Severe trauma induces aberrant inflammatory monokine, depressed immunostimulatory monokine production and diminished monocyte (Mphi) antigen-presenting cell(APC) capacity. This contradictory appearance of over activated and depressed MO functions is linked to development of post-injury Multiple Organ Dysfunction Syndrome (MODS) and could result if the post-injury microenvironment preferentially favored Mphi to inflammatory macrophage differentiation over differentiation to DC, the most potent APC. We found that trauma patients who develop post-injury MODS and Mphi APC defects have a MO to DC differentiation defect corresponding to their increased pathology. We will now test the hypothesis that severe injury induced PGE2 production, heat shock protein release, and activation of innate immunity receptors combines to alter MO receptor expression, signal transduction, and monokine production, unbalancing MO differentiation toward inflammatory macrophage and away from DC generation and tissue DC replacement by: I. Determining if the post-injury differential EP expression correlates to patient Mphi differentiation dysfunctions, altered TLR expression, and/or altered HSP-27 induced responses. II. Linking alteration in EP and/or TLR receptors to altered signal transduction during Mphi to DC vs. Mphi to Mac differentiation in patients and normals. Ill. Determining how activation of tissue DC alters after trauma and whether tissue DC or tissue Mac EP and TLR changes parallel the peripheral MO alterations. These experiments should provide insight into how aberrant macrophage function and depressed monocyte APC function develop after severe injury. The interaction of HSP-27 in the development or amelioration of these Mphi dysfunctions will also be dissected with possible prophylactic implications. Most importantly these experiments may suggest how currently available EP and/or TLR agonist or antagonist might be utilized therapeutically in the modulation of MODS development in trauma patients.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM036214-20
Application #
6912695
Study Section
Special Emphasis Panel (ZRG1-SSS-W (04))
Program Officer
Somers, Scott D
Project Start
1997-10-01
Project End
2007-06-30
Budget Start
2005-07-01
Budget End
2006-06-30
Support Year
20
Fiscal Year
2005
Total Cost
$385,373
Indirect Cost
Name
University of Rochester
Department
Surgery
Type
Schools of Dentistry
DUNS #
041294109
City
Rochester
State
NY
Country
United States
Zip Code
14627
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Bandyopadhyay, Gautam; Bankey, Paul E; Miller-Graziano, Carol L (2012) Trauma patients' elevated tumor necrosis related apoptosis inducing ligand (TRAIL) contributes to increased T cell apoptosis. Clin Immunol 145:44-54
Bankey, Paul E; Banerjee, Sanjib; Zucchiatti, Andrea et al. (2010) Cytokine induced expression of programmed death ligands in human neutrophils. Immunol Lett 129:100-7
Kotz, Kenneth T; Xiao, Wenzong; Miller-Graziano, Carol et al. (2010) Clinical microfluidics for neutrophil genomics and proteomics. Nat Med 16:1042-7
Miller-Graziano, Carol L; De, Asit; Laudanski, Krzysztof et al. (2008) HSP27: an anti-inflammatory and immunomodulatory stress protein acting to dampen immune function. Novartis Found Symp 291:196-208;discussion 208-11, 221-
Laudanski, Krzysztof; De, Asit; Miller-Graziano, Carol (2007) Exogenous heat shock protein 27 uniquely blocks differentiation of monocytes to dendritic cells. Eur J Immunol 37:2812-24
Laudanski, Krzysztof; De, Asit; Pellegrini, Joanmarie et al. (2006) Simultaneous aberrations in Mphi and T cell function adversely affect trauma patients' clinical outcome: a possible faulty IL-13 feedback loop. Clin Immunol 118:332-41
Laudanski, Krzysztof; De, Asit; Brouxhon, Sabine et al. (2004) Abnormal PGE(2) regulation of monocyte TNF-alpha levels in trauma patients parallels development of a more macrophage-like phenotype. Shock 22:204-12
De, Asit K; Laudanski, Krzysztof; Miller-Graziano, Carol L (2003) Failure of monocytes of trauma patients to convert to immature dendritic cells is related to preferential macrophage-colony-stimulating factor-driven macrophage differentiation. J Immunol 170:6355-62
De, A K; Kodys, K M; Yeh, B S et al. (2000) Exaggerated human monocyte IL-10 concomitant to minimal TNF-alpha induction by heat-shock protein 27 (Hsp27) suggests Hsp27 is primarily an antiinflammatory stimulus. J Immunol 165:3951-8

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