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The Influence of Macrophage-Activating Lipopeptide-2 in Regard to Liver-Specific Changes Within a Murine Two-Hit
Weikang Wang1,2,1, Ding Xu3,4, Peng Luo5,6,5
1Department of Orthopedic Trauma Surgery, RWTH Aachen University, Aachen, Germany. wangweikang0116@163.com.
Abstract:
Trauma hemorrhage (TH) and subsequent sepsis are well known to frequently result in severe organ damage. Although macrophage-activating lipopeptide-2 (MALP-2) has been described to exert beneficial effects on organ damage, and further clinical course after both isolated trauma and sepsis, little is known about the impact of MALP-2 in a clinically realistic two-hit scenario of TH and subsequent sepsis. As the liver represents a key organ for the posttraumatic immune response and development of complications, the effects of MALP-2 on the posttraumatic hepatic immunologic response and tissue damage were investigated in a murine "two-hit" model. In C57BL/6 mice, blood pressure-controlled (35 ± 5 mm Hg) TH was induced. Cecal ligation and puncture (CLP) was performed 48 h after TH. Mice were divided into two control groups (control 1, TH and laparotomy without CLP; control 2, TH and CLP) and three experimental groups (TH + CLP) treated with MALP-2 at different timepoints (ETH, end of TH; ECLP, end of CLP; 6CLP, 6 h after CLP). The observation time lasted for 168 h after induction of TH. Kupffer cells (KC) were isolated and cultured, and MPO activity was analyzed. Cell culture supernatants were taken for cytokine analysis (TNF-α, IL-6, MCP-1, GM-CSF, IL-10). Histological analysis was performed using the Hepatic Injury Severity Scoring (HISS). Statistical evaluation was carried out using SPSS (version 24.0.0; IBM, Armonk, NY, USA). MPO activity of control 1 group was lowest compared with all the other groups (p < 0.01). MPO activity of control 2 group was significantly higher than that in all experimental groups (ETH (p < 0.01), ECLP (p < 0.01), and 6CLP (p = 0.03)). Within the experimental groups, MPO activity was significantly reduced in the ETH (p = 0.04) and the ECLP (p < 0.01) groups compared with the 6CLP group. Moreover, ETH was also associated with the most pronounced reduction of cytokine expression by KC (p < 0.05). HISS revealed the largest damage in the group control 2. TH and subsequent sepsis lead to a distinct immunologic reaction in the liver with an increase of cytokine expression of KC and pronounced infiltration of granulocytes with associated severe tissue damage. MALP application decreases the hepatic immune response and liver damage, with the most pronounced effects if applied at the end of TH.
Insights
Trauma hemorrhage and sepsis cause severe organ damage. Macrophage-activating lipopeptide-2 (MALP-2) treatment, especially at the end of trauma hemorrhage, significantly reduces liver inflammation and damage in a two-hit mouse model.
Area of Science:
- Immunology
- Pathology
- Pharmacology
Background:
- Trauma hemorrhage (TH) and subsequent sepsis frequently lead to severe organ damage.
- The liver plays a crucial role in post-traumatic immune responses and complication development.
- The impact of macrophage-activating lipopeptide-2 (MALP-2) in a combined TH and sepsis model is not well understood.
Purpose of the Study:
- To investigate the effects of MALP-2 on the hepatic immune response and tissue damage in a murine two-hit model of TH and sepsis.
- To determine the optimal timing for MALP-2 administration to mitigate liver injury.
Main Methods:
- A murine two-hit model involving TH followed by cecal ligation and puncture (CLP) was established.
- Mice were treated with MALP-2 at different time points: end of TH (ETH), end of CLP (ECLP), and 6 hours after CLP (6CLP).
- Hepatic immune responses were assessed by analyzing Kupffer cell (KC) cytokine production and myeloperoxidase (MPO) activity, alongside histological evaluation of liver damage (HISS).
Main Results:
- TH and sepsis induced significant hepatic immune cell activation, cytokine release, granulocyte infiltration, and tissue damage.
- MALP-2 treatment reduced MPO activity and cytokine expression in KCs compared to controls.
- Early administration of MALP-2 (ETH and ECLP) resulted in significantly lower MPO activity and hepatic injury scores compared to later administration (6CLP).
- ETH treatment showed the most pronounced reduction in KC cytokine expression and overall liver damage.
Conclusions:
- The "two-hit" model of TH followed by sepsis triggers a robust hepatic immune response and significant liver damage.
- MALP-2 administration effectively mitigates this post-traumatic, sepsis-induced hepatic immune response and tissue damage.
- Administering MALP-2 at the end of trauma hemorrhage (ETH) provides the most significant protective effect against liver injury in this model.
