Humans, livestock and rat monocrotaline (MCT) pneumotoxicity is associated with a spectrum of pulmonary vascular lesions reminescent of idiopathic pulmonary hypertension in humans. Studies in our laboratories demonstrates that the polyamines have a central role in the MCT-caused pathogenic vascular structural remodeling. Research proposed herein explores molecular and biochemical mechanisms through which polyamines comprise an obligatory link between the initial hypertensive stimuli and the vascular thickening. To test the hypothesis that polyamines mediate MCT-induced endothelial dysfuntion, (1) autoradiograph and immunocytochemistry will be used to determine if endothelial cells in the lungs of MCT-treated rats exhibit a temporally enhanced ODC activity related to perivascular edema formation; (2) Cultured endothelial cells will be used to determine if MCT- derived pyrroles directly provoke polyamine dependent endothelial injury; and (3) Perfused lungs isolated from MCT-treated rats will be used to determine if MCT-induced depression of endothelial serotonin uptake is polyamine-dependent. To assess mechanisms by which polyamines mediate MCT-induced hypertensive pulmonary vascular remodeling, autoradiograph and immunocytochemistry will be used to determine; (5) if MCT enhances polyamine biosynthetic activity in specific vascular cells that are functionally related to vascular remodeling; and (6) if DNA and protein synthesis are activated in the same cell types in which polyamine biosynthesis is enhanced. (7) In vitro hybridization will be employed to determine ODC and Collagen gene(s) expression and modulation at the individual cell level; (8) cultured cells and isolated pulmonary arteries will be used to determine if enhanced collagen gene expression is regulated by altered ODC gene expression; (9) Molecular mechanisms by which MCT alters ODC gene expression will be explored. Potentially clinically relevant studies will determine (10) if MCT pneumotoxicity can be reversed by polyamine biosynthesis inhibition. Rats exposed to chronic hypoxia (an established pulmonary hypertension model) will be studied to: (11) characterize the time-dependent effects of hypoxic exposure on lung polyamine biosynthesis, (12) determine if polyamine biosynthesis inhibition forestalls hypoxic pneumotoxicity, and (13) immunocytochemically identify lung cell types in which chronic hypoxia enhances ODC content.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Modified Research Career Development Award (K04)
Project #
5K04HL002055-04
Application #
3074255
Study Section
Toxicology Subcommittee 2 (TOX)
Project Start
1988-06-01
Project End
1993-05-31
Budget Start
1991-06-01
Budget End
1992-05-31
Support Year
4
Fiscal Year
1991
Total Cost
Indirect Cost
Name
University of Kentucky
Department
Type
Schools of Medicine
DUNS #
832127323
City
Lexington
State
KY
Country
United States
Zip Code
40506
Hartsfield, C L; Lipke, D; Lai, Y L et al. (1997) Pulmonary mechanical and immunologic dysfunction in a murine model of AIDS. Am J Physiol 272:L699-706
Bummer, P M; Aziz, S; Gillespie, M N (1995) Inhibition of pulmonary surfactant biophysical activity by cationic polyamino acids. Pharm Res 12:1658-63
Bummer, P M; Baughn, J A; Sanders, L P et al. (1994) Surfactant disposition in rats with monocrotaline-induced pneumotoxicity. Toxicology 90:53-62
Bummer, P M; Sanders, L P; Pauly, T H et al. (1994) In vitro inactivation of pulmonary surfactant replacement preparations by serum albumin. Am J Med Sci 307:401-4
Baybutt, R C; Aziz, S M; Fagerland, J A et al. (1994) Monocrotaline alters type II pneumocyte morphology and polyamine regulation. Toxicol Appl Pharmacol 129:188-95
Aziz, S M; Olson, J W; Gillespie, M N (1994) Multiple polyamine transport pathways in cultured pulmonary artery smooth muscle cells: regulation by hypoxia. Am J Respir Cell Mol Biol 10:160-6
Aziz, S M; Lipke, D W; Olson, J W et al. (1994) Role of ATP and sodium in polyamine transport in bovine pulmonary artery smooth cells. Biochem Pharmacol 48:1611-8
Aziz, S M; Sandefer, E P; Pauly, T H et al. (1993) Comparative disposition kinetics of 111In-labeled group B streptococcus and neutrophils during onset of sepsis-induced pulmonary hypertension. Biol Neonate 63:86-95
Aziz, S M; Pauly, T H; Gillespie, M N (1993) Intrinsic microbicidal activity and pulmonary hypertension in isolated newborn piglet lungs. Pediatr Res 34:32-7
Pauly, T H; Aziz, S M; Horstman, S J et al. (1992) Impact of prostaglandin and thromboxane synthesis blockade on disposition of group B streptococcus in lung and liver of intact piglet. Pediatr Res 31:14-7

Showing the most recent 10 out of 20 publications