Sem H. Phan, Ph.D, M.D.
Professor, Department of Pathology

shphan@umich.edu

Research in this laboratory is directed at understanding the cellular and molecular mechanisms of tissue repair and fibrosis. Current focus is on the origins and phenotypes of the fibroblasts that emerge de novo in pulmonary fibrosis and the various mediators, including cytokines, that regulate this process. The key phenotype that characterizes active fibrosis is the myofibroblast with features intermediate between a fibroblast and a smooth muscle cell. This phenotype is characterized by high levels of extracellular matrix production, cytokine (e.g. TGFb) gene expression and a-smooth muscle actin expression. Myofibroblast differentiation from fibroblasts can be induced by TGFb, IL-4, IL-13 or endothelin-1. One project is directed at how TGFb1 induces a-smooth muscle actin gene expression as a marker of myofibroblast differentiation. Transcriptional regulation of the a-smooth muscle actin gene is being analyzed using a promoter construct. Initial studies have uncovered the importance of a number of transcription factors and their corresponding cis elements, including a TGFb control element (TCE) and Smad binding element (SBE). The presence of additional putative regulatory elements suggest a more complex regulatory mechanism, and some of these are currently under study A second project is focused on the novel telomerase expressing phenotype that is induced in a rodent model of lung injury and fibrosis. This phenotype is not present in normal lung and is induced in a time-dependent manner in parallel with the expansion in the lung fibroblast population during active fibrosis. The role of this phenotype is unknown but may be related to its promotion of fibroblast proliferative capacity and resistance to apoptosis. The studies in this project are directed at cloning the promoter sequences of the telomerase reverse transcriptase (TERT) component to see how this gene is being regulated. This appears to be key to the expression of telomerase activity since most cells already express the other components, such as the RNA component (TERC), but do not express activity due to lack of TERT expression. The promoter construct will then be used in studies of transcriptional regulation. Additionally the telomerase expressing phenotype can differentiate to the myofibroblast under the influence of TGFb and IL-4. Although both cytokines suppress telomerase expression, current studies suggest that suppression of telomerase per se is sufficient to induce differentiation. The mechanism of how telomerase inhibition leads to induction of a-smooth muscle actin gene expression is under investigation. A related project looks at the potential extra-pulmonary origin of these lung different lung fibroblast populations using bone marrow chimera mice. Finally the potential role of a novel gene FIZZ1 in lung inflammation and fibrosis is suggested by preliminary evidence that it has the ability to induce myofibroblast differentiation in vitro.

Representative Publications

Hashimoto, N., Jin, H., Liu, T., Chensue, S.W., and Phan, S.H.: Bone marrow derived progenitor cells in pulmonary fibrosis. J. Clin. Invest. 2004; 113:243-252.

Liu, T., Dhanasekaran, S.M., Jin, H., Tomlins , S.A. , Chinnaiyan A.M., and Phan, S.H.: Induction of FIZZ-1 expression in lung injury and fibrosis. Am. J. Pathol. 2004; 164:1315-1326.

Liu, T., Jin, H., Ullenbruch, M., Hu, B., Hashimoto, N., Moore , B., McKenzie, A., and Phan, S.H. Regulation of FIZZ1 expression in bleomycin-induced lung fibrosis: role of IL-4/IL-13 and mediation via STAT-6. J. Immunol. 2004; 173: 3425-3431.

Hu, B., Wu, Z., Jin, H., Hashimoto, N., Liu, T., and Phan, S.H.: C/EBP b isoforms and the regulation of a -smooth muscle actin expression by IL-1 b . J. Immunol. 2004; 173: 4661-4668.

Lin, J., Cho, E.A., Chen, X., Levitan, I. , Patel1, S.R., Ullenbruch, M., Phan, S.H., Park, J.P., and Dressler, G.R.: Kielin/Chordin-Like Protein 1 (KCP1) a Novel Enhancer of BMP Signaling Mediates Renal Fibrotic Disease. Nat. Med. 2005; 11:387-393

Gharaee-Kermani, M., Hatano, K., Nozaki, Y., and Phan, S.H.: Gender-based differences in bleomycin-induced pulmonary fibrosis. Am. J. Pathol. 2005; 166:1593-1606

Huaux, F., Gharaee-Kermani, M., Liu, T., Morel, V., McGarry, B., Ullenbruch, M., Kunkel, S.L., Wang, J., Xing, Z., and Phan, S.H.: Role of Eotaxin-1 (CCL11) and CC chemokine Receptor 3 (CCR3) in bleomycin-induced lung injury and fibrosis. Am. J. Pathol. 2005; 167:1485-96

Hu, B., Tack, D.C., Liu, T., Wu, Z., Ullenbruch, M.R., and Phan, S.H.: Role of Smad3 in the regulation of rat telomerase reverse transcriptase by TGFß. Oncogene. 2006; 25:1030–41

Hu B, Wu Z, Liu T, Ullenbruch MR, Jin H, and Phan SH: Gut-enriched Krüppel-like Factor represses TGFß signaling by inhibiting Smad3. Am. J. Respir. Cell Mol. Biol. 2007; 36:78-84

Liu TJ, Chu ng MJ, Ullenbruch M, Yu H, Jin H, Hu B, Choi YY, Ishikawa F, and Phan SH: Telomerase deficiency impairs bleomycin-induced pulmonary fibrosis in mice. J. Clin. Invest. 2007; 117:3800-9