Oxidant injury by hyperoxia of rat lung initially results in alveolar epithelium and capillary endothelium injury with influx of inflammatory cells and subsequent progression to fibrosis. Although the critical roles of soluble factors produced by inflammatory cells in the recruitment of fibroblasts in initiating fibrogenesis are at present the focus of extensive investigation, few studies have been directed towards examining the earlier molecular events that occur prior to any observable alterations in lung pathology or physiology. There is even less known on the effects of aging on the ability of cells to respond to oxidative stress. We hypothesize that the genes expressed acutely by lung cells in response to oxidative stress depend on the extent of cellular damage and predict the subsequent progression to lung fibrosis. One or another of these early genetic responses may become defective with age and be associated with the irreversible decline in lung function. Here we propose to study the variety of genetic responses (anti-oxidants, heat shock proteins and DNA damage) to increasing levels of oxidative damage in the whole lung to determine the specificity of the response and whether these responses are age-related. We will localize these genetic responses at the histological level by in situ hybridization since the cellular response in the lung is likely to involve specific sites and cell types. Finally, attempts will be made to relate the production of various mediators involved in lung fibrosis with one of the acute or early cellular responses to stress. We expect that those studies will show that a certain level of damage must be achieved before the mediators of irreversible lung damage will be induced. A comparison of the responses in various aged animals will establish whether protective genetic responses are reduced with aging.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Physician Scientist Award (K11)
Project #
5K11AG000516-02
Application #
3084960
Study Section
Biological and Clinical Aging Review Committee (BCA)
Project Start
1991-04-01
Project End
1996-03-31
Budget Start
1992-04-01
Budget End
1993-03-31
Support Year
2
Fiscal Year
1992
Total Cost
Indirect Cost
Name
Johns Hopkins University
Department
Type
Schools of Medicine
DUNS #
045911138
City
Baltimore
State
MD
Country
United States
Zip Code
21218
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Choi, A M; Pignolo, R J; apRhys, C M et al. (1995) Alterations in the molecular response to DNA damage during cellular aging of cultured fibroblasts: reduced AP-1 activation and collagenase gene expression. J Cell Physiol 164:65-73
Choi, A M; Sylvester, S; Otterbein, L et al. (1995) Molecular responses to hyperoxia in vivo: relationship to increased tolerance in aged rats. Am J Respir Cell Mol Biol 13:74-82
Camhi, S L; Lee, P; Choi, A M (1995) The oxidative stress response. New Horiz 3:170-82
Jacoby, D B; Choi, A M (1994) Influenza virus induces expression of antioxidant genes in human epithelial cells. Free Radic Biol Med 16:821-4

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