Peter A. Ward, M.D.
Godfrey D. Stobbe Professor,
Department of Pathology

pward@umich.edu

Research Interests:

Regulation and role of complement activation products, adhesion-promoting molecules and cytokines in the inflammatory response and in sepsis; signaling pathways in phagocytes

The main focus of our laboratory is the regulation of the inflammatory response. An in vivo model of acute lung injury induced by the intrapulmonary deposition of IgG immune complexes in rats has been developed. The role of various adhesion molecules (e.g. ICAM-1, VCAM-1), cytokines (e.g. TNFa), chemokines (e.g. MIP-2, CINC), anti-inflammatory interleukins (e.g. IL-10, IL-13), complement factors (e.g. C5a), and endogenous protease inhibitors (e.g. TIMP-2 and SLPI) are studied in this model as well as in vitro.

A second area of research is sepsis. Major features of sepsis are the systemic responses (e.g. failing blood pressure, etc.) and the susceptibility to intrapulmonary infection. In an effort to understand this process, rats develop sepsis by cecal ligation/puncture and are then evaluated for increased susceptibility to injury after a direct pulmonary insult (airway instillation lipopolysaccharide or IgG immnue complex deposition). We find that adhesion molecules, cytokines, and especially the complement factor C5a contribute to the enhanced lung injury in the state of sepsis.

In addition, we study some of the signaling molecules such as MAP-kinases and the transcription factor NF-kB involved in the inflammatory response. Our laboratory routinely uses some of the standard cellular and molecular biological techniques such as cloning, RT-PCR, Southern, Western and Northern blot analysis, ELISA, chemotaxis, antibody production, bacterial and mammalian expression of proteins, transfections etc.

Representative Publications:

Riedemann, N.C., Guo, R.F., Bernacki, K.D., Reuben, J.S., Laudes, I.J., Neff, T.A., Gao, H., Speyer, C., Sarma, J.V., z etoune, F.S., and Ward, P.A .: Regulation by C5a of neutrophil activation during sepsis. Immunity, 2003 19:193-202.

Neff, T.A., Guo, R.F., Neff, S.B., Sarma, J.V., Speyer, C.L., Gao, H., Bernacki, K.D., Huber-Lang, M., McGuire, S., Hoesel, L.M., Riedemann, N.C., Beck-Schimmer, B., Zetoune, F.S., Ward, P.A.: Relationship of acute lung inflammatory injury to Fas/FasL system. Am J Pathol. 2005 166(3):685-694.

Huber-Lang, M.*, Sarma, J.V.*, Rittirsch, D.*, Schreiber, H., Weiss, M., Flierl, M., Younkin, E., Schneider, M., Suger-Wiedeck, H., Gebhard, F., McClintock , S.D. , Neff, T., Zetoune, F., Brueckner, U., Guo, R.F., Monk, P.N., and Ward, P.A .: Changes in the novel orphan, C5a receptor (C5L2), during experimental sepsis and sepsis in humans. J. Immunol. 2005 174:1104-1110. * The three first authors contributed equally.

Niederbichler, A.D., Hoesel, L.M., Westfall, M.V., Gao, H., Ipaktchi, K.R., Sun, L., Zetoune, F.S., Su, G.L., Arbabi, S., Sarma, J.V., Wang , S.C. , Hemmila, M.R., and Ward, P.A.: An essential role for complement C5a in the pathogenesis of septic cardiac dysfunction. JEM. 2005, 203(1): 53-61.

Wang, X., Adler, K.B., Chaudry, I.H., and Ward, P.A.: A better understanding of organ dysfunction requires proteomic involvement. J. Proteome Res. 2006 5:1060-1062.

Huber-Lang, M.*, Sarma, J.V.*, Zetoune, F.S.*, Rittirsch, D., Neff, T.A., McGuire, S.R., Lambris, J.D., Warner, R.L., Flierl, M.A., Hoesel, L.M., Gebhard, F., Younger, J.G., Drouin, S.M., Wetsel, R.A., Ward, P.A.: Generation of C5a in the Absence of C3: A New Complement Activation Pathway *Authors contributed equally. Published online: 21 May 2006 . Nat Med. 2006 12:682-687.

Guo, R.F., Riedemann, N.C., Sun, L., Gao, H., Reuben, J.S., Sarma, J.V., Zetoune, F.S., and Ward, P.A.: Divergent signaling pathways in leukocytes during sepsis. J Immunol. 2006 177:1306-1313.

Ishida-Okawara, A., Nagi-Miura, N., Oharaseki, T., Takahashi, K., Okumra, A., Tachikawa, H., Kashiwamura, S., Okamura, H., Ohno, N., Okada, H., Ward, P.A., Suzuki, K.: Neutrophil activation and arteritis induced by C. albicans water-soluble mannoproteins-ß-glucan complex (CAWS). Exp. Molecul. Path. 2007 Jan 4; [Epub ahead of print] Exp Mol Pathol. 2007; 82:220-226.

Hoesel, L.M., Niederbichler, A.D., and Ward, P.A.: Complement-related molecular events in sepsis leading to heart failure. Mol. Immunol. 2006 July 26, [Epub]. 2007 44:95-102.

Leinhase, I., Rozanski, M., Harhausen, D., Thurman, J.M., Schmidt, O.I., Hossini, A.M., Taha , M.E. , Rittirsch, D., Ward, P.A., Holers, V.M., Ertel, W., Stahel, P.F.: Inhibition of the alternative complement activation pathway in traumatic brain injury by a monoclonal anti-factor B antibody: a randomized placebo-controlled study in mice. J. Neuroinflammation, 2007 4:13 .