Mark L. Entman, M.D.
Department of Medicine
Department of Biochemistry and Molecular Biology
Education and Awards
- M.D., 1963, Duke University Medical School
- Chief, Section of Cardiovascular Sciences
- Scientific Director, DeBakey Heart Center
- Cardiology Fellow, 1964-1965, Duke University Medical Center
- Postdoctoral, 1965-1966, Duke University Medical Center
- Howard Hughes Medical Investigator, 1972-1978
- Roussell Award for Cardiology, 1985
- Outstanding Research Award, International Society of Heart Research, 1986
- Research Merit Award, National Heart, Lung and Blood Institute, 1987
- Distinguished Alumnus, Duke University, 1997
Cellular and Molecular Mechanisms of Cardiac Injury and Repair
Dr. Entman's research interests focus on the role of the immune system and inflammatory signaling in cardiac injury and repair. The central focus relates to cardiac injury arising from dysregulation normally protective immune and inflammatory mechanisms. Initial studies focus on the potential injury associated with the intent inflammation occurring after reperfusion of a myocardial infarction. While this inflammatory reaction was critical for repair, evidence suggested the possibility that the acute inflammation could also cause cardiac injury. For a decade, the primary focus of the laboratory was pathophysiologic mechanisms mediating leukocyte entry and motility in the heart. This led to the definitive description of the cellular site of chemokine induction and factors which modulated it. Our study of the role of chemokine induction in orchestration of cardiac responses to injury helped define the signaling mechanisms by which mast cells, neutrophils, mononuclear cells, and stem cells entered the myocardium and mediated injury and repair.
Under normal circumstances, chemokine induction is relatively brief and rapidly suppressed during immune regulation. We began a group of studies to examine potential consequence prolonged induction or inappropriate induction of chemokines in cardiac injury. The model of non-infarctive repetitive injury of the myocardium resulted in prolonged elevation of MCP-1 with a consequent fibrotic cardiomyopathy; genetic deletion of MCP-1 completely prevented the pathology. Subsequent studies demonstrated that prolonged MCP-1 induction caused dysregulated uptake of monocytes and T-lymphocyte into the myocardium followed by the production of a unique fibroblast species that appears to be necessary for interstitial fibrosis to occur in this model. The generation of this fibroblast species and interstitial fibrosis is inhibited in the intact mouse by genetic deletion of MCP-1, IL-13 (Th2 lymphokine), or LFA-1 (adhesion molecule necessary for lymphocyte transendothelial migration) associated with a Th2/M2 response. Our studies suggest that interstitial fibrosis arises from a poorly regulated immune inflammatory reaction resulting in generation of CD45+, CD34+ fibroblast precursors mediating interstitial fibrosis. We have subsequently demonstrated that pertinence of this mechanism to fibrotic cardiomyopathies associated with angiotensin-2 treatment, transaortic constriction, and aging. Continuing work in the laboratory specifically addresses the signaling mechanisms cellular responses associated with immune dysregulation and its role in interstitial fibrosis of the heart.
In a parallel series of studies, we demonstrated that fibrosis tissue associated with scar formation (adaptive fibrosis) arises from an entirely different fibroblast specie. A recent study has demonstrated that fibroblast responsible for cardiac scar formation after myocardial infarction arise from a population of resident CD44+ mesenchymal stem cells which rapidly proliferate in response to signals associated with myocardial infarction. In aging mice, these same CD44+ mesenchymal stem cells are functionally deficient and also develop significant defects in lineage choice. These observations are associated with the finding in the aging mouse is a poorly developed scar after myocardial infarction. This observation parallels similar observations in aging patients.
Taken together, these studies suggest that fibroblast function is controlled by local signaling as well as the biology of specific fibroblasts precursors with specific pathophysiologic function. The observation that the signaling mechanisms and precursors are different allows for consideration of the possibility of individually modulating the different fibroblasts responses associated with cardiac disease.