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Review
. 2015 Aug 20:6:404.
doi: 10.3389/fimmu.2015.00404. eCollection 2015.

Antimicrobial Peptides in Human Sepsis

Affiliations
Review

Antimicrobial Peptides in Human Sepsis

Lukas Martin et al. Front Immunol. .

Abstract

Nearly 100 years ago, antimicrobial peptides (AMPs) were identified as an important part of innate immunity. They exist in species from bacteria to mammals and can be isolated in body fluids and on surfaces constitutively or induced by inflammation. Defensins have anti-bacterial effects against Gram-positive and Gram-negative bacteria as well as anti-viral and anti-yeast effects. Human neutrophil peptides (HNP) 1-3 and human beta-defensins (HBDs) 1-3 are some of the most important defensins in humans. Recent studies have demonstrated higher levels of HNP 1-3 and HBD-2 in sepsis. The bactericidal/permeability-increasing protein (BPI) attenuates local inflammatory response and decreases systemic toxicity of endotoxins. Moreover, BPI might reflect the severity of organ dysfunction in sepsis. Elevated plasma lactoferrin is detected in patients with organ failure. HNP 1-3, lactoferrin, BPI, and heparin-binding protein are increased in sepsis. Human lactoferrin peptide 1-11 (hLF 1-11) possesses antimicrobial activity and modulates inflammation. The recombinant form of lactoferrin [talactoferrin alpha (TLF)] has been shown to decrease mortality in critically ill patients. A phase II/III study with TLF in sepsis did not confirm this result. The growing number of multiresistant bacteria is an ongoing problem in sepsis therapy. Furthermore, antibiotics are known to promote the liberation of pro-inflammatory cell components and thus augment the severity of sepsis. Compared to antibiotics, AMPs kill bacteria but also neutralize pathogenic factors such as lipopolysaccharide. The obstacle to applying naturally occurring AMPs is their high nephro- and neurotoxicity. Therefore, the challenge is to develop peptides to treat septic patients effectively without causing harm. This overview focuses on natural and synthetic AMPs in human and experimental sepsis and their potential to provide significant improvements in the treatment of critically ill with severe infections.

Keywords: antimicrobial peptides; naturally occurring peptides; sepsis; synthetic; therapy.

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Figures

Figure 1
Figure 1
Different modes of action of antimicrobial peptides. AMPs may have direct neutralizing effects on bacteria e.g., by membrane disruption through pore forming or by targeting internal structures of bacteria. In addition to direct effects, AMPs may modulate cells of the adaptive immunity (neutrophils, t-cells, macrophages) to control inflammation and/or to increase bacterial clearance. Modified from Ref. (3). AMPs, antimicrobial peptides.
Figure 2
Figure 2
Antimicrobial peptides play a central role in innate and adaptive immunity. A given stimulus by bacteria leads to the release of constitutively expressed AMPs in different cells (here: epidermis). AMPs are released by neutrophils and will activate and recruit macrophages, monocytes, dendritic cells, and T-cells. A direct anti-endotoxin effect of AMPs may decrease the activation of immune cells and thus lead to a decrease in pro-inflammatory cytokine release. Modified from Ref. (26). AMPs, antimicrobial peptides; LPS, lipopolysaccharide; PMNs, neutrophils.
Figure 3
Figure 3
Mortality of patients with severe sepsis and septic shock treated with talactoferrin or placebo. The mortality is reported in relation to disease severity as expressed by the APACHE-II score. A positive effect of oral talactoferrin treatment on mortality in sepsis is detectable in patients with higher severity of disease (APACHE-II > 25). Patients with a lower APACHE-II score benefited less (APACHE-II 20–24) or not at all (APACHE-II < 19). APACHE-II score, Acute Physiology and Chronic Health Evaluation-II score. Reprinted with permission from Guntupalli et al. (67).

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