Sem H. Phan, Ph.D., M.D.
Professor of Pathology
Campus Address:
M4204 MSI
1301 Catherine Road
Ann Arbor, Michigan 48109-0602
Phone: 734/763-6454
shphan@s.imap.itd.umich.edu
Dr. Sem H. Phan, Chair, Graduate Program Committee
Annual Report | Clinical Interests | Research Interests | Biography
Departmental Annual Report
Clinical Interests
Pathology, Interstitial Lung diseases, Pulmonary fibrosis, Adult respiratory distress syndrome (ARDS), Immunopathology
Research Interests
Lung injury and fibrosis, cytokines, myofibroblast
biology and differentiation, smooth muscle actin gene expression, Pulmonary
immunopathology
Research in this laboratory is directed at understanding the cellular and molecular mechanisms of tissue repair and fibrosis. Typically inflammation and an immune response follows many forms of tissue injury, characterized by the influx of a variety of leukocytes. These cells appear activated and are known to express elevated levels of a number of mediators, including cytokines such as interleukin-1 (IL-1), tumor necrosis factor (TNF ), monocyte chemoattractant protein-1 (MCP-1) and transforming growth factor (TGF ). These mediators have the potential of amplifying the inflammatory and immune responses, as well as recruiting and activating fibroblasts. Increased proliferation and extracellular matrix expression by these latter cells could then result in the progressive fibrotic lesion. Recent studies using a rodent model of lung injury and fibrosis, demonstrate that elevation in TGF 1 and MCP-1 expression under the direction of TNF is found to occur primarily in eosinophils, which subsequently shift to the activated fibroblasts or myofibroblasts. This period of heightened cytokine expression is accompanied by the de novo appearance of myofibroblasts, which is heralded by expression of -smooth muscle actin. These cells are primarily responsible for the extracellular matrix accumulation characteristic of fibrotic lesions, and they appear to be derived from peribronchiolar and perivascular adventitial fibroblasts. In this model, cessation of active fibrosis is accompanied by the gradual disappearance of the myofibroblast. Hence the focus of the studies is currently to delineate the mechanisms for eosinophil recruitment and activation and to understand how myofibroblasts emerge and disappear. Preliminary evidence indicates that IL-5 and eotaxin may be key cytokines in eosinophil recruitment and perhaps activation to express diverse potentially fibrogenic cytokines.
Ongoing studies using transgenic eotaxin knockout mice suggest that this chemokine is required for fibrosis to occur, while treatment with anti-IL-5 antibodies is also effective in ablating fibrosis. The importance of the cytokine MCP-1 is also being analyzed in studies using transgenic CCR2 (MCP-1 receptor) knockout mice. The appearance of the myofibroblast is studied as a differentiation event dependent on the expression of -smooth muscle actin. These studies focus on the regulation of the -smooth muscle actin promoter using multiple promoter constructs and site-directed mutagenesis. Recent studies have also focused on the role of apoptosis in healing or repair versus fibrosis, in the progression from tissue injury. Evidence of DNA fragmentation can be demonstrated at the latter stages, which may be important in terminating the matrix synthetic or fibrotic phase to enable proper repair. The possibility that impaired apoptosis on the part of the recruited and activated eosinophils and/or myofibroblasts may instead result in progressive fibrosis, is being investigated. In vitro studies suggest that myofibroblasts are sensitive to IL-1 -induced apoptosis, which could be reversed by the NO synthetase (iNOS) inhibitor L-NMMA. Studies are ongoing to determine the in vivo relevance of these findings and to delineate the apoptotic pathways involved. Initial studies have already shown that the level of expression of the anti-apoptotic protein, bcl-2, correlates with survival of the myofibroblast. TGF affords protection to the myofibroblast from IL-1 induced apoptosis by inhibition of iNOS expression and preventing a decline in bcl-2 expression. It appears that the expression of the pro-apoptotic protein, bax, is not affected by this treatment. These studies should provide insight into the mechanisms by which inflammatory cells interact with mesenchymal cells in tissue repair and fibrosis.
Brief Biography
Academic Training: PhD Chemistry 1975 Indiana University; MD 1976 Indiana
University
Residency Training: Anatomic Pathology 1976-1980 University of Connecticut
Health Center; Board Certified 1979
Current Positions: Professor & Director of Graduate Program, Department
of Pathology; Associate Editor, American Journal of Pathology Research
Interests: Mechanisms of tissue/cell injury, repair and fibrosis; regulation
of cytokine and collagen gene expression; chemokines and chemotactic recruitment
of eosinophils and fibroblasts; myofibroblast role in fibrosis; regulation
of alpha-smooth muscle actin gene expression and myofibroblast differentiation;
myofibroblast apoptotic pathways in fibrosis; role of eosinophils in fibrosis.