Hypertensive pulmonary vascular disease is among the leading causes of cardiovascular morbidity and mortality in patients beyond the fifth decade of life. The disease also is frequently observed in newborns where it can occur idiopathically or as a complication of congenital heart abnormalities. There currently are no pharmacotherapeutic interventions capable of forestalling progression of hypertensive pulmonary vascular disease; this deficiency can be traced largely to an incomplete understanding of the factors that govern pulmonary arterial wall structure and function.

Research in Dr. Gillespie's laboratory focuses on defining inter- and intracellular signaling pathways that contribute to development of hypertensive pulmonary vascular remodeling. A comprehensive, hierarchical approach is used wherein studies in cultured vascular cells are integrated with experiments in intact animal models to identify targets for pharmacologic intervention. One major project focuses on defining the cellular sources and pathologic roles of epidermal and transforming growth factors in hypertensive pulmonary vascular disease. A second project explores mechanisms governing pulmonary arterial cell disposition of the polyamines, a family of low molecular weight organic cations necessary for high fidelity DNA, RNA, and protein synthesis. Specific experiments determine how transmembrane polyamine transport is regulated and how transport interacts with de novo biosynthesis to regulate cell polyamine contents. Companion studies are developing selective inhibitors of transmembrane polyamine transport as potential therapeutic agents in vascular and neoplastic diseases.

A final project focuses on novel molecular therapeutic strategies for treatment of pulmonary hypertension. Based upon findings that expression of genes in response to hypertensive stimuli is driven by specific families of transacting factors, studies are underway to devise constructs between hypoxia-sensitive enhancer elements and genes encoding therapeutic peptides. It is proposed that pulmonary arterial cells transfected with such constructs will exhibit increased expression of therapeutic peptides which prevent vascular remodeling in response to pulmonary.

1. Horrod, K.S., Olson J.W., and Gillespie M.N., Regulation of ornithine decarboxylase and S-adenosylmethionine decarboxylase by hypoxia in cultured bovine pulmonary artery smooth muscle cells. Am. J. Physiol. Lung Cell Molec. Physiol. 271: L31-L37, 1996.

2. Gosland, M.P., Gillespie M.N., Tsuboi, C.P., Tofiq, S., Olson J.W., Crooks, P.A., and Aziz, S.M., Reversal of doxorubicin, etoposide, vinblastin, and taxol resistance in multidrug resistant human sarcoma cells by a polymer of spermine. Cancer Chemother. Pharmacol., 37: 593-600, 1996.

3. D. Cohen, E. Fitzpatrick, C. Hartsfield, M. Avdiushko, and M.N. Gillespie.Abnormal Lung Cytokine Synthesis by Immunodeficient T Cells in Murine AIDS-Associated Intersitial Pneumonitis.Ann. N.Y. Acad. Sci.796:47-58 (1996).

4. Hartsfield, C.L., Fitzpatrick, E., Cohen, D.A., and Gillespie, M.N., Pulmonary mechanical and immunologica dysfunction in a mutine model of AIDS. Amer. J. PhO'Connor WN, and . Pulmonary hypertension in a murine model of the acquired immunodeficiency syndrome. Am. J. Physiol. Lung Cell Molec. Physiol. 272: L699-L706, 1997.

5. Cohen, D.A., Fitzpatrick, E., Hartsfield, C.L., Gillespie, M.N., Avidushko, M., and Kaplan, A.M. Pulmonary lymphoid cell activation and cytokine expression in murine AIDS-associated interstitial pneumonitis. Am. J. Resp. Cell. Biol. 16: 153-161, 1997.

6. Cassis, L.A., Shenoy, U., Lipke, D.W., Baughn, J.A., Fettinger, M. and Gillespie, M.N., Lung angiotensin II receptor binding characteristics during development of monocrotaline-induced pulmonary hypertension. Biochem. Pharmacol. 54: 27-31, 1997.

7. P. Babal and M.N. Gillespie.Cultured Rat Pulmonary Artery Smooth Muscle Cells Exhibit at Least Two Polyamine Transport Phenotypes that Differ Morphologically and in Response to Hypoxia.Chest 114:34-35 (1998).

8. M.N. Gillespie, D.W. Killilea, M. Solomon, P. Babal, S.P. LeDoux, and G.L. Wilson.Hypoxia Causes Oxidant Lesions in the Rat Pulmonary Artery Smooth Muscle Cell VEGF Gene; Potential Link to VEGF mRNA Expression.Chest 114:45 (1998).

9. J.C. Parker, M.N. Gillespie, A.E. Taylor and S.L. Martin.Capillary filtration coefficient, vascular resistance, and compliance in isolated, perfused mouse lungs.J. Appl. Physiol. 87:1421-1427 (1999).

10. P. Babal, S.M. Manuel, J.W. Olson, and M.N. Gillespie. Regulation of Polyamine Uptake by Hypoxia in Rat Lungs and Pulmonary Arteries. Interactions Between Endothelial and Smooth Muscle Cells. Amer. J. Physiol: Lung Cell Molec. Physiol. 278:L610-L617 (2000).

11. D.W. Killilea, R. Hester, R. Balczon, P. Babal, and M.N. Gillespie. Free Radical Production in Hypoxic Pulmonary Artery Smooth Muscle Cells. Amer. J. Physiol: Lung Cell Molec. Physiol. 279:L408-L412 (2000).

12. P. Babal, M. Ruchko, J.W. Olson, and M.N. Gillespie. Interactions Between Agmatine and Polyamine Uptake Pathways in Rat Pulmonary Artery Endothelial Cells. Gen. Pharmacol. 34:255-261 (2000).

13. P. Babal, M. Ruchko, C.C. Campbell, S.P. Gilmour, J.L. Mitchell, J.W. Olson, and M.N. Gillespie. Regulation of Ornithine Decarboxylase Activity and Polyamine Transport by Agmatine in Rat Pulmonary Artery Endothelial Cells. J. Pharmacol. Exp. Ther. 296:372-377 (2001).

14. R. Chen, K.S. Harrod, J.W. Olson, and M.N. Gillespie. Regulation of Gadd153 mRNA Expression by Hypoxia in Pulmonary Artery Smooth Muscle Cells. Res. Com. Chem. Path. Pharmacol. 108:3-14 (2000).

15. V. Grishko, M. Solomon, G.L. Wilson, S.P. LeDoux, and M.N. Gillespie. Oxygen Radical-Induced Mitochondrial DNA Damage and Repair in Pulmonary Vascular Endothelial Cell Phenotypes. Am.. J. Physiol.: Lung Cell Molec. Physiol. 280:L1300-L1308 (2001).

16. V. Grishko, M. Solomon, J.F. Breit, D.W. Killilea, S. P. LeDoux, G.L.Wilson, and M.N. Gillespie. Hypoxia Promotes Oxidative Base Modifications in the Pulmonary Artery Endothelial Cell VEGF Gene. FASEB J. 15: 1267-1269 (2001).

17. M.N. Gillespie. (1) Nuclear DNA Is a Target of Oxidants Generated During Hypoxic Signaling: Implications for Gene Expression; and (2) Mitochondrial DNA Integrity May Govern Lung Vascular Endothelial Cell Survival After Xanthine Oxidase-Induced Injury. Am. Thorac. Soc., San Francisco, CA (2001).

18. P. Babal, M. Ruchko, K. Ault-Ziel, L. Cronenberg, J.W. Olson, and M.N. Gillespie. Regulation of Ornithine Decarboxylase Activity and Polyamine Import by Hypoxia in Pulmonary Artery Endothelial Cells. Amer. J. Physiol: Lung Cell Molec. Physiol. 282:L840-L846 (2002).

20. A.W. Dobson, V. Grishko, S.P. LeDoux, M.R. Kelly, G.L. Wilson, and M.N. Gillespie. Enhanced mtDNA Repair Capacity Protects Pulmonary Artery Endothelial Cells from Oxidant-Mediated Death. Amer. J. Physiol: Lung Cell Molec. Physiol. 283:205-210 (2002).