Suppressed pulmonary innate immune responses after burn injury are regulated by mTOR (INM7P.429)

Abstract

Abstract Severe trauma, such as burn injury, leads to metabolic and immune dysregulation often resulting in overwhelming bacterial pulmonary infection. Neutrophils accumulate in the lung and exhibit decreased oxidative burst late after injury, which may lead to susceptibility to infection. Substrates of the mammalian target of Rapamycin (mTOR), a key kinase in metabolic signaling, have been implicated in neutrophil trafficking and oxidative burst. We hypothesize that mTOR regulates the innate immune response after burn injury. Mice received a 20% total body surface area burn, and half of the burned mice were treated 5 times per week with Rapamycin to inhibit mTOR. After 14 days we assayed the bactericidal response of pulmonary neutrophils by quantifying dihydrorhodamine (DHR) oxidation. While mTOR inhibition did not impact the number of pulmonary neutrophils, oxidative burst was increased compared to untreated burn mice (DHR mean fluorescence intensity, untreated=56.42; Rapamycin=92.29; p<0.05, n=5). Following pulmonary infection with Pseudomonas aeruginosa, neutrophil oxidative burst was decreased by Rapamycin treatment, corresponding to a 10-fold increase in bacterial load compared to untreated mice. These data suggest that mTOR plays a central role in regulating bactericidal oxidative burst by neutrophils after trauma. We propose that metabolic regulators may be relevant targets to improve innate immune function and consequently infection clearance in burn patients.