24 publications