The pathophysiological mechanisms of local microvascular injury as well as secondary organ injury following thermal skin burns are not well understood. Neutrophils and vascular endothelial cells, together with inflammatory mediators and adhesion molecules, appear to play an important role in these events. It appears that local (skin) and remote (lung) injury after thermal trauma results from a complex interplay of cytokines (TNFa, IL-1), adhesion molecules (endothelial and leukocytic), and the complement activation products. It is postulated that cytokines play a major role in upregulation of both leukocytic and endothelial adhesion molecules. In order to explore the roles of these molecules, the applicants will assess the extent to which cytokine blockade protects against skin and lung vascular injury after thermal trauma of skin, evaluate the roles of adhesion molecules, and determine if blocking of C5a is protective. Since cytokine release and complement activation occur after thermal trauma and products of both mediator systems can activate neutrophils, they will assess the upregulation of CD11b and CD18 and the down regulation of L-selectin on blood neutrophils, after thermal injury, as surrogates of intravascular activation of these cells. Protective interventions will be evaluated for their ability to prevent these changes reflective of intravascular activation of neutrophils. At the tissue level, they will monitor E- and P- selectins, and ICAM-1 in skin and lung tissue sections. The studies will also be extended to include human burn patients.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM048477-04
Application #
2518987
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Project Start
1994-09-01
Project End
1999-08-31
Budget Start
1997-09-01
Budget End
1999-08-31
Support Year
4
Fiscal Year
1997
Total Cost
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Pathology
Type
Schools of Medicine
DUNS #
791277940
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
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Mulligan, M S; Schmid, E; Till, G O et al. (1997) C5a-dependent up-regulation in vivo of lung vascular P-selectin. J Immunol 158:1857-61
Schmid, E; Piccolo, M T; Friedl, H P et al. (1997) Requirement for C5a in lung vascular injury following thermal trauma to rat skin. Shock 8:119-24
Schmid, E; Warner, R L; Crouch, L D et al. (1997) Neutrophil chemotactic activity and C5a following systemic activation of complement in rats. Inflammation 21:325-33
Mulligan, M S; Schmid, E; Beck-Schimmer, B et al. (1996) Requirement and role of C5a in acute lung inflammatory injury in rats. J Clin Invest 98:503-12