The novel β‐defensin DEFB123 prevents lipopolysaccharide‐mediated effects<i>in vitro</i>and<i>in vivo</i>

Motzkus, Dirk; Schulz-Maronde, Sandra; Heitland, Aleksandra; Schulz, Axel; Forssmann, Wolf‐Georg; Jübner, Martin; Maronde, Erik

doi:10.1096/fj.05-4970fje

Cited by 84 publications

(85 citation statements)

References 56 publications

(72 reference statements)

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“…In In recent years, LPS-neutralizing antimicrobial peptides have been in the focus of sepsis research (18)(19)(20)(21)(22)28). In most cases, however, the applied excess concentration ratio of peptide to LPS, necessary for sufficiently high LPS inactivation, was in the range of 1,000, or even higher, thus being insufficiently selective for LPS with respect to cytotoxic effects against physiological mammalian cells.…”

Section: Discussionmentioning

confidence: 99%

“…The physicochemical properties of LPS suggest that cationic amphiphilic agents could effectively neutralize its lipid A moiety. A number of studies have used natural proteins, peptides, or modified variants thereof to neutralize LPS and, thus, to protect it from endotoxin-mediated immunostimulation (1, 10), and in some cases, a significant protection from LPSinduced lethality in vivo was observed (10,19). However, these approaches required very high peptide/LPS molar ratios, precluding their use in humans due to the intrinsic cytotoxicity of the peptides at these concentrations.…”

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confidence: 99%

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New Antiseptic Peptides To Protect against Endotoxin-Mediated Shock

Gutsmann

Rázquin-Olazarán

Kowalski

et al. 2010

Antimicrob Agents Chemother

109

147

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Systemic bacterial infections are associated with high mortality. The access of bacteria or constituents thereof to systemic circulation induces the massive release of immunomodulatory mediators, ultimately causing tissue hypoperfusion and multiple-organ failure despite adequate antibiotic treatment. Lipid A, the "endotoxic principle" of bacterial lipopolysaccharide (LPS), is one of the major bacterial immunostimuli. Here we demonstrate the biological efficacy of rationally designed new synthetic antilipopolysaccharide peptides (SALPs) based on the Limulus anti-LPS factor for systemic application. We show efficient inhibition of LPS-induced cytokine release and protection from lethal septic shock in vivo, whereas cytotoxicity was not observed under physiologically relevant conditions and concentrations. The molecular mechanism of LPS neutralization was elucidated by biophysical techniques. The lipid A part of LPS is converted from its "endotoxic conformation," the cubic aggregate structure, into an inactive multilamellar structure, and the binding affinity of the peptide to LPS exceeds those of known LPS-binding proteins, such as LPS-binding protein (LBP). Our results thus delineate a novel therapeutic strategy for the clinical management of patients with septic shock.The life-threatening clinical consequences of sepsis and septic shock arise from recognition of microbial immunostimulatory molecules by the hosts' professional immune cells and the release of hemodynamically active mediators. The most potent immunostimulatory constituents are part of the microbial cell envelope, such as lipopolysaccharide (LPS) or lipoproteins. They are released continuously due to cell growth and division and massively liberated as a consequence of the attack of the immune system. In the case of Gram-negative bacteria, the most potent factor is LPS, which, therefore, is also called an endotoxin. LPS concentrations in blood serum as low as 1 ng/ml are able to cause sepsis. Septic shock resulting from bacterial infection remains a frequent cause of death, particularly in intensive care units, with more than 200,000 people dying each year in the United States alone. Death by septic shock can happen despite appropriate broad-range antibiotic treatment, which may kill bacteria but is not only incapable of neutralizing immunostimulatory LPS but also may promote its release into circulation (11).The response of mammalian cells to LPS is initiated by its interaction with serum proteins such as lipopolysaccharidebinding protein (LBP) and specific receptors and/or binding proteins of immune cells such as soluble CD14 (sCD14) and membrane-bound CD14 (mCD14), which finally leads to cell activation through the Toll-like receptor 4 (TLR4)-MD-2 pathway (31). The hydrophobic moiety of LPS, lipid A, anchoring LPS to the bacterial outer membrane, constitutes the "endotoxic principle" of LPS (24). Enterobacterial lipid A consists of a diglucosamine backbone phosphorylated at positions 1 and 4Ј, to which six acyl chains are linked at positions 2,3 a...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

New Antiseptic Peptides To Protect against Endotoxin-Mediated Shock

Gutsmann

Rázquin-Olazarán

Kowalski

et al. 2010

Antimicrob Agents Chemother

109

147

View full text Add to dashboard Cite

show abstract

“…5,6 In vitro, b-defensin peptides showed protective action against LPS-mediated effects via abolishing induction of mitogen-activated protein kinase. 29 Elucidation of the pathophysiological role of the human b-defensin 1 peptide in infectious and inflammatory diseases such as sepsis needs to be confirmed in an additive genetic animal model. Since the members of the defensin family have overlapping effect, a single gene knockout model will compromise the investigation of the biologic role of the target gene.…”

Section: Snpsmentioning

confidence: 99%

“…Consistent with this view were the findings indicating that defensins did suppress the release of proinflammatory cytokines and adhesion molecules in vivo. 29,31 Thus, DEFB1 could both play a direct antimicrobial role and have a modulating effect on the inflammatory response. In summary, DEFB1 plays an important role in the host immune response to severe sepsis.…”

Section: Snpsmentioning

confidence: 99%

Genomic variations within DEFB1 are associated with the susceptibility to and the fatal outcome of severe sepsis in Chinese Han population

Huang

et al. 2007

Genes Immun

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Sepsis is a systemic inflammatory response syndrome to infection. Human b-defensin 1 (DEFB1) is a multifunctional mediator in infection and inflammation, which has been largely explored in ex vivo studies. The present case-control study was designed to investigate whether DEFB1 genomic variations are associated with the susceptibility to and the outcome of severe sepsis in 211 patients with severe sepsis and 157 ethnic-matched healthy controls. After correcting for multiple testing, the À44G/C was the only polymorphism found to show significant associations with both the susceptibility to and the fatal outcome of severe sepsis (P ¼ 0.0049, odd ratio (OR) 1.971 and P ¼ 0.002, OR 2.406, respectively). Haplotype À20A/À44C/À52G showed a protective role against severe sepsis (P ¼ 0.0066, OR 0.6751), whereas haplotype À20G/À44G/À52G served as a risk factor for the fatal outcome of severe sepsis (P ¼ 0.0052, OR 2.427). These findings provide further evidence that b-defensin 1 may play a role in the pathogenesis of severe sepsis.

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“…They kill gram-negative bacteria, gram-positive bacteria, and fungi and inhibit some viral infections (18,21,25,28,48); chemoattract monocytes, macrophages, CD45 RA ϩ /CD4 ϩ T lymphocytes, mast cells, and immature dendritic cells (10,21,62); enhance antigen-specific immune responses (9,38); and even possibly regulate pigmentation and body weight via modulation of Mc1r and Mc4r (1). Defensins also bind to bacterial membranes (7,17) and lipopolysaccharides (17,39) and neutralize select bacterial toxins (23,31,32). Binding of human neutrophil peptide ␣-defensins (HNPs) and human ␤-defensins (HBDs) to these materials may facilitate receptor-mediated internalization of microbial antigens to immature dendritic cells (61) or attenuate antigen-induced proinflammatory cytokine responses (44).…”

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confidence: 99%