Numerous cytotoxic drugs have been found to induce lung damage and pulmonary fibrosis. Although the underlying mechanisms are poorly understood, and may differ for each agent, the interaction of two antineoplastic drugs, or one such drug with previously damaged lung tissue, are two of several risk factors for the development of pulmonary fibrosis. The overall goals of this project are to determine the extent of lung damage resulting from the interaction of lung-toxic cytotoxic drugs with each other or with previously damaged lung tissue in mice, and to investigate some possible mechanisms for such interactions. Bleomycin and cyclophosphamide (CP) will be used since they have been used clinically in combination and each has been shown to produce lung damage in humans and animals. Studies will include 2 dose combinations of bleomycin and CP (including 2 doses of the same drug), or one dose in animals with existing lung damage. Preexisting lung damage, similar to that seen in some human lung lesions, will be induced in mice with O,S,S-trimethyl phosphorodithioate (OSS) and butylated hydroxytoluene (BHT). OSS is a systemic lung toxin that we recently showed produces a diffuse alveolar lesion in rats and mice similar to the BHT-induced lesion in mice. Two different """"""""initiating"""""""" lung toxins will be used to investigate whether there are any toxin-specific interactions. Combination treatments may result in decreased, as well as increased, lung damage. Any treatments resulting in altered lung damage will be investigated to provide a better understanding of the mechanisms underlying each potential outcome of pulmonary interactions involving cytotoxic drugs. The extent of lung damage following various combination treatments will be assessed by measuring the total lung content of hydroxproline, an amino acid found primarily in collagen, and by histopathology. The time course of lung cell division, after single drug treatments, will also be used as an indirect measure of lung damage. These data will be considered when designing treatment schedules which involve a second agent since it has been hypothesized that pulmonary fibrosis develops when normal epithelial cell repair is inhibited or as the result of time-dependent additive lung damage. Mechanistic studies will involve correlating the effects of the non-lung-toxic and lung-toxic drug treatments with changes in pulmonary and hepatic mixed-function activities, pulmonary bleomycin hydrolase activity, pulmonary cell repair processes, and changes in the pulmonary glutathione system. Each of these factors has been implicated in modulating the pulmonary toxicity of CP or bleomycin and could be altered by preexisting lung damage or previous cytotoxic drug therapy thereby changing the pulmonary toxicity of subsequently administered doses of the same, or a different drug. Treatment regimens resulting in enhanced lung damage will also be used for studies on changes in collagen synthesis and the degradation of newly synthesized collagen. The results of these studies will reveal any differences in these parameters that are related to the species treated or the damaging agents employed.
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