Hongwei Gao, M.D., Ph.D. Assistant Professor of Anaesthesia Harvard Medical School Tel: (617) 732-7454 Fax: (617) 264-5142 Email: hgao@zeus.bwh.harvard.edu

Education Postdoctoral Fellow, Pathology, University of Michigan, 2002-2006 Ph.D., Microbiology and Molecular Genetics, Michigan State University, 2002 M.D., Joint Eight-Year-Program, Nankai University and Tianjin Medical University, 1994

The long-term objective of my lab is to dissect the cellular and molecular mechanisms that regulate immune and inflammatory events during lung injury and multi-organ failure in sepsis. In recent years, it has become clear that the complement system plays an important immunoregulatory role at the interface of innate and acquired immunity during inflammation. Our research uses a combination of cell biology, molecular biology, immunology, and experimental pathology to identify the function of complement, especially C5a and its receptors, in acute lung injury and pulmonary dysfunction during sepsis. We are also interested in dissecting the function of transcription factors, cytokines and their networks of interaction, which underlie the inflammatory process in airway injury. Ultimately, a more complete knowledge of the causative mechanisms in airway injury and multi-organ failure will promote the goal of devising more effective strategies for the prevention and treatment of lung diseases and sepsis.

One project that we recently developed is determining the molecular pathways involved in Stat3 activation in the inflamed lungs.  We have demonstrated that expression and activation of Stat3 were accompanied by increased gene expression of IL-6, IL-10, and SOCS3 in IgG-immune complex-injured lung.  Activation of Stat3 is macrophage and neutrophil-dependent.  IL-6, IL-10, and C5a contribute to Stat3 activation. More recently, we demonstrate that Stat3 and SOCS3 can participate in lung inflammatory outcomes and seem to play a dual role in both IgG immune complex and LPS lung injury models and alveolar macrophages. Currently, we are using adenovirus-mediated siRNA expression to study function of Stat3 and SOCS3 in acute lung injury.  To investigate the potential mechanisms that SOCS3 regulates immune complex- and LPS-mediated Stat3 activation, we are performing proteomic analysis to identify SOCS3 associated protein complexes in alveolar macrophages.

Second project that we are working on is characterization of the roles of the two C5a receptors, C5aR and C5L2, in development of lung injury and sepsis. We cloned rat C5L2, a new C5a binding receptor. We further studied its expression and functional role during sepsis. Our work demonstrate that C5L2 is up-regulated in organs and neutrophils during sepsis, and that increased expression of C5L2 is negatively-correlated to serum IL-6 levels in septic mice, suggesting that it may function as a new decoy receptor for C5a. Currently, we are employing siRNA-mediated knockdown and gene-knockout approach to study the function of C5aR and C5L2 in mouse liver and lungs during sepsis.

1. Gao, H., Guo, R.F., Speyer, C.L., Reuben, J., Neff, T.A., Hoesel, M., Riedemann, N.C., McClintock, S.D., Sarma, V.J., Rooijen, N.V., Zetoune, F.S. and Ward, P.A. (2004). Stat3 activation in acute lung injury. J. Immunol.172 (12):7703-12.
2. Speyer, C.L., Gao, H., Rancilio, N.J., McClintock, S.D., Sarma, J.V. and Ward, P.A. (2004). Novel chemokine responsiveness and mobilization of neutrophils during sepsis. Am J Pathol. 165(6):2187-96.
3. Gao, H., Neff, T.A., Guo, R.F., Speyer, C.L., Sarma, V.J., Tomlins, S., Man, Y., Riedemann, N.C., Hoesel, L.M., Younkin, E., Zetoune, F.S. and Ward, P.A. (2005). Evidence for a functional role of the second C5a receptor, C5L2. FASEB J. 1003-05.
4. Niederbichler, A.D., Hoesel, M.L., Westfall, M.V., Gao, H., Ipaktchi, K.R., Sun, L., Zetoune, F.S., Su, G.L., Arbabi, S., Sarma, V.J., Wang, S.C., Hemmila, M.R. and Ward, P.A. (2006). An Essential Role for Complement C5a in the Pathogenesis of Septic Cardiac Dysfunction. J. Exp. Med. 203(1): 53-61.
5. Gao, H., Neff, T.A. and Ward, P.A. (2006). Regulation of lung inflammation in the model of IgG immune complex injury. Annual Review in Pathology 1: 215-42.
6. Gao, H., Rancilio, N.J., Guo, R.F., Sarma,J.V. and Ward, P.A. (2006). Overexpression of SOCS3 enhances IgG immune complex-induced lung injury. J. Immunol. 177(1): 612-20.
7. Gao, H., and Ward, P.A. (2007). Targeting STAT 3 and SOCS 3 in the lung inflammation response. Expert Opin Ther Targets. 11(7):869-80.
8. Flierl, M.A., Rittirsch, D, Nadeau, B.A., Chen, A, Sarma, J.V., Zetoune, F.S., McGuire, S.R., List, R.P., Hoesel, L.M., Gao, H., Rooijen, N.V., Huber-Lang, M.S., Neubig, R.R. and Ward, P.A. (2007). Phagocyte-derived catecholamines enhance acute inflammatory injury. Nature 449(7163):721-5.
9. Flierl* MA, Rittirsch* D, Gao*, H., Hoesel LM, Nadeau BA, Day DE, Zetoune FS, Sarma JV, Huber-Lang MS, Ferrara JLM, Ward PA. Adverse Functions of IL-17A. in Experimental Sepsis. FASEB 2008;22(7):2198-205. * Co-first authors.

Lab Personnel:

Postdoctoral Fellow Dawei Guo, M.D., Ph.D.

Research Associate (Picture unavailable) Wei Zhang, M.D., Ph.D.

Ph.D. Graduate Students Chunguang Yan, B.Sc.