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.
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