Lloyd Fleisher
Professor of Pharmacology

B.A.: Brooklyn College, Brooklyn, New York, Biology, 1967.
Ph.D.: City University of New York, Mount Sinai Medical Center, 1977.

E-mail: lloyd_fleisher@ncsu.edu

Professional Experience:

7/77-8/78: Research Trainee, Institute of Psychiatric Research, Indiana University, Indianapolis, IN.

9/78-5/80: Research Fellow, Department of Pathology, Albert Einstein College of Medicine, Bronx, NY.

6/80-10/82: Research Associate, Department of Medicine, Columbia University College of Physicians and Surgeons, New York, NY.

11/82-6/88: Assistant Professor of Pharmacology, Department of Molecular Biomedical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, NC.

7/88-6/95: Associate Professor of Pharmacology, Department of Molecular Biomedical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, NC.

7/95-present: Professor of Pharmacology, Department of Molecular Biomedical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, NC.

Research Area:

Intraocular inflammation (uveitis) is common medical problem, not only in man, but in many animal species including dogs, cats, and horses. Uveitis is often a recurrent illness which is painful, difficult to treat, and results, not uncommonly, in permanent blindness. The primary focus of our research has been the identification and characterization of specific mediators of the intraocular inflammatory response and the intracellular mechanisms controlling their production and release. In particular, we have characterized the roles of the inflammatory mediators interleukin-1 (IL-1) and tumor necrosis factor-a (TNF-a), cytokines that are released by inflammatory leukocytes as they infiltrate the ciliary body of the eye during a uveitic response.

Click on image to enlarge
Over the past few years we have studied the effects of these cytokines on the ocular pigmented ciliary epithelium (PE), a cellular monolayer in the anterior portion of the eye, lying between the aqueous humor and the vascular stroma of the ciliary body. The PE occupies an ideal location as a target for IL-1 and TNF-a, since it is the first cellular barrier encountered by leukocytes as they exit through the capillaries of the ciliary body. Using cultured rabbit PE cells, an in vitro cellular system developed in our laboratory, we have found that PE respond to IL-1, and to a lesser extent to TNF-a, by releasing IL-6, a multifunctional cytokine that modulates proliferation of lymphoid and nonlymphoid cells and is an important component of the inflammatory and immune responses. More recently we have found that IL-1 stimulates PE to release matrix metalloproteinase-9 (MMP-9), an extracellular proteinase that may play an essential role in the tissue remodeling accompanying the uveitic response. Analysis of the production of MMP-9, and a related enzyme, MMP-2, using a method called gelatin zymography, is illustrated in the accompanying figure. Furthermore, using specific inhibitors of intracellular protein kinases, electromobility shift assays, and an enhanced green fluorescent protein reporter plasmid, we have identified a unique signaling cascade in PE cells whereby IL-1 activates a protein kinase C dependent pathway which leads to activation of the transcription factor, NF-kB, and stimulation of MMP-9 production and release. It is this pathway that is the current focus of our research endeavors.

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Selected Publications:

Fleisher, L.N., Ferrell, J.B., Smith, M.G. and M.C. McGahan: Lipid mediators of tumor necrosis factor-a-induced uveitis. Invest Ophthalmol Vis Sci 32:2293-2299, 1991.

Fleisher, L.N., Ferrell, J.B. and McGahan, M.C.: Synergistic uveitic effects of tumor necrosis factor-a and interleukin-1ß. Invest Ophthalmol Vis Sci 33:42-49, 1992.

Fleisher, L.N., Ferrell, J.B., and M.C. McGahan: Mediators of the ocular inflammatory response to IL-1ß plus TNFa. Graefe Archiv Clin Exp Ophthalmol 233:94-100, 1995.

Fleisher, L.N., Ferrell, J.B., and M.C. McGahan: Inflammation induced changes in adenosine 3',5'-cyclic monophosphate production by ciliary epithelial cell bilayers. Exp Eye Res 60:165-171, 1995.

Allen, J.B., M.C. McGahan, Y. Ogawa, D.C. Sellon, B.D. Clark and L.N. Fleisher: Intravitreal transforming growth factor-ß2 decreases cellular infiltration in endotoxin-induced ocular inflammation in rabbits. Curr Eye Res 15:95-103, 1996.

Allen, J.B., M.C. McGahan, J.B. Ferrell, K.B. Adler and L.N. Fleisher: Nitric oxide synthase inhibitors exert differential time-dependent effects on LPS-induced uveitis. Exp Eye Res 62:21-28, 1996.

Fleisher, L.N., McGahan, M.C., Ferrell, J.B. and I. Pagan: Interleukin-1ß increases prostaglandin E2 stimulated adenosine 3', 5'-cyclic monophosphate production in rabbit pigmented ciliary epithelium. Exp Eye Res 63:91-104, 1996.

Fleisher, L.N., McGahan, M.C. and J.B. Ferrell. Rabbit pigmented ciliary epithelium produces interleukin-6 in response to inflammatory cytokines. Exp. Eye Res. 70:271-279, 2000.

McGahan, M.C., Harned, J., Mukunnemkeril, M. Goralska, M., Fleisher, L. and Ferrell, J.B.2005. Iron alters glutamate secretion by regulating cytosolic aconitase activity. Am. J. Physiol.288: C1117-1124.

Harned, J., Fleisher, L.N., McGahan, M.C. 2006. Lens epithelial cells synthesize and secrete ceruloplasmin: effects of ceruloplasmin and transferrin on iron efflux and intracellular iron dynamics. Exp. Eye Res. 83:721-727.

Goralska, M., Fleisher, L.N., McGahan, M.C. September 2007. Ferritin H- and L-Chains in Fiber Cell Canine and Human Lenses of Different Ages. IOVS, Vol. 48, No.9

Links:

Fleisher Lab Personnel

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