The Influence of Macrophage-Activating Lipopeptide 2 (MALP-2) on Local and Systemic Inflammatory Response in a Murine Two-Hit Model of Hemorrhagic Shock and Subsequent Sepsis

Abstract

Pulmonary complications after severe trauma and sepsis remain to be the main cause for adverse outcome. MALP-2 has been described to exert beneficial effects on organ damage and the further course after isolated trauma and sepsis. However, the impact of MALP-2 on a clinically realistic two-hit scenario of trauma and subsequent sepsis remains unknown. We, therefore, investigated if the systemic inflammatory response and pulmonary immune response and damage are beneficially modulated by MALP-2 in a murine two-hit model. Blood pressure-controlled trauma-hemorrhage (TH) and cecal ligation and puncture (CLP) were induced in C57/BL6 mice. Mice were divided into 2 control groups (control 1: TH without CLP; control 2: TH and CLP) and 3 experimental groups treated with MALP-2 at different time points (ETH, end of TH; ECLP, end of CLP; and 6CLP 6 h after CLP). Survival rates were assessed over the observation period of 168 h after the induction of TH. Concentrations of plasma inflammatory cytokines and chemokines (TNF-α, IL-6, MIP-1α, IFN-γ, and IL-10) were assessed, and bacterial clearance of the lungs was determined. Furthermore, pulmonary MPO activity assay to evaluate the infiltration of polymorphonuclear neutrophils (PMN) and histological evaluation were performed. Survival rates were evaluated. Compared with control group 1, the level of TNF-α in the ECLP group showed a significant increase (ECLP, 2.27 pg./ml ± 1.39 vs. control 1: 0.16 pg./ml ± 0.11, p = 0.021). In contrast, levels of IFN-γ were significantly reduced in groups ETH and 6CLP compared with control group 1 (control 1: 8.92 pg./ml ± 4.38 vs. ETH: 1.77 pg./ml ± 4.34, p = 0.026 resp. vs. 6CLP: 1.83 pg./ ml ± 4.49, p = 0.014). While systemic concentrations of inflammatory mediators were not

Long Non-coding RNA MALAT1 Promotes Sepsis-Induced Testicular Injury by Targeting MiR-103-3p to Modulate TRPV4 Expression

“…Sepsis is an important cause of organ dysfunction in patients and poses a certain threat to the life safety of ICU patients 30 . The in ammatory response is a key feature in the development of organ damage in sepsis 31 . Testicular injury is one of the complications of sepsis, and when LPS activates sepsis, the proin ammatory factors released by in ammatory cells will affect the function of the testes to some extent 32 , and the production of sperm and testosterone is likely to be impaired As a result, and the reproductive function of male patients will be seriously affected 4 .…”

Pushing the envelope: Immune mechanism and application landscape of macrophage-activating lipopeptide-2

“…MALP-2 also reduces mortality and lung and liver injury in mice with trauma and sepsis. MALP-2 should be used at the earliest sepsis diagnosis, and a larger cohort is needed to determine the optimal dose of MALP-2 ( 62 , 63 ). Intra-pulmonary neutropenia is inevitably strongly associated with increased survival in septic mice.…”

Innate immunity and immunotherapy for hemorrhagic shock

“…Xu Ding et al. reported that macrophage-activating lipopeptide-2 (MALP-2), as an agonist of TLR, given at the earliest can reduce pulmonary damage and polymorphonuclear neutrophil infiltration in an HS mouse model ( 125 ).…”

“…The direct administration by a receptor agonist can block the binding of TLR ligands with their receptor, interfere with intracellular signaling molecules, and prevent signal amplification, which is a promising approach for treating HS-induced immune dysregulation. Xu Ding et al reported that macrophage-activating lipopeptide-2 (MALP-2), as an agonist of TLR, given at the earliest can reduce pulmonary damage and polymorphonuclear neutrophil infiltration in an HS mouse model (125).…”