In conclusion, this meta-analysis showed that serum concentration of IL-6 within the first 24 h after trauma could be useful for the prediction of post-traumatic complications, particularly MOF/MODS and mortality.

Background: Extremity fracture is frequently seen in multiple traumatized patients. Local post-traumatic inflammatory reactions as well as local and systemic interactions have been described in previous studies. However, trauma severity and its impact on the local immunologic reaction remains unclear. Therefore, fracture-associated local inflammation was investigated in a porcine model of isolated and combined trauma to gain information about the early inflammatory stages. Material and Methods: Polytrauma (PT) consisted of lung contusion, liver laceration, femur fracture, and controlled hemorrhage. Monotrauma (MT) consisted of femur fracture only. The fracture was operatively stabilized and animals were monitored under ICU-standard for 72 h. Blood, fracture hematoma (FH) as well as muscle samples were collected throughout the experimental period. Levels of local and systemic pro-and anti-inflammatory as well as angiogenetic cytokines were measured by ELISA. Results: Both groups showed a significant decrease in pro-inflammatory IL-6 in FH over time. However, concentrations in MT were significantly higher than in PT. The IL-8 concentrations initially decreased in FH, but recovered by the end of the observation period. These dynamics were only statistically significant in MT. Furthermore, concentrations measured in muscle tissue showed inverse kinetics compared to those in FH. The IL-10 did not present statistical resilient dynamics over time, although a slight increase in FH was seen by the end of the observation time in the MT group. Conclusions: Time-dependent dynamics of the local inflammatory response were observed. Trauma severity showed a significant impact, with lower values in pro-as well as angiogenetic mediators. Fracture repair could be altered by these trauma-related changes of the local immunologic milieu, which might serve as a possible explanation for the higher rates of delayed or non-union bone repair in polytraumatised patients.

Hemorrhagic shock/resuscitation (HS/R) is closely associated with overwhelming oxidative stress and systemic inflammation. As an effective activator of the nuclear factor-erythroid factor 2 related factor 2 (Nrf2) pathway, sulforaphane (SFN) exerts antioxidant and anti-inflammatory effects. We explored SFN's effects on alveolar macrophages (AMs), systemic inflammation, and pulmonary damage in an isolated murine HS/R model. Male C57/BL6 wild type and transgenic antioxidant response element (ARE)-luciferase (luc) mice (both n ¼ 6 per group) were exposed to either pressurecontrolled HS/R (mean arterial pressure 35-45 mm Hg for 90 min) or sham procedure (surgery without HS/R) or were sacrificed without intervention (control group). Fluid resuscitation was performed via the reinfusion of withdrawn blood and 0.9% saline. Sulforaphane or 0.9% saline (vehicle) was administrated intraperitoneally. Mice were sacrificed 6, 24, or 72 h after resuscitation. Bioluminescence imaging of ARE-luc mice was conducted to measure pulmonary Nrf2 activity. Plasma was collected to determine systemic cytokine levels. Alveolar macrophages were isolated before measuring cytokines in the supernatant and performing immunofluorescence staining, as well as Western blot for intracellular Nrf2. Histological damage was assessed via the acute lung injury score and wet/dry ratio. Hemorrhagic shock/resuscitation was associated with pulmonary Nrf2 activation. Sulforaphane enhanced pulmonary Nrf2 activity and the Nrf2 activation of AM, while it decreased lung damage. Sulforaphane exerted down-regulatory effects on AM-generated and systemic pro-inflammatory mediators, while it did not have such effects on IL-10. In conclusion, SFN beneficially enhances pulmonary Nrf2 activity and promotes Nrf2 accumulation in AMs' nuclei. This may exert not only local protective effects but also systemic effects via the down-regulation of pro-inflammatory cytokines. The administration of Nrf2 activator post-HS/R may represent an innovative treatment strategy.

In response to different stimuli (e.g., infections), naive macrophages polarize into M1 macrophages, which have the potential to secrete numerous proinflammatory cytokines and extracellular vesicles (EVs). EVs are important mediators of intercellular communication. Via horizontal transfer, EVs transport various molecules (e.g., proteins, DNA, and RNA) to target cells. This in vitro study elucidated that M1-EVs from macrophages induced by interferon-γ (IFN-γ) and lipopolysaccharide (LPS) 24 h (M1), but not M0-EVs from untreated macrophages (M0), shifted M0 into M1 phenotype via activating the nuclear factor-κB pathway. The characteristics of these EVs were assessed by transmission electron microscopy (TEM), nanoparticle tracking analysis (NTA), and a western blot assay. RAW 264.7 cells were incubated with M1-EVs (experimental group) or PBS (sham group) or M0-EVs (control group) for 24 h. The viability, change of shape, and phenotype differentiation of the macrophages were identified by a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, flow cytometry, and immunofluorescence staining. The TLR4-NFκB pathway of RAW264.7 macrophages was assessed by a western blot assay. M1-EVs but not M0-EVs were incorporated by the RAW264.7 cells and directly induced polarization of RAW264.7 macrophages to M1 macrophages. This polarization was demonstrated by significant upregulation of the M1 macrophage marker CD86 in the experimental group (49.93 ± 5.0%) as compared with that in the control and sham groups (1.22% and 1.46%, respectively) and significant upregulation of iNOS in the experimental group (75 ± 5.0%) as compared with that in the control and sham groups (0%). Furthermore, cell viability was higher (1.3 times) in the experimental group as compared with that in both the sham and control groups. The regulatory mechanism of M1-EVs on RAW 264.7 macrophages polarization and activation was triggered by the