Interstitial pulmonary fibrosis (IPF) may result from a wide range of processes. Some of these processes are of known and some of unknown origin. The formation of reactive oxygen species (ROS) in the lung is known to cause significant, acute lung damage that eventuates into IPF. Thus, it is possible that the free radicals derived from molecular oxygen represent a common etiology for lung fibrosis caused by a diversified group of chemicals including exposure to toxic levels of O2, air pollutants, some anti-neoplastic drugs, herbicides and lung toxins. There is a wide gap in our knowledge regarding the generation of ROS and increased collagen synthesis and deposition. It is known that ROS stimulate the synthesis of prostaglandins and related compounds and it is becoming apparent that the members of the prostanoid family play an important role in the regulation of collagen metabolism. The major goal of the proposed study is to test the hypothesis that the formation of prostaglandins (PGs) and thromboxane A2 (TxA2) constitute a link between ROS and increased collagen synthesis and accumulation following intratracheal administration of a variety of mixtures known to generate ROS in the lung. In this regard, experiments will be carried out to assess the effects of different oxidants on the circulating and lung levels of PGs and TxA2 and total lung collagen content following intratracheal administration. Morphometric and electron microscopic techniques will be employed to evaluate the derangement in lung structure by characterizing the influx of inflammatory cells by type and fibroblasts in lesions, volume of stainable collagen in lesions and volume of reactive lesions per lung. Biochemical tests will be employed to assess collagen and prostaglandin synthesizing and degrading abilities of the lung. If it can be demonstrated that the members of the prostanoid family act as mediators of oxidant-induced increased collagen synthesis and accumulation, then the effectiveness of drugs that inhibit PGs and TxA2 synthesis against lung fibrosis will also be evaluated. The criteria for evaluation of effectiveness for each compound will be at both the morphometric and biochemical levels. We believed that a multidisciplinary approach, as proposed in this project, will provide a better understanding of the pathophysiological mechanisms responsible for the genesis of IPF as well as in controlling the inflammatory sequelae frequently associated with IPF.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL027354-08
Application #
3339131
Study Section
Toxicology Study Section (TOX)
Project Start
1981-07-01
Project End
1989-06-30
Budget Start
1988-07-01
Budget End
1989-06-30
Support Year
8
Fiscal Year
1988
Total Cost
Indirect Cost
Name
University of California Davis
Department
Type
Schools of Veterinary Medicine
DUNS #
094878337
City
Davis
State
CA
Country
United States
Zip Code
95618
Chen, J; Giris, N (1997) Species differences in PAF receptor binding in the lungs between hamster and guinea pig. J Lipid Mediat Cell Signal 16:63-74
Wild, J S; Hyde, D M; Hubbell, H R et al. (1996) Dose-related effects of Ampligen (poly(I).poly(C12U)), a mismatched double-stranded RNA, in a bleomycin-mouse model of pulmonary fibrosis. Exp Lung Res 22:375-91
Giri, S N; Hollinger, M A (1996) Effect of nordihydroguaiaretic acid and ibuprofen on bleomycin and hyperoxia-induced changes in lung superoxide dismutase, prostaglandins and lethality. Arch Toxicol 70:271-6
Braun, R K; Sterner-Kock, A; Kilshaw, P J et al. (1996) Integrin alpha E beta 7 expression on BAL CD4+, CD8+, and gamma delta T-cells in bleomycin-induced lung fibrosis in mouse. Eur Respir J 9:673-9
Giri, S N; Sharma, A K; Hyde, D M et al. (1995) Amelioration of bleomycin-induced lung fibrosis by treatment with the platelet activating factor receptor antagonist WEB 2086 in hamsters. Exp Lung Res 21:287-307
Giri, S N; Hollinger, M A (1995) Effect of cadmium on lung lysosomal enzymes in vitro. Arch Toxicol 69:341-5
Gurujeyalakshmi, G; Giri, S N (1995) Molecular mechanisms of antifibrotic effect of interferon gamma in bleomycin-mouse model of lung fibrosis: downregulation of TGF-beta and procollagen I and III gene expression. Exp Lung Res 21:791-808
Iyer, S N; Wild, J S; Schiedt, M J et al. (1995) Dietary intake of pirfenidone ameliorates bleomycin-induced lung fibrosis in hamsters. J Lab Clin Med 125:779-85
Blaisdell, R J; Giri, S N (1995) Mechanism of antifibrotic effect of taurine and niacin in the multidose bleomycin-hamster model of lung fibrosis: inhibition of lysyl oxidase and collagenase. J Biochem Toxicol 10:203-10
Blaisdell, R J; Schiedt, M J; Giri, S N (1994) Dietary supplementation with taurine and niacin prevents the increase in lung collagen cross-links in the multidose bleomycin hamster model of pulmonary fibrosis. J Biochem Toxicol 9:79-86

Showing the most recent 10 out of 41 publications