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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

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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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).

Mentions: A different recombinant form of lactoferrin is talactoferrin alpha (TLF). TLF and lactoferrin possess identical molecular structures, biological activity and in other biochemical properties except for their nature of glycosylation (67). In a phase II study, 194 sepsis patients with at least one organ dysfunction were enrolled and assigned to a TLF or placebo group. Patients under medication with oral TLF showed a lower 28-day mortality rate with a sustained effect on mortality after 6 months. The decrease in mortality was more pronounced in patients with a higher severity of disease as expressed by APACHE-II scores above 25 points (Figure 3). Nonetheless, there was no significant difference regarding ICU days or ventilator-free days (67). Due to the promising results, a phase II/III study was initiated (safety and efficacy of TLF in patients with severe sepsis, OASIS; NCT 01273779). Surprisingly, the study was prematurely terminated due to the recommendation of the data safety monitoring board because of a higher 28-day mortality rate in the talactoferrin group. Here, the reason for failure remains unclear. One could speculate that oral administration is not the ideal route in critically ill patients who often suffer from gastroparesis and disturbed bowel motility.


Antimicrobial Peptides in Human Sepsis.

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

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).
© Copyright Policy
Related In: Results  -  Collection

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

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).
Mentions: A different recombinant form of lactoferrin is talactoferrin alpha (TLF). TLF and lactoferrin possess identical molecular structures, biological activity and in other biochemical properties except for their nature of glycosylation (67). In a phase II study, 194 sepsis patients with at least one organ dysfunction were enrolled and assigned to a TLF or placebo group. Patients under medication with oral TLF showed a lower 28-day mortality rate with a sustained effect on mortality after 6 months. The decrease in mortality was more pronounced in patients with a higher severity of disease as expressed by APACHE-II scores above 25 points (Figure 3). Nonetheless, there was no significant difference regarding ICU days or ventilator-free days (67). Due to the promising results, a phase II/III study was initiated (safety and efficacy of TLF in patients with severe sepsis, OASIS; NCT 01273779). Surprisingly, the study was prematurely terminated due to the recommendation of the data safety monitoring board because of a higher 28-day mortality rate in the talactoferrin group. Here, the reason for failure remains unclear. One could speculate that oral administration is not the ideal route in critically ill patients who often suffer from gastroparesis and disturbed bowel motility.

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