Limits...
Antimicrobial Peptides in Human Sepsis.

Martin L, van Meegern A, Doemming S, Schuerholz T - Front Immunol (2015)

Bottom Line: The recombinant form of lactoferrin [talactoferrin alpha (TLF)] has been shown to decrease mortality in critically ill patients.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Intensive Care and Intermediate Care, University Hospital RWTH Aachen , Aachen , Germany.

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.

No MeSH data available.


Related in: MedlinePlus

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.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4542572&req=5

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.

Mentions: Antimicrobial peptides prevent and control microbial infections by both direct antimicrobial killing and innate immune modulation (4, 9, 37, 38). Direct antimicrobial killing is achieved by the disruption of bacterial cell membranes or translocation into bacteria to affect internal targets (3) (Figure 1). The cationic amphipathic AMPs bind to the negatively charged phospholipids of the bacterial cell membranes (3). It is assumed that pore formation and non-specific membrane permeabilization lead to a disruption of the membrane (Figure 1). Recently, there has been increasing evidence that molecules on the cell surface act as targets for the AMPs and induce direct killing (10, 39). However, the immunostimulatory properties have been more appreciated for their diversity, including cell migration, survival and proliferation, induction of antimicrobial and immune mediators such as cytokines/chemokines, wound healing, and angiogenesis (Figure 2) (4, 40). The results show that HBD-2 seems to be chemotactic for cells that express the human chemokine receptor CCR6 (41). CCR6 is preferentially expressed by immature monocytic dendritic cells (DCs) and CD8 + T-cells that have the memory phenotype (42). Additionally, HNP 1–3 are chemotactic for monocytes, immature DCs and CD4+ and CD8+ T-cells (43, 44). Furthermore, they induce the release of pro-inflammatory cytokines such as IFN-λ, IL-6, and IL-10 from T-cells as well as TNF-α and IL-1β from monocytes (45, 46). These processes contribute to the maturation of DCs, which link the innate and adaptive immune systems. Stimulation with TNFα contributes to this maturation. DCs activate CD4+ T-cells (and their subsets) and CD8+ T-cells as well as B-cells. In turn, monocytes may be induced by a peptide to differentiate into DCs (47).


Antimicrobial Peptides in Human Sepsis.

Martin L, van Meegern A, Doemming S, Schuerholz T - Front Immunol (2015)

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.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4542572&req=5

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.
Mentions: Antimicrobial peptides prevent and control microbial infections by both direct antimicrobial killing and innate immune modulation (4, 9, 37, 38). Direct antimicrobial killing is achieved by the disruption of bacterial cell membranes or translocation into bacteria to affect internal targets (3) (Figure 1). The cationic amphipathic AMPs bind to the negatively charged phospholipids of the bacterial cell membranes (3). It is assumed that pore formation and non-specific membrane permeabilization lead to a disruption of the membrane (Figure 1). Recently, there has been increasing evidence that molecules on the cell surface act as targets for the AMPs and induce direct killing (10, 39). However, the immunostimulatory properties have been more appreciated for their diversity, including cell migration, survival and proliferation, induction of antimicrobial and immune mediators such as cytokines/chemokines, wound healing, and angiogenesis (Figure 2) (4, 40). The results show that HBD-2 seems to be chemotactic for cells that express the human chemokine receptor CCR6 (41). CCR6 is preferentially expressed by immature monocytic dendritic cells (DCs) and CD8 + T-cells that have the memory phenotype (42). Additionally, HNP 1–3 are chemotactic for monocytes, immature DCs and CD4+ and CD8+ T-cells (43, 44). Furthermore, they induce the release of pro-inflammatory cytokines such as IFN-λ, IL-6, and IL-10 from T-cells as well as TNF-α and IL-1β from monocytes (45, 46). These processes contribute to the maturation of DCs, which link the innate and adaptive immune systems. Stimulation with TNFα contributes to this maturation. DCs activate CD4+ T-cells (and their subsets) and CD8+ T-cells as well as B-cells. In turn, monocytes may be induced by a peptide to differentiate into DCs (47).

Bottom Line: The recombinant form of lactoferrin [talactoferrin alpha (TLF)] has been shown to decrease mortality in critically ill patients.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Intensive Care and Intermediate Care, University Hospital RWTH Aachen , Aachen , Germany.

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.

No MeSH data available.


Related in: MedlinePlus