Acute, regional inflammatory response after traumatic brain injury: Implications for cellular therapy

Abstract

While cellular therapy has shown promise in the management of traumatic brain injury (TBI), microenvironment interactions between the intracerebral milieu and therapeutic stem cells are poorly understood. We sought to characterize the acute, regional inflammatory response after TBI. Rats underwent a controlled cortical impact (CCI) injury or sham injury, were sacrificed at 6, 12, 24, 48, and 72 hours, and intracerebral fluid (IF) was isolated from the direct injury, penumbral, ipsilateral frontal, contralateral regions. Cortical and hippocampal areas were also isolated. Regional cytokine levels were measured. PMN oxidative burst and marker expression were assessed after incubation with the IF. Immunohistochemistry identified intracerebral CD68+ cells (microglia/macrophages). The pro-inflammatory cytokines IL-1α, IL-1β, IL-6, and TNF-α were significantly elevated after CCI in the injury and penumbral regions. Increases in the same cytokines were localized to the cortex and the hippocampus. Increased PMN expression of CD11b and L-selectin was identified after incubation with injury or penumbral area IF, without change in PMN oxidative burst. CD68+ cells were noted in the direct injury and penumbral areas. The local cerebral milieu in the first 48 hrs after TBI is highly pro-inflammatory. This response is most pronounced in areas at or proximal to the direct injury. The local, acute pro-inflammatory response after TBI may serve as a therapeutic target of early cell therapy or, conversely, may create an unfavorable local milieu, limiting the efficacy of early cellular therapy.

Low-Level Laser Light Therapy Improves Cognitive Deficits and Inhibits Microglial Activation after Controlled Cortical Impact in Mice

“…We found a robust reduction in microglial activation 48 h post-CCI, the peak of microgliosis in our CCI model and other experimental TBI models (Harting et al, 2008;Ziebell and Morganti-Kossmann, 2010). To our knowledge these are the first data to show an anti-inflammatory effect of LLLT in the immune response to TBI.…”

Subacute Neural Stem Cell Therapy for Traumatic Brain Injury

“…Although a hyperacute cell transplantation (Ͻ24 h after injury) strategy has shown cell survival and behavioral benefit [5-7, 16, 24], recent work is revealing that the acute, central nervous system proinflammatory microenvironment is suboptimal for survival of grafted cells [25]. We chose the 7-d time point because the optimal time window may be after the acute inflammatory cascade, including cytokine release, macrophage/microglia infiltration, and edema (which all appear to resolve around d 5-6 after injury), yet prior to glial scar formation (which is observed to begin forming around d 10 -14) [25,26].…”

Probing the mechanical properties of TNF-α stimulated endothelial cell with atomic force microscopy

“…In healthy patients, the plasma level of TNF-α is generally smaller than 1 pg/mL, but its concentration can be abnormally high in the presence of atherosclerosis, [9][10][11][12] during tumorigenesis and tumor growth, 13 in patients with rheumatoid arthritis, 14 in women undergoing pre-eclamptic pregnancies, 15 and in obese individuals. 16 In incidences of acute trauma, elevated circulating levels of TNF-α have also been reported, including, but not limited to, traumatic brain injury 17 and hemorrhagic shock. 18,19 Also, others have reported that soluble forms of membrane receptors (TNFR) rather than TNF-α are initially released following trauma (based on serum levels one hour after arrival at a trauma center) and may serve as an indirect indicator that TNF-α associates with trauma.…”