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; role of complement in sepsis

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 immune 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. Currently, the role of IL-17A in sepsis is being investigated.

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

Flierl, M.A., Rittirsch, D., Nadeau, B.A., Chen, A.J., Sarma, J.V., Zetoune, F.S., McGuire, S.R., List, R.P., Day, D.E., Hoesel, L.M., Gao, H., Van Rooijen, N., Huber-Lang, M.S., Neubig, R.R., Ward, P.A.: Phagocyte-derived catecholamines enhance acute inflammatory injury.  Nature 2007 449:721-725.  PMID: 17914358.

Rittirsch, D., Flierl, M.A., and Ward, P.A.: Harmful molecular mechanisms in sepsis.  Nat Rev Immun.  2008 8:776-787.  PMID: 18802444.  PMCID: PMC2786961.

Flierl, M.A., Rittirsch, D., Nadeau, B.A., Sarma, J.V., Day, D.E., Lentsch, A.B., Huber-Lang, M.S., and Ward, P.A.:  Upregulation of phagocyte-derived catecholamines augments the acute inflammatory response.  PLoS One.  2009 4(2):e4414. [Epub 2009 Feb 12]  PMID: 19212441.  PMCID: PMC2636885

Ward, P.A.: The sepsis seesaw: seeking a heart salve.  Nature Medicine Bench to Bedside.  2009 15:497-498.  PMID: 19424210.

Rittirsch, D., Flierl, M.A., Day, D.E., Nadeau, B.A., Zetoune, F.S., Sarma, J.V., Werner, C.M., Wanner, G.A., Simmen, H.P., Huber-Lang, M.S., and Ward, P.A.:  Cross-talk between TLR4 and Fcγ receptor III (CD16) pathways.  PLoS Pathogens.  Epub 2009 Jun 5, 5(6):e10000464.  PMID:  19503602.  PMCID: PMC2685003.

Hemmila, M.R., Mattar, A., Taddonio, M.A., Arbabi, S., Hamouda, T., Ward, P.A., Wang, S.C., Baker, J.R., Jr.:  Topical nanoemulsion therapy reduces bacterial wound infection and inflammation after burn injury.  Surgery. 2010 Feb 26. [Epub ahead of print]  PMID: 20189619.  NIHMSID170651

Ward, P.A., Zetoune, F.S., and Sarma, J.V: Defective innate immunity and hyper-inflammatory responses in sepsis.  Proceedings of the 8th World Congress on Trauma, Shock, Inflammation and Sepsis, TSIS 2010, March 9-13th, pp. 9-12.

Ward, P.A.: The harmful role of C5a on innate immunity in sepsis.  J. Innate Immun. (DOI:10.1159/000317194) Published Online: June 26, 2010.

Speyer, C.L. and Ward, P.A.: Role of endothelial chemokines and their receptors during inflammation.  J. Invest. Surg.  2011;24:18-27.  PMID: 21275526. 

Atefi, G., Zetoune, F.S., Herron, T.J., Jalife, J., Bosmann, M., Al-Aref, R., Sarma, J.V., and Ward, P.A.: Complement dependency of cardiomyocyte release of mediators during sepsis.  FASEB J. 2011 Jul;25(7):2500-2508.

Bosmann, M., Russkamp, N.F., Patel, V.R., Zetoune, F.S., Sarma, J.V., and Ward, P.A.: The outcome of polymicrobial sepsis is independent of T and B cells.  SHOCK 2011 36(4):396-401.  PMID: 21701414.

Flierl, M.A., Rittirsch, D., Weckbach, S., Huber-Lang, M., Ipaktchi, K., Ward, P.A. and Stahel, P.F.: Disturbances of the hypothalamic-pituitary-adrenal axis and plasma electrolytes during experimental sepsis.  Ann of Intensive Care, 2011, 1:53. PMID: 22208725.

Bosmann, M., and Ward, P.A.:  Role of C3, C5 and anaphylatoxin receptors in acute lung injury and in sepsis.  Adv Exp Med Biol.  2012;946:147-159.

Bosmann, M., Sarma, J.V., Atefi, G., Zetoune, F.S., and Ward, P.A.:  Evidence for anti-inflammatory effects of C5a on the innate IL-17A/IL-23 axis.  FASEB J. 2012 26:1640-1651.

Ward, P.A.: Immunosuppression in sepsis.  JAMA. 2011 Dec 21;306(23):2618-9.  PMID: 22187286. 

Bosmann, M., Grailer, J.J., Zhu, K., Matthay, M.A., Sarma, J.V., Zetoune, F.S. and Ward, P.A.: Anti-inflammatory effects of β2 adrenergic receptor agonists in experimental acute lung injury.   FASEB J. 2012 26:2137-2144. 

Ward, P.A., Guo, R.F., and Riedemann,N.C.: Manipulation of the complement system for benefit in sepsis.  Crit Care Res Pract. 2012 Epub 2012 Mar 5.  PMID: 22482043.

Bosmann, M., Haggadone, M., Hemmila, M., Zetoune, F., Sarma, J.V. and Ward, P.A.:  Complement activation product C5a is a selective suppressor of TLR4-induced, but not TLR3-induced, production of IL-27 (p28) from macrophages.  J. Immunol. 2012;188;5086-5093.  PMCID:PMC3345104.