Immune dysfunction, susceptibility to sepsis and multiple organ failure are complications associated with thermal injury. Evidence suggests that activation of a pro-inflammatory cascade after burn injury plays an important role in their development. With regards to this, macrophages (Mphi) are major producers of pro-inflammatory mediators with increased productive capacity being observed post-burn. Thus, Mphi hyperactivity (as defined by increased productive capacity for pro-inflammatory mediators) may be of fundamental importance in the development of these complications. Nonetheless, the precise mechanisms responsible for the alterations in Mphi activity are unclear. We have utilized a murine scald burn model (3rd degree, 25 percent total body surface area) and our preliminary results indicated that at 4-7 days post-burn Mphi were """"""""hyperactive"""""""" as increased productive capacity for nitric oxide, TNF-alpha, IL-6 and PGE2 was observed. Furthermore, at 4-7 days post-burn, but not earlier, Mphi hyperactivity was responsible for the suppression of T cell function and at 7 days post-burn mice were significantly more susceptible to the lethal effects of sepsis. With regards to T cells, we have observed significant mortality (approximately 75 percent) during the initial 48 hr. post-burn period in mice lacking gamma/delta T cells (gamma/delta T cell knock-out mice) and Mphi isolated from surviving mice at 7 days post-burn appear not to be """"""""hyperactive"""""""". These findings suggest a dual role for gamma/delta T cells in burn injury pathogenesis; 1) survival early and; 2) induction of Mphi hyperactivity later. Our preliminary results suggest that Mphi hyperactivity post-burn is related to alterations in sensitivity to CAMP, however, the mediators and mechanisms responsible for Mphi hyperactivity post-burn and its role in immune dysfunction remain to elucidated. Moreover, the impact of burn excision, a common clinical practice, on Mphi hyperactivity and susceptibility to sepsis post-burn is unknown. It is our hypothesis that Mphi hyperactivity post-burn is mediated by gamma/delta T cells and altered cAMP responses leading to the development of immune dysfunction. Therefore, we propose to determine the following: 1) The relationship between gamma/delta T cells, Mphi and survival early (initial 48 hr.) post-burn; 2) The role of gamma/delta T cells in the induction of Mphi hyperactivity late (7 days) post-burn; 3) The mechanisms responsible for Mphi hyperactivity post-burn; and 4) The effect of burn wound excision on Mphi hyperactivity and increased susceptibility to sepsis. A more comprehensive understanding of the relationship between Mphi activity, T cell function, and the development of immune dysfunction following thermal injury should hopefully provide the basis for improved therapeutic regimes in the treatment of burn patients.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-SSS-W (19))
Program Officer
Somers, Scott D
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Alabama Birmingham
Schools of Medicine
United States
Zip Code
Daniel, Tanjanika; Alexander, Michelle; Hubbard, William J et al. (2006) Nitric oxide contributes to the development of a post-injury Th2 T-cell phenotype and immune dysfunction. J Cell Physiol 208:418-27
Alexander, Michelle; Daniel, Tanjanika; Chaudry, Irshad H et al. (2004) MAP kinases differentially regulate the expression of macrophage hyperactivity after thermal injury. J Cell Physiol 201:35-44
Toth, Balazs; Alexander, Michelle; Daniel, TanJanika et al. (2004) The role of gammadelta T cells in the regulation of neutrophil-mediated tissue damage after thermal injury. J Leukoc Biol 76:545-52
Schwacha, Martin G; Chaudry, Irshad H; Alexander, Michelle (2003) Regulation of macrophage IL-10 production postinjury via beta2 integrin signaling and the P38 MAP kinase pathway. Shock 20:529-35
Alexander, Michelle; Chaudry, Irshad H; Schwacha, Martin G (2002) Relationships between burn size, immunosuppression, and macrophage hyperactivity in a murine model of thermal injury. Cell Immunol 220:63-9
Schwacha, Martin G; Chaudry, Irshad H (2002) The cellular basis of post-burn immunosuppression: macrophages and mediators. Int J Mol Med 10:239-43
Schwacha, M G; Knoferl, M W; Chaudry, I H (2000) Does burn wound excision after thermal injury attenuate subsequent macrophage hyperactivity and immunosuppression? Shock 14:623-8