Peter A. Ward,
Godfrey D. Stobbe Professor,
Department of Pathology
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 has been developed in mice. 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. Our earlier studies have shown that sepsis developing in rodents after cecal ligation and puncture (CLP) is associated with activation of complement and generation of the anaphylatoxin, C5a, which then interacts with its receptors (C5aR, C5L2) present on a variety of cells, both myeloid and myeloid-derived cells. Such interactions appear to be associated with the multiorgan failure of sepsis. Currently, we have a focus on C5a being able to interact with cardiomyocytes, resulting in heart failure. Cardiac dysfunction is a major complication of sepsis, resulting in septic shock. Currently, two of my former postdoctoral fellows at the University of Jena, Germany, are making plans to initiate Phase II Clinical Trials in humans with sepsis, using a “humanized’ version of a mouse antibody that neutralizes C5a.
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, Western and Northern blot analysis, ELISA, antibody production, bacterial and mammalian expression of proteins, transfections, etc.
Grailer JJ, Kalbitz M, Zetoune FS, Ward PA. Persistent Neutrophil Dysfunction and Suppression of Acute Lung Injury in Mice following Cecal Ligation and Puncture Sepsis. J Innate Immun. 2014 May 23. [Epub ahead of print] PMID: 24861731.
Grailer JJ, Canning BA, Kalbitz M, Haggadone MD, Dhond RM, Andjelkovic AV, Zetoune FS, Ward PA. Critical role for the NLRP3 inflammasome during acute lung injury. J Immunol. 2014 Jun 15;192(12):5974-83. doi: 10.4049/jimmunol.1400368. Epub 2014 May 2. PMID: 24795455; PMCID: PMC4061751.
Grailer JJ, Haggadone MD, Sarma JV, Zetoune FS, Ward PA. Induction of M2 Regulatory Macrophages through the β(2)-Adrenergic Receptor with Protection during Endotoxemia and Acute Lung Injury. J Innate Immun. 2014 Mar 14. [Epub ahead of print] PMID: 24642449.
Bosmann M, Strobl B, Kichler N, Rigler D, Grailer JJ, Pache F, Murray PJ, Müller M, Ward PA. Tyrosine kinase 2 promotes sepsis-associated lethality by facilitating production of interleukin-27. J Leukoc Biol. 2014 Jul 96(1):123-31. doi: 10.1189/jlb.3A1013-541R. PMID: 24604832; PMCID: PMC4056273.
Unnewehr H, Rittirsch D, Sarma JV, Zetoune F, Flierl MA, Perl M, Denk S, Weiss M, Schneider ME, Monk PN, Neff T, Mihlan M, Barth H, Gebhard F, Ward PA, Huber-Lang M. Changes and regulation of the C5a receptor on neutrophils during septic shock in humans. J Immunol. 2013 Apr 15;190(8):4215-25. doi: 10.4049/jimmunol.1200534. PMID: 23479227.
Bosmann M, Meta F, Ruemmler R, Haggadone MD, Sarma JV, Zetoune FS, Ward PA. Regulation of IL-17 family members by adrenal hormones during experimental sepsis in mice. Am J Pathol. 2013 Apr 182(4):1124-30. doi: 10.1016/j.ajpath.2013.01.005. PMID: 23499051; PMCID: PMC3620417.
Wang X, Ward PA. Opportunities and challenges of disease biomarkers: a new section in the Journal of Translational Medicine. J Transl Med. 2012 Dec 5;10:240. doi: 10.1186/1479-5876-10-240. Retraction in: J Transl Med. 2013 11:144. PMID: 23217078; PMCID: PMC3543303.
Bosmann M, Haggadone MD, Hemmila MR, Zetoune FS, Sarma JV, Ward PA. 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 May 15;188(10):5086-93. doi: 10.4049/jimmunol.1102914. PMID: 22491257; PMCID: PMC3345104.
Bosmann M, Grailer JJ, Zhu K, Matthay MA, Sarma JV, Zetoune FS, Ward PA. Anti-inflammatory effects of β2 adrenergic receptor agonists in experimental acute lung injury. FASEB J. 2012 May 26(5):2137-44. doi: 10.1096/fj.11-201640. PMID: 22318967; PMCID: PMC3336792.
Bosmann M, Sarma JV, Atefi G, Zetoune FS, Ward PA. Evidence for anti-inflammatory effects of C5a on the innate IL-17A/IL-23 axis. FASEB J. 2012 Apr 26(4):1640-51. doi: 10.1096/fj.11-199216. PMID: 22202675; PMCID: PMC3316904.
Bosmann M, Russkamp NF, Ward PA. Fingerprinting of the TLR4-induced acute inflammatory response. Exp Mol Pathol. 2012 Dec;93(3):319-23. doi: 10.1016/j.yexmp.2012.08.006. PMID: 22981705; PMCID: PMC3518574.
Bosmann M, Haggadone MD, Hemmila MR, Zetoune FS, Sarma JV, Ward PA. 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 May 15 188(10):5086-93. doi: 10.4049/jimmunol.1102914. PMID: 22491257; PMCID: PMC3345104.
Bosmann M, Sarma JV, Atefi G, Zetoune FS, Ward PA. Evidence for anti-inflammatory effects of C5a on the innate IL-17A/IL-23 axis. FASEB J. 2012 Apr;26(4):1640-51. doi: 10.1096/fj.11-199216. PMID: 22202675; PMCID: PMC3316904.
Bosmann M, Ward PA. Role of C3, C5 and anaphylatoxin receptors in acute lung injury and in sepsis. Adv Exp Med Biol. 2012 946:147-59. doi: 10.1007/978-1-4614-0106-3_9. Review. PMID: 21948367; PMCID: PMC3372066.
Bosmann M, Ward PA. Therapeutic potential of targeting IL-17 and IL-23 in sepsis. Clin Transl Med. 2012 Apr 27;1(1):4. doi: 10.1186/2001-1326-1-4. PMID: 23369364; PMCID: PMC3552565.
Bosmann M, Grailer JJ, Zhu K, Matthay MA, Sarma JV, Zetoune FS, Ward PA. Anti-inflammatory effects of β2 adrenergic receptor agonists in experimental acute lung injury. FASEB J. 2012 May;26(5):2137-44. doi: 10.1096/fj.11-201640. PMID: 22318967; PMCID: PMC3336792.
Sarma JV, Ward PA. New developments in C5a receptor signaling. Cell Health Cytoskelet. 2012 Jul 1;4:73-82. PMID: 23576881; PMCID: PMC3619443.
Ward PA, Guo RF, Riedemann NC. Manipulation of the complement system for benefit in sepsis. Crit Care Res Pract. 2012 2012:427607. doi: 10.1155/2012/427607. PMID: 22482043; PMCID: PMC3303540.
Flierl MA, Rittirsch D, Weckbach S, Huber-Lang M, Ipaktchi K, Ward PA, Stahel PF. Disturbances of the hypothalamic-pituitary-adrenal axis and plasma electrolytes during experimental sepsis. Ann Intensive Care. 2011 Dec 30;1:53. doi: 10.1186/2110-5820-1-53. PMID: 22208725; PMCID: PMC3264499.
Bosmann M, Russkamp NF, Patel VR, Zetoune FS, Sarma JV, Ward PA. The outcome of polymicrobial sepsis is independent of T and B cells. Shock. 2011 Oct;36(4):396-401. doi: 10.1097/SHK.0b013e3182295f5f. PMID: 21701414; PMCID: PMC3175304.
Atefi G, Zetoune FS, Herron TJ, Jalife J, Bosmann M, Al-Aref R, Sarma JV, Ward PA. Complement dependency of cardiomyocyte release of mediators during sepsis. FASEB J. 2011 Jul;25(7):2500-8. doi: 10.1096/fj.11-183236. PMID: 21478262; PMCID: PMC3114524.
Speyer CL, Ward PA. Role of endothelial chemokines and their receptors during inflammation. J Invest Surg. 2011 24(1):18-27.doi:10.3109/08941939.2010.521232. Review. PMID: 21275526.
Ward PA. The harmful role of c5a on innate immunity in sepsis. J Innate Immun. 2010 2(5):439-45. doi: 10.1159/000317194. Review. PMID: 20588003; PMCID: PMC2968761.
Rittirsch D, Flierl MA, Day DE, Nadeau BA, Zetoune FS, Sarma JV, Werner CM, Wanner GA, Simmen HP, Huber-Lang MS, Ward PA. Cross-talk between TLR4 and FcgammaReceptorIII (CD16) pathways. PLoS Pathog. 2009 Jun;5(6):e1000464. doi: 10.1371/journal.ppat.1000464. PMID: 19503602; PMCID: PMC2685003.
Flierl MA, Rittirsch D, Nadeau BA, Sarma JV, Day DE, Lentsch AB, Huber-Lang MS, Ward PA. Upregulation of phagocyte-derived catecholamines augments the acute inflammatory response. PLoS One. 2009 4(2):e4414. doi: 10.1371/journal.pone.0004414. PMID: 19212441; PMCID: PMC2636885.
Ward PA. The sepsis seesaw: seeking a heart salve. Nat Med. 2009 May;15(5):497-8. doi: 10.1038/nm0509-497. PMID: 19424210.
Rittirsch D, Flierl MA, Ward PA. Harmful molecular mechanisms in sepsis. Nat Rev Immunol. 2008 Oct;8(10):776-87. doi: 10.1038/nri2402. Review. PMID: 18802444; PMCID: PMC2786961.
Flierl MA, Rittirsch D, Nadeau BA, Chen AJ, Sarma JV, Zetoune FS, McGuire SR, List RP, Day DE, Hoesel LM, Gao H, Van Rooijen N, Huber-Lang MS, Neubig RR, Ward PA. Phagocyte-derived catecholamines enhance acute inflammatory injury. Nature. 2007 Oct 11;449(7163):721-5. PMID: 17914358.