In severe burns with sepsis, granulocyte production is arrested despite elevated levels of the primary granulopoietic growth factor, granulocyte colony-stimulating factor (G-CSF). The inability of granulocytic cells to respond to G-CSF may be a a consequence of G-CSF receptor down regulation in these cells. While bone marrow (BM) myeloid G-CSF receptor status in vivo is unknown, in vitro studies have demonstrated that bioactive products released as the result of bacterial infection and massive tissue injury (e.g., LPS and TNF-2) can down regulate G-CSF receptors on immatue myeloid cells and neutrophils. Accordingly, the investigator hypothesizes that G-CSF receptor on myeloid cells of the granulocytic lineage is down regulated in burn sepsis leading to impairred granulocyte production. This hypothesis will be tested in murine burn / Pseudomonas aeruginosa sepsis model.
Four specific aims will be addressed.
The first aim i s to demonstrate the down regulation of G-CSF receptor density in bone marrow cells in burned/infected mice as specific times after injury.
The second aim i s to determine the stage(s) in the development of bone marrow myeoloid cells where maturation is impaired and where G-CSF receptors are down regulated.
The third aim i s to evaluate the ability of PGE2, a recognized mediator of burn-induced immunosuppression, on G-CSF receptor expression on murine myeloid cells (NFS-60 and 32Dc13) in vitro.
The fourth aim i s to determine whether burn/sepsis bone marrow myelosuppression and G-CSF receptor down regulation can be ameliorated by blocking PGE2 production or activity, with indomethacin (a nonspecific COX inhibitor), SC19920 (a selective PGE2 receptor antagonist), or SC-236 (a specific COX-2 inhibitor).

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
1R01GM056424-01A1
Application #
2634848
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Project Start
1998-05-01
Project End
2001-04-03
Budget Start
1998-05-01
Budget End
1999-04-30
Support Year
1
Fiscal Year
1998
Total Cost
Indirect Cost
Name
Loyola University Chicago
Department
Surgery
Type
Schools of Medicine
DUNS #
791277940
City
Maywood
State
IL
Country
United States
Zip Code
60153
Cohen, Mitchell J; Carroll, Colleen; He, Li-Ke et al. (2007) Severity of burn injury and sepsis determines the cytokine responses of bone marrow progenitor-derived macrophages. J Trauma 62:858-67
Cohen, Mitchell J; Shankar, Ravi; Stevenson, Julia et al. (2004) Bone marrow norepinephrine mediates development of functionally different macrophages after thermal injury and sepsis. Ann Surg 240:132-41
Deng, Jiangping; Muthu, Kuzhali; Gamelli, Richard et al. (2004) Adrenergic modulation of splenic macrophage cytokine release in polymicrobial sepsis. Am J Physiol Cell Physiol 287:C730-6
de Silva, Kumudika I; Daud, Asif N; Deng, JiangPing et al. (2003) Prostaglandin E2 mediates growth arrest in NFS-60 cells by down-regulating interleukin-6 receptor expression. Biochem J 370:315-21
Gamelli, Richard; He, Li-Ke; Hahn, Elisabeth (2002) Granulocyte colony-stimulating factor: release is not impaired after burn wound infection. J Trauma 53:284-9; discussion 289-90
Tang, Y; Shankar, R; Gamboa, M et al. (2001) Norepinephrine modulates myelopoiesis after experimental thermal injury with sepsis. Ann Surg 233:266-75
Santangelo, S; Gamelli, R L; Shankar, R (2001) Myeloid commitment shifts toward monocytopoiesis after thermal injury and sepsis. Ann Surg 233:97-106
Santangelo, S; Shoup, M; Gamelli, R L et al. (2000) Prostaglandin E2 receptor antagonist (SC-19220) treatment restores the balance to bone marrow myelopoiesis after burn sepsis. J Trauma 48:826-30; discussion 830-1
Nissen, N N; Shankar, R; Gamelli, R L et al. (1999) Heparin and heparan sulphate protect basic fibroblast growth factor from non-enzymic glycosylation. Biochem J 338 ( Pt 3):637-42
Tang, Y; Shankar, R; Gamelli, R et al. (1999) Dynamic norepinephrine alterations in bone marrow: evidence of functional innervation. J Neuroimmunol 96:182-9

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