Patients with severe
burns are highly susceptible to
bacterial infection. While immunosuppression facilitates
infection, the contribution of soft tissues to
infection beyond providing a portal for bacterial entry remains unclear. We showed previously that
glutathione S-transferase S1 (gstS1), an
enzyme with conjugating activity against the lipid peroxidation byproduct
4-hydroxynonenal (4HNE), is important for resistance against
wound infection in Drosophila muscle. The importance of the mammalian functional counterpart of GstS1 in the context of
wounds and
infection has not been investigated. Here we demonstrate that the presence of a
burn wound dramatically affects expression of both human (
hGSTA4) and mouse (mGsta4) 4HNE scavengers.
hGSTA4 is down-regulated significantly within 1 wk of thermal
burn injury in the muscle and fat tissues of patients from the large-scale collaborative
Inflammation and the Host Response to Injury multicentered study. Similarly, mGsta4, the murine GST with the highest catalytic efficiency for 4HNE, is down-regulated to approximately half of normal levels in mouse muscle immediately postburn. Consequently, 4HNE
protein adducts are increased 4- to 5-fold in mouse muscle postburn. Using an open
wound infection model, we show that deletion of mGsta4 renders mice more susceptible to
infection with the prevalent
wound pathogen Pseudomonas aeruginosa, while muscle
hGSTA4 expression negatively correlates with
burn wound infection episodes per patient. Our data suggest that
hGSTA4 down-regulation and the concomitant increase in 4HNE adducts in human muscle are indicative of susceptibility to
infection in individuals with severely thermal
injuries.