Polyamines and diamines are required for optimum cellular function including proliferation and differentiation, DNA, RNA and protein synthesis. We have found 25 fold increases of ornithine decarboxylase (ODC) activity in rats after 3-5 days of exposure to .85 atm oxygen; other determinants of polyamine metabolism also increase. Thirty day old rats may tolerate 1.0 atm oxygen exposure better than 60 day old rats because their DNA synthesis occurs earlier. We will test the possibility that decreased DNA synthesis due to hypoxia is secondary to suppression polyamine metabolism; and enzyme involved in spermidine synthesis may be suppressed by oxidation products. Several toxic drugs, including bleomycin and paraquat, may be toxic to the lung in part because they are taken into lung cells by polyamine transport systems or they have other interactions with polyamines. Recently anti-metabolites of polyamine metabolism have been developed which have relatively little toxicity but can suppress DNA synthesis in some tissues. We plan to use oxygen toxicity as a model of acute lung injury (ARDS) and intratracheal bleomycin as a model of interstitial lung disease, and determine the influence of polyamine metabolism upon these models. In addition to metabolic and biochemical determinations we will do autoradiography using 3H thymidine and 3H difluoromethylornithine (DFMO) which is a specific inhibitor of ODC and can be used to localize ODC in cells. We will attempt to suppress DNA synthesis with anti-metabolites such as DFMO to determine the role of polyamines in acute lung injury and repair and in the process of interstitial pneumonitis (pulmonary fibrosis); we hope to be able to suppress interstitial pneumonitis.
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