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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL027309-08
Application #
3339074
Study Section
Pathology A Study Section (PTHA)
Project Start
1981-04-01
Project End
1990-03-31
Budget Start
1988-04-01
Budget End
1990-03-31
Support Year
8
Fiscal Year
1988
Total Cost
Indirect Cost
Name
University of California Los Angeles
Department
Type
Schools of Medicine
DUNS #
119132785
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Elsayed, N M; Ellingson, A S; Tierney, D F et al. (1990) Effects of ozone inhalation on polyamine metabolism and tritiated thymidine incorporation into DNA of rat lungs. Toxicol Appl Pharmacol 102:1-8
Elsayed, N M; Mustafa, M G; Mead, J F (1990) Increased vitamin E content in the lung after ozone exposure: a possible mobilization in response to oxidative stress. Arch Biochem Biophys 282:263-9
Yano, S (1990) Multiple isoelectric variants of copper, zinc-superoxide dismutase from rat liver. Arch Biochem Biophys 279:60-9
Elsayed, N M; Tierney, D F (1989) Hyperoxia and xanthine dehydrogenase/oxidase activities in rat lung and heart. Arch Biochem Biophys 273:281-6
Yano, S; Tierney, D F (1989) Butyrate increases catalase activity and protects rat pulmonary artery smooth muscle cells against hyperoxia. Biochem Biophys Res Commun 164:1143-8
Tierney, D F; Hacker, A D (1989) Polyamines, DNA synthesis, and tolerance to hyperoxia of mice and rats. Am Rev Respir Dis 139:387-92
Elsayed, N M; Tierney, D F; Hacker, A D (1988) Effects of food restriction and hyperoxia on rat survival and lung polyamine metabolism. J Appl Physiol 64:2010-6
Sherman, M P; Evans, M J; Campbell, L A (1988) Prevention of pulmonary alveolar macrophage proliferation in newborn rabbits by hyperoxia. J Pediatr 112:782-6
Evans, M J; Plopper, C G (1988) The role of basal cells in adhesion of columnar epithelium to airway basement membrane. Am Rev Respir Dis 138:481-3
Evans, M J; Sherman, M P; Campbell, L A et al. (1987) Proliferation of pulmonary alveolar macrophages during postnatal development of rabbit lungs. Am Rev Respir Dis 136:384-7

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