Neutralization of Endotoxin In Vitro and In Vivo by a Human Lactoferrin-Derived Peptide

Zhang, Gui-Hang; Mann, David; Tsai, Chao-Ming

doi:10.1128/iai.67.3.1353-1358.1999

Cited by 129 publications

(55 citation statements)

References 40 publications

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“…In the treatment of coliform mastitis, bacterial growth should be inhibited to reduce the exposure of the quarter and the cow to LPS, and the effect of the LPS release should be neutralized to reduce the severity of the disease (Erskine et al, 1991). Zhang et al (1999) studied a human Lf-derived 33-mer synthetic peptide (Lf-33) as a potential treatment for LPSinduced septic shock. In a mouse model, administration of Lf-33 simultaneously with LPS significantly reduced mortality compared with LPS alone.…”

Section: Discussionmentioning

confidence: 99%

The efficacy of bovine lactoferrin in the treatment of cows with experimentally inducedEscherichia colimastitis

Kutila

Suojala

Lehtolainen

et al. 2004

Vet Pharm & Therapeutics

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The effect of bovine lactoferrin (Lf) was studied in experimental Escherichia coli mastitis, using enrofloxacin as a comparator. Mastitis was induced in six clinically healthy primiparous dairy cows by infusing 1500 colony-forming units of E. coli into a single udder quarter. The challenge was repeated into a contralateral quarter of the same cows 3 weeks later. At the first challenge, three cows were treated with 1.5 g of bovine lactoferrin intramammarily three times (12, 20 and 36 h postchallenge, PC), and the other three cows received 5 mg/kg of enrofloxacin (Baytril) parenterally (12, 36 and 60 h PC). Flunixin meglumine (2.2 mg/kg) was administered to all cows twice at 24-h intervals. During the second challenge, the treatments for the two groups were reversed. Intramammary challenge with E. coli produced clinical mastitis in all cows, but the severity of the disease varied markedly. No statistically significant differences between treatment groups were observed in clinical signs such as rectal temperature, rumen motility and general attitude. Milk somatic cell count, daily milk yield and bacterial counts in cows treated with Lf and those receiving enrofloxacin also did not differ significantly. However, a trend for a more rapid elimination of bacteria was seen in the cows treated with enrofloxacin. Milk NAGase activity also decreased significantly faster in the group treated with enrofloxacin. The concentration of lipopolysaccharide in milk compared with the number of bacteria was significantly lower in Lf than in enrofloxacin-treated cows (20 h PC).

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Section: Discussionmentioning

confidence: 99%

The efficacy of bovine lactoferrin in the treatment of cows with experimentally inducedEscherichia colimastitis

Kutila

Suojala

Lehtolainen

et al. 2004

Vet Pharm & Therapeutics

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“…Our results indicate differential regulation of pro-inflammatory and anti-inflammatory mediators by lactoferrin during LPS-induced endotoxaemia. These findings may be of importance when considering clinical utilization of lactoferrin as a post-surgical therapeutic, with imparted protection through concerted actions such as reduced TNF-α production in endotoxic shock, ability to bind LPS [55], direct bacteriostatic effects [56] and protective effects on gut structure [8]. Further studies will be necessary to determine the mechanism(s) by which lactoferrin maintains biological homeostasis.…”

Section: Discussionmentioning

confidence: 99%

Differential effects of prophylactic, concurrent and therapeutic lactoferrin treatment on LPS-induced inflammatory responses in mice

Kruzel

Harari

Mailman

et al. 2002

Clinical and Experimental Immunology

122

100

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SUMMARYMice injected with endotoxin develop endotoxaemia and endotoxin-induced death, accompanied by the oxidative burst and overproduction of inflammatory mediators. Lactoferrin, an iron binding protein, provides a natural feedback mechanism to control the development of such metabolic imbalance and protects against deleterious effects of endotoxin. We investigated the effects of intraperitoneal administration of human lactoferrin on lipopolysaccharide (LPS)-induced release of tumour necrosis factor alpha (TNF-α ), interleukin 6 (IL-6), interleukin 10 (IL-10) and nitric oxide (NO) in vivo . Lactoferrin was administered as a prophylactic, concurrent or therapeutic event relative to endotoxic shock by intravenous injection of LPS. Inflammatory mediators were measured in serum at 2, 6 and 18 h postshock induction. Administration of lactoferrin 1 h before LPS resulted in a rather uniform inhibition of all mediators; TNF by 82%, IL-6 by 43%, IL-10 by 47% at 2 h following LPS injection,and reduction in NO (80%) at 6 h post-shock. Prophylactic administration of lactoferrin at 18 h prior to LPS injection resulted in similar decreases in TNF-α (95%) and in NO (62%), but no statistical reduction in IL-6 or IL-10. Similarly, when lactoferrin was administered as a therapeutic post-induction of endotoxic shock, significant reductions were apparent in TNF-α and NO in serum, but no significant effect was seen on IL-6 and IL-10. These results suggest that the mechanism of action for lactoferrin contains a component for differential regulation of cellular immune responses during in vivo models of sepsis.

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“…Several natural, analogs and de novo designed peptides are reported to have LPS neutralization activity [2,[30][31][32][33][34]. The suggested mechanism for LPS neutralization is that the peptides Figure 3.…”

Section: Antiendotoxic Activitymentioning

confidence: 99%

Short KR‐12 analogs designed from human cathelicidin LL‐37 possessing both antimicrobial and antiendotoxic activities without mammalian cell toxicity

Jacob

Park

Bang

et al. 2013

Journal of Peptide Science

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KR-12 (residues 18-29 of LL-37) was known to be the smallest peptide of human cathelicidin LL-37 possessing antimicrobial activity. In order to optimize α-helical short antimicrobial peptides having both antimicrobial and antiendotoxic activities without mammalian cell toxicity, we designed and synthesized a series of KR-12 analogs. Highest hydrophobic analogs KR-12-a5 and KR-12-a6 displayed greater inhibition of lipopolysaccharide (LPS)-stimulated tumor necrosis factor-α production and higher LPS-binding activity. We have observed that antimicrobial activity is independent of charge, but LPS neutralization requires a balance of hydrophobicity and net positive charge. Among KR-12 analogs, KR-12-a2, KR-12-a3 and KR-12-a4 showed much higher cell specificity for bacteria over erythrocytes and retained antiendotoxic activity, relative to parental LL-37. KR-12-a5 displayed the strongest antiendotoxic activity but almost similar cell specificity as compared with LL-37. Also, these KR-12 analogs (KR-12-a2, KR-12-a3, KR-12-a4 and KR-12-a5) exhibited potent antimicrobial activity (minimal inhibitory concentration: 4 μM) against methicillin-resistant Staphylococcus aureus. Taken together, these KR-12 analogs have the potential for future development as a novel class of antimicrobial and anti-inflammatory therapeutic agents.

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Neutralization of Endotoxin In Vitro and In Vivo by a Human Lactoferrin-Derived Peptide

Cited by 129 publications

References 40 publications

The efficacy of bovine lactoferrin in the treatment of cows with experimentally inducedEscherichia colimastitis

The efficacy of bovine lactoferrin in the treatment of cows with experimentally inducedEscherichia colimastitis

Differential effects of prophylactic, concurrent and therapeutic lactoferrin treatment on LPS-induced inflammatory responses in mice

Short KR‐12 analogs designed from human cathelicidin LL‐37 possessing both antimicrobial and antiendotoxic activities without mammalian cell toxicity

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