Hemorrhagic Shock Shifts the Serum Cytokine Profile from Pro- to Anti-Inflammatory after Experimental Traumatic Brain Injury in Mice

Abstract

Secondary insults, such as hemorrhagic shock (HS), worsen outcome from traumatic brain injury (TBI). Both TBI and HS modulate levels of inflammatory mediators. We evaluated the addition of HS on the inflammatory response to TBI. Adult male C57BL6J mice were randomized into five groups (n=4 [naïve] or 8/group): naïve; sham; TBI (through mild-to-moderate controlled cortical impact [CCI] at 5 m/sec, 1-mm depth), HS; and CCI+HS. All non-naïve mice underwent identical monitoring and anesthesia. HS and CCI+HS underwent a 35-min period of pressure-controlled hemorrhage (target mean arterial pressure, 25-27 mm Hg) and a 90-min resuscitation with lactated Ringer's injection and autologous blood transfusion. Mice were sacrificed at 2 or 24 h after injury. Levels of 13 cytokines, six chemokines, and three growth factors were measured in serum and in five brain tissue regions. Serum levels of several proinflammatory mediators (eotaxin, interferon-inducible protein 10 [IP-10], keratinocyte chemoattractant [KC], monocyte chemoattractant protein 1 [MCP-1], macrophage inflammatory protein 1alpha [MIP-1α], interleukin [IL]-5, IL-6, tumor necrosis factor alpha, and granulocyte colony-stimulating factor [G-CSF]) were increased after CCI alone. Serum levels of fewer proinflammatory mediators (IL-5, IL-6, regulated upon activation, normal T-cell expressed, and secreted, and G-CSF) were increased after CCI+HS. Serum level of anti-inflammatory IL-10 was significantly increased after CCI+HS versus CCI alone. Brain tissue levels of eotaxin, IP-10, KC, MCP-1, MIP-1α, IL-6, and G-CSF were increased after both CCI and CCI+HS. There were no significant differences between levels after CCI alone and CCI+HS in any mediator. Addition of HS to experimental TBI led to a shift toward an anti-inflammatory serum profile--specifically, a marked increase in IL-10 levels. The brain cytokine and chemokine profile after TBI was minimally affected by the addition of HS.

Acute CSF interleukin-6 trajectories after TBI: Associations with neuroinflammation, polytrauma, and outcome

“…Experimental studies using a TBI + hemorrhagic shock mouse model have reported increased serum IL-10 levels, but decreased serum IL-6 levels, in the TBI + hemorrhagic shock group compared to isolated TBI (Shein et al, 2014). Varied definitions and models of polytrauma vs. hypotension/shock across clinical and animal studies may account for differences in reported inflammatory profiles.…”

Innate immune responses to trauma

“…This cholinergic anti-inflammatory pathway seems to be critically involved in the control of systemic inflammation and BBB breakdown 119 . Activation of the sympathetic ANS (the ‘sympathetic storm’) after TBI or after an additional hemorrhagic shock can result in massive peripheral release of epinephrine and/or norepinephrine, which causes enhanced, but also reprogrammed and suppressed, immune responses 122–124 . After TBI, plasma norepinephrine is associated with a poor outcome, and patients exhibit signs of endotheliopathy and coagulopathy 125 .…”

Inflammatory reaction after traumatic brain injury: therapeutic potential of targeting cell–cell communication by chemokines

“…These approaches enable kinetic studies of mediator production in TBI animal models [20–23]. For example, more than one study reported expression of IL-1β, TNF-α, IL-6, CCL2, CCL3, CXCL1, CXCL2, CXCL8/IL-8, CXCL10, CCR2, CCR5, CXCR4 and CX3CR1within 6 hr of TBI.…”

“…CCL2 was one of the initial chemokines identified as significantly upregulated within 24 hr in rodent models of TBI at both the mRNA and protein level (Figure 2B) [20–23, 41, 42, 60–64]. In situ hybridization, immunohistochemistry and immunofluorescence techniques have shown CCL2 expression in both GFAP-positive astrocytes [60, 61] and cells with macrophage morphology and markers [61, 64].…”