Mark L. Entman, M.D. - Faculty
Professor, Departments of Medicine, and Pathology & Immunology
Chief, Cardiovascular Sciences Section
M.D., Duke Medical School
Postdoctoral, Duke Research Training Program
Research Interests and Expertise:
Our studies on cardiovascular inflammation have concentrated on inflammatory response following reperfusion of the infarcted myocardium. Our aim is to dissect the cellular and molecular events which result sequentially in accelerated reperfusion-induced inflammation followed by ventricular healing and scar formation. Paradoxically, it appears that reperfusion induced inflammation, while potentially extending injury, also facilitates healing of the infarct. Our strategy includes identification of the cellular and molecular events that result in injury and identification of potential factors which might reduce inflammatory injury by suppressing cytotoxic reactions. Current projects involve the cellular and molecular control of the expression of cytokines and chemokines that control cell trafficking in the region of initial injury. The molecular induction of adhesion molecules and/or surface expression controls cellular trafficking and potential cytotoxic reactions. Similarly, adhesion molecule inactivation through internalization or proteolysis appears to be an important cellular event that controls and limits inflammatory injury. In addition, sequential expression and suppression of pro-inflammatory and anti-inflammatory cytokines, chemokines and growth factors appear to be a critical in cardiac healing. The control of these steps is being studied in vitro and modeled in cell culture. Induction of chemokines and cytokines in the area of reperfusion is being assessed by immunocytochemical techniques as well as by in situ hybridization. The cells of origin of each of these cytokines and chemokines are being evaluated as a function of time of ischemia and reperfusion. The studies are being carried out in models of ischemia and reperfusion which have been developed in the awake dog and the awake mouse, after allowing dissipation of cardiac trauma. The former is important because it allows extensive investigation in in vitro modeling based on our ability to obtain cardiac lymph (extracellular fluid) during the ischemia and reperfusion process and assess the content of cells and cytokines in the extracellular fluid at various times. The latter is critical since we have developed genetic knockouts of several of the key cellular adhesion molecules, cytokine receptors, growth factor mediators and chemokines responsible for the control of cell adhesion, migration and secretion. This will allow us to dissect more carefully the relationship between cell trafficking and function in cardiac injury and effective healing. We have developed technology in the mouse that has enabled 1) demonstration of mesenchymal progenitor cell development into cardiac muscle after cardiac injury and 2) a chemokine-dependent cardiomyopathy that is initiated by reactive oxygen. These models expand our repertoire of cellular responses mediating cardiac repair and remodeling.
Frangogiannis, N.G., Perrard, J.L., Mendoza, L.H., Burns, A.R., Lindsey, M.L., Ballantyne, C.M., Michael, L.H., Smith, C.W. and Entman, M.L.: Stem cell factor induction is associated with mast cell accumulation following canine myocardial ischemia and reperfusion. Circulation, 98:687-698, 1998.
Frangogiannis, N.G., Mendoza, L.H., Lindsey, M.L., Ballantyne, C.M., Michael, L.H., Smith, C.W. and Entman, M.L.: Interleukin-10 is induced in the reperfused myocardium and may modulate the reaction to injury. Journal of Immunology, 165:2798-2808, 2000.
Lindsey, M., Wedin, K., Brown, M.D., Keller, C., Evans, A.J., Smolen, J., Burns, A.R., Rossen, R.D., Michael, L. and Entman, M.L.: Matrix-dependent mechanism of neutrophil-mediated release and activation of Matrix Metalloproteinase 9 in myocardial ischemia/reperfusion. Circulation, 103:2181-2187, 2001.
Jackson, K.A., Majka, S.M., Wang, H., Pocius, J., Hartley, C.J., Majesky, M.W., Entman, M.L., Michael, L.H., Hirschi, K.K. and Goodell, M.A.: Regeneration of ischemic cardiac muscle and vascular endothelium by adult stem cells. Journal of Clinical Investigation, 107:1395-1402, 2001.
Frangogiannis, N.G., Mendoza, L.H., Lewallen, M., Michael, L.H., Smith, C.W. and Entman, M.L.: Induction and suppression of interferon-inducible protein (IP)-10 in reperfused myocardial infarcts may regulate angiogenesis. FASEB Journal, (April 5, 2001) 10.1096/fj.00-0745fje; (Summary published 15:1428-1430, 2001).
Lakshminarayanan, V., Lewallen, M., Frangogiannis, N., Evans, A.J., Wedin, K.E., Michael, L.H. and Entman, M.L.: Reactive oxygen intermediates induce monocyte chemotactic protein-1 in vascular endothelium after brief ischemia. American Journal of Pathology, 159:1301-1311, 2001.
Gould, K.E., Taffet, G.E., Michael, L.H., Christie, R.M., Konkol, D.L., Pocius, J.S., Zachariah, J.P., Chaupin, D.F., Daniel, S.L., Sandusky, G.E., Jr., Hartley, C.J. and Entman, M.L.: Heart failure and greater infarct expansion in middle-aged mice: A relevant model for post-infarction failure. American Journal of Physiology Heart Circ. Physiology, 282:H615-H621, 2002.
Dewald, O., Frangogiannis, N.G., Zoerlein, M., Duerr, G.D., Klemm, C., Knuefermann, P., Taffet, G., Michael, L.H., Crapo, J.D., Welz, A. and Entman, M.L.: Develop-ment of murine ischemic cardiomyopathy is associated with a transient inflamma-tory reaction and depends on reactive oxygen species. Proceedings of the National Academy of Sciences, 100:2700-2705, 2003.
Frangogiannis, N.G., Mendoza, L.H., Ren, G., Akrivakis, S., Jackson, P.L., Michael, L.H., Smith, C.W. and Entman, M.L.: MCSF expression is induced in healing myocardial infarcts and may regulate monocyte and endothelial cell phenotype. American Journal of Physiology, Heart and Circulatory Physiology, 285:H483-H492, 2003).
Oh, H., Bradfute, S.B., Gallardo, T.D., Nakamura, T., Gaussin, V., Mishina, Y., Pocius, J., Michael, L.H., Behringer, R.R., Garry, D.J., Entman, M.L. and Schneider, M.D.: Cardiac progenitor cells from adult myocardium: Homing, differentiation, and fusion after infarction. Proceedings of the National Academy of Sciences, 100: 12313-12318, 2003.
For a complete list of Dr. Entman's publications, visit PubMed.
Dr. Mark Entman
Baylor College of Medicine
One Baylor Plaza, FBRN-F622
Houston, TX 77030 Phone: 713-798-4188