Ph.D., Rockefeller University, 1967
Professor, Departments of Biochemistry and Cell Biology and Pathology
Research Interests: Biochemistry and cell biology of inflammatory and tumor cells and their products
Acute and chronic inflammatory responses are important host defenses against foreign substances or pathogens. These responses are largely mediated by neutrophils and macrophages, which release proteases, cytokines, and a number of other mediators of inflammation in the course of defending the host. We study the mechanisms of action of serine proteases and metalloproteases from activated neutrophils and develop specific inhibitors to control the tissue destruction which may otherwise injure the host during an inflammatory response. Because invasiveness and metastatic spread of tumor cells involves tissue degradation by the same families of proteinases as is seen in inflammation, we have extended our studies to include evaluation of agents intended to block tumor spread or tumor-stimulated vessel growth (angiogenesis). Our methods include biophysical probes of enzyme active sites and kinetic measurements. We also measure neutrophil and macrophage phagocytic activity and release of oxidants by flow cytometry. We have made extensive use of a complete interstitial extracellular matrix from rat smooth muscle cells which we label biosynthetically and employ as a substrate for inflammatory cells and tumor cells and their proteases. We employ matrices on porous membrane filters to quantitate inhibition of invasive migration of neutrophils, macrophages, endothelial cells, and tumor cells by proteinase inhibitors and other modulatory agents. Our collaboration with colleagues in the Department of Oral Biology and Pathology has led to a series of clinical trials on a class of proteinase inhibitors with additional pleiotropic downregulatory actions on inflammatory and tumor cells. The trials of these inhibitors, which are nonantimicrobial derivatives of tetracyclines, target potential applications in management of cancer, acute respiratory distress syndrome, periodontal disease, and cardiovascular complications of smoking. To understand how inflammatory cells communicate we study paracrine mechanisms of activation by cytokines, using immunofluorescence and flow cytometry to measure levels of expression of cell surface receptors and other marker proteins which are sensitive to the state of activation of the cells.
Lee, H.M., Golub, L.M., Chan, D., Leung, M., Schroeder, K., Wolff, M., Simon, S.R., and Crout, R. (1997) Alpha-1-proteinase inhibitor in gingival crevicular fluid of humans with adult periodontitis: serpinolytic inhibition by doxycycline. J. Periodont. Res. 32:9-19.
Carney, D.E., Lutz, C.J., Picone, A.., Gatto, L.A., Ramamurthy, N.S., Golub, L.M., Simon, S.R., Searles, B., Paskanik, A., Snyder, K., Finck, C., Schiller, H.J., and Nieman, G.F. (1999) Matrix metalloproteinase inhibitor prevents acute lung injury after cardiopulmonary bypass. Circulation 100:400-406.
Lukkonen, A., Sorsa, T., Salo, T., Tervahartiala, T., Koivunen, E., Golub, L.M., Simon, S.R., and Stenman, U.H. (2000) Down-regulation of trypsinogen-2 expression by chemically modified tetracyclines: association with reduced cancer cell migration. Int. J. Cancer 86:577-581.
Ying, Q.L., and Simon, S.R. (2000) DNA from bronchial secretions modulates elastase inhibition by alpha-1-proteinase inhibitor and oxidized secretory leukoprotease inhibitor. Am. J. Respir. Cell Molec. Physiol. 23:506-513.
Gu, Y., Lee, H.M., Roemer, E.J., Musacchia, L., Golub, L.M., and Simon, S.R. (2001) Inhibition of tumor cell invasiveness by chemically modified tetracyclines. Curr. Med. Chem. 8:261-270.
Ying, Q.L., and Simon, S.R. (2002) Elastolysis by proteinase 3 and its inhibition by alpha-1-proteinase inhibitor: a mechanism for the incomplete inhibition of ongoing elastolysis. Am. J. Respir. Cell Mol. Biol. 26:356-361