IGF-I gene transfer effects on inflammatory elements present after thermal trauma

1 Shriners Hospitals for Children and Department of Surgery, and 2 Department of Human Genetics and Biological Chemistry, University of Texas Medical Branch, Galveston, Texas 77550 Submitted 24 January 2003 ; accepted in final form 9 June 2003 Major thermal injury results in severe prolonged responses with three components: a hypermetabolic response, inflammatory responses, and endogenous wound-healing processes. We showed that use of liposome-mediated gene transfer of the insulin-like growth factor I (IGF-I) reduces burn-induced inflammatory responses and enhances wound healing. In the present study, we found transient increased levels of IGF-I protein in rats exposed to thermal trauma via liposomal gene transfer in an effort to define the transcriptional events that occur after IGF-I delivery at the site of injury. The beneficial effects of IGF-I gene transfer act partly via amelioration of burn-induced inflammatory responses that mediate cell death through caspase-3 activity and Bax expression. IGF-I gene transfer induces selective stimulation of activation protein-1 DNA-binding activity and activation of antiapoptotic, but not inflammatory, NF- B transcription factors. Data were consistent with our hypothesis that the beneficial effects of IGF-I gene transfer on burned rats act in part via activation protein-1 and NF- B transcriptional regulation and the concordance between the results obtained with antiapoptotic, as opposed to the proapoptotic, sequences as well as the corresponding changes in measures of cell death via Bax and caspase-3 mechanisms. nuclear factor- B; thermal injury; activation protein-1; caspase-3; Bax Address for reprint requests and other correspondence: M. R. K. Dasu, Shriners Hospitals for Children, 815 Market St., Galveston, TX 77550 (E-mail: drmohan{at}utmb.edu ).