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Published on: June 15, 2019
The anti-inflammatory effect of the synthetic antimicrobial peptide 19-2.5 in a murine sepsis model: a prospective
Introduction:
Increasing rates of multi-resistant bacteria are a major problem in the treatment of critically ill patients. Furthermore, conventional antibiotics lead to the release of bacterial derived membrane parts initiating pro-inflammatory cascades with potential harm to the patient. Antimicrobial peptides (AMP) may kill bacteria without releasing pro-inflammatory factors. Thus, we compared three newly developed synthetic anti-lipopolysaccharide peptides (SALPs) with a broader range of efficacy to suppress cytokine release in plasma and CD14 mRNA expression in organ tissue in a murine, polymicrobial sepsis model.
Methods:
A randomized, experimental trial was conducted in an animal research facility. Male NMRI mice (n = 90; 8- to 12-weeks old) were randomized to the following six groups: (i) sham operation and parenteral vehicle (NaCl 0.9%) administration (sham); (ii) cecal ligation and puncture (CLP) and vehicle infusion (sepsis-control), (iii) CLP and polymyxin B infusion (polyB), or (iv to vi) CLP and infusion of three different synthetic antimicrobial peptides Peptide 19-2.5 (Pep2.5), Peptide 19-4 (Pep4) or Peptide 19-8 (Pep8). All animals underwent arterial and venous catheterization for hemodynamic monitoring 48 hours prior to CLP or sham-operation. Physical appearance and behavior (activity), plasma cytokine levels, and CD14 mRNA expression in heart, lung, liver, spleen and kidney tissue were determined 24 hours after CLP or sham operation.
Results:
Only Pep2.5 significantly enhanced the activity after CLP, whereas none of the therapeutic regimens elevated the mean arterial pressure or heart rate. The strongly elevated IL-6, IL-10 and monocyte chemoattractant protein serum levels in septic animals were significantly reduced after Pep2.5 administration (P < 0.001, P < 0.001, and P < 0.001, respectively). Similarly, Pep2.5 significantly reduced the sepsis-induced CD14 mRNA expression in heart (P = 0.003), lung (P = 0.008), and spleen tissue (P = 0.009) but not in kidney and liver.
Conclusions:
Structurally variable SALPs exhibit major differences in their anti-inflammatory effect in vivo. Continuous parenteral administration of Pep2.5 is able to reduce sepsis-induced cytokine release and tissue inflammation.
Insights
Synthetic antimicrobial peptides (SALPs) show promise in treating sepsis. Peptide 19-2.5 (Pep2.5) effectively reduced inflammatory markers and tissue damage in a murine sepsis model, offering a potential new therapeutic strategy.
Area of Science:
- Sepsis research
- Immunology
- Drug discovery
Background:
- Rising antimicrobial resistance necessitates novel treatments for critically ill patients.
- Conventional antibiotics can exacerbate inflammation by releasing bacterial components.
- Antimicrobial peptides (AMPs) offer a potential alternative by targeting bacteria without inducing pro-inflammatory responses.
Purpose of the Study:
- To compare the efficacy of three synthetic anti-lipopolysaccharide peptides (SALPs) in suppressing inflammation during polymicrobial sepsis.
- To evaluate the impact of SALPs on cytokine release and CD14 mRNA expression in a murine sepsis model.
Main Methods:
- A randomized experimental trial involving 90 male NMRI mice subjected to cecal ligation and puncture (CLP) or sham operation.
- Mice received either vehicle, polymyxin B, or one of three SALPs (Pep2.5, Pep4, Pep8) via infusion.
- Hemodynamic monitoring, assessment of physical activity, plasma cytokine levels, and tissue CD14 mRNA expression were performed 24 hours post-CLP.
Main Results:
- Peptide 19-2.5 (Pep2.5) significantly improved animal activity post-CLP.
- Pep2.5 administration markedly reduced elevated IL-6, IL-10, and monocyte chemoattractant protein serum levels.
- Pep2.5 significantly decreased sepsis-induced CD14 mRNA expression in heart, lung, and spleen tissues.
Conclusions:
- Synthetic anti-lipopolysaccharide peptides (SALPs) demonstrate varying in vivo anti-inflammatory effects.
- Continuous parenteral administration of Pep2.5 effectively mitigates sepsis-induced cytokine release and tissue inflammation.
