Rishabh Sharma1, Akram Zamani1, Larissa K Dill1,2, Mujun Sun1, Erskine Chu1, Marcus J Robinson3, Terence J O'Brien1,2,4, Sandy R Shultz1,2,4, Bridgette D Semple5,6,7. 1. Department of Neuroscience, Central Clinical School, Monash University, Level 6, The Alfred Centre, 99 Commercial Road, Melbourne, VIC, 3004, Australia. 2. Department of Neurology, Alfred Health, Prahran, VIC, Australia. 3. Department of Immunology and Pathology, Central Clinical School, Monash University, Melbourne, VIC, Australia. 4. Department of Medicine (Royal Melbourne Hospital), The University of Melbourne, Parkville, VIC, Australia. 5. Department of Neuroscience, Central Clinical School, Monash University, Level 6, The Alfred Centre, 99 Commercial Road, Melbourne, VIC, 3004, Australia. Bridgette.Semple@monash.edu. 6. Department of Neurology, Alfred Health, Prahran, VIC, Australia. Bridgette.Semple@monash.edu. 7. Department of Medicine (Royal Melbourne Hospital), The University of Melbourne, Parkville, VIC, Australia. Bridgette.Semple@monash.edu.
Abstract
BACKGROUND: Traumatic brain injury (TBI) is a major cause of disability in young children, yet the factors contributing to poor outcomes in this population are not well understood. TBI patients are highly susceptible to nosocomial infections, which are mostly acquired within the first week of hospitalization, and such infections may modify TBI pathobiology and recovery. In this study, we hypothesized that a peripheral immune challenge such as lipopolysaccharide (LPS)-mimicking a hospital-acquired infection-would worsen outcomes after experimental pediatric TBI, by perpetuating the inflammatory immune response. METHODS: Three-week-old male mice received either a moderate controlled cortical impact or sham surgery, followed by a single LPS dose (1 mg/kg i.p.) or vehicle (0.9% saline) at 4 days post-surgery, then analysis at 5 or 8 days post-injury (i.e., 1 or 4 days post-LPS). RESULTS: LPS-treated mice exhibited a time-dependent reduction in general activity and social investigation, and increased anxiety, alongside substantial body weight loss, indicating transient sickness behaviors. Spleen-to-body weight ratios were also increased in LPS-treated mice, indicative of persistent activation of adaptive immunity at 4 days post-LPS. TBI + LPS mice showed an impaired trajectory of weight gain post-LPS, reflecting a synergistic effect of TBI and the LPS-induced immune challenge. Flow cytometry analysis demonstrated innate immune cell activation in blood, brain, and spleen post-LPS; however, this was not potentiated by TBI. Cytokine protein levels in serum, and gene expression levels in the brain, were altered in response to LPS but not TBI across the time course. Immunofluorescence analysis of brain sections revealed increased glia reactivity due to injury, but no additive effect of LPS was observed. CONCLUSIONS: Together, we found that a transient, infection-like systemic challenge had widespread effects on the brain and immune system, but these were not synergistic with prior TBI in pediatric mice. These findings provide novel insight into the potential influence of a secondary immune challenge to the injured pediatric brain, with future studies needed to elucidate the chronic effects of this two-hit insult.
BACKGROUND:Traumatic brain injury (TBI) is a major cause of disability in young children, yet the factors contributing to poor outcomes in this population are not well understood. TBI patients are highly susceptible to nosocomial infections, which are mostly acquired within the first week of hospitalization, and such infections may modify TBI pathobiology and recovery. In this study, we hypothesized that a peripheral immune challenge such as lipopolysaccharide (LPS)-mimicking a hospital-acquired infection-would worsen outcomes after experimental pediatric TBI, by perpetuating the inflammatory immune response. METHODS: Three-week-old male mice received either a moderate controlled cortical impact or sham surgery, followed by a single LPS dose (1 mg/kg i.p.) or vehicle (0.9% saline) at 4 days post-surgery, then analysis at 5 or 8 days post-injury (i.e., 1 or 4 days post-LPS). RESULTS:LPS-treated mice exhibited a time-dependent reduction in general activity and social investigation, and increased anxiety, alongside substantial body weight loss, indicating transient sickness behaviors. Spleen-to-body weight ratios were also increased in LPS-treated mice, indicative of persistent activation of adaptive immunity at 4 days post-LPS. TBI + LPSmice showed an impaired trajectory of weight gain post-LPS, reflecting a synergistic effect of TBI and the LPS-induced immune challenge. Flow cytometry analysis demonstrated innate immune cell activation in blood, brain, and spleen post-LPS; however, this was not potentiated by TBI. Cytokine protein levels in serum, and gene expression levels in the brain, were altered in response to LPS but not TBI across the time course. Immunofluorescence analysis of brain sections revealed increased glia reactivity due to injury, but no additive effect of LPS was observed. CONCLUSIONS: Together, we found that a transient, infection-like systemic challenge had widespread effects on the brain and immune system, but these were not synergistic with prior TBI in pediatric mice. These findings provide novel insight into the potential influence of a secondary immune challenge to the injured pediatric brain, with future studies needed to elucidate the chronic effects of this two-hit insult.
Authors: M J Bell; P M Kochanek; L A Doughty; J A Carcillo; P D Adelson; R S Clark; S R Wisniewski; M J Whalen; S T DeKosky Journal: J Neurotrauma Date: 1997-07 Impact factor: 5.269
Authors: James P Barrett; Rebecca J Henry; Kari Ann Shirey; Sarah J Doran; Oleg D Makarevich; Rodney M Ritzel; Victoria A Meadows; Stefanie N Vogel; Alan I Faden; Bogdan A Stoica; David J Loane Journal: J Neurosci Date: 2020-02-06 Impact factor: 6.167
Authors: Ibrahim M Alharfi; Tanya Charyk Stewart; Ibrahim Al Helali; Hani Daoud; Douglas D Fraser Journal: J Neurotrauma Date: 2013-12-19 Impact factor: 5.269
Authors: Steven Biesmans; Theo F Meert; Jan A Bouwknecht; Paul D Acton; Nima Davoodi; Patrick De Haes; Jacobine Kuijlaars; Xavier Langlois; Liam J R Matthews; Luc Ver Donck; Niels Hellings; Rony Nuydens Journal: Mediators Inflamm Date: 2013-07-10 Impact factor: 4.711