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.
| Piccolo, M T; Wang, Y; Verbrugge, S et al. (1999) Role of chemotactic factors in neutrophil activation after thermal injury in rats. Inflammation 23:371-85 |
| Seekamp, A; Hultquist, D E; Till, G O (1999) Protection by vitamin B2 against oxidant-mediated acute lung injury. Inflammation 23:449-60 |
| 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 |
