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Innate defense regulator peptide 1018 in wound healing and wound infection.

Steinstraesser L, Hirsch T, Schulte M, Kueckelhaus M, Jacobsen F, Mersch EA, Stricker I, Afacan N, Jenssen H, Hancock RE, Kindrachuk J - PLoS ONE (2012)

Bottom Line: IDR-1018 was significantly less cytotoxic in vitro as compared to either LL-37 or HB-107.Furthermore, administration of IDR-1018 resulted in a dose-dependent increase in fibroblast cellular respiration.However, no significant differences in bacterial colonization were observed.

View Article: PubMed Central - PubMed

Affiliation: Department of Plastic Surgery, BG University Hospital Bergmannsheil, Ruhr University Bochum, Bochum, Germany. lars.steinstraesser@ruhr-uni-bochum.de

ABSTRACT
Innate defense regulators (IDRs) are synthetic immunomodulatory versions of natural host defense peptides (HDP). IDRs mediate protection against bacterial challenge in the absence of direct antimicrobial activity, representing a novel approach to anti-infective and anti-inflammatory therapy. Previously, we reported that IDR-1018 selectively induced chemokine responses and suppressed pro-inflammatory responses. As there has been an increasing appreciation for the ability of HDPs to modulate complex immune processes, including wound healing, we characterized the wound healing activities of IDR-1018 in vitro. Further, we investigated the efficacy of IDR-1018 in diabetic and non-diabetic wound healing models. In all experiments, IDR-1018 was compared to the human HDP LL-37 and HDP-derived wound healing peptide HB-107. IDR-1018 was significantly less cytotoxic in vitro as compared to either LL-37 or HB-107. Furthermore, administration of IDR-1018 resulted in a dose-dependent increase in fibroblast cellular respiration. In vivo, IDR-1018 demonstrated significantly accelerated wound healing in S. aureus infected porcine and non-diabetic but not in diabetic murine wounds. However, no significant differences in bacterial colonization were observed. Our investigation demonstrates that in addition to previously reported immunomodulatory activities IDR-1018 promotes wound healing independent of direct antibacterial activity. Interestingly, these effects were not observed in diabetic wounds. It is anticipated that the wound healing activities of IDR-1018 can be attributed to modulation of host immune pathways that are suppressed in diabetic wounds and provide further evidence of the multiple immunomodulatory activities of IDR-1018.

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Efficacy in wound healing of IDR-1018 peptide in a murine dose-response model.Peptides were administered every 48 hours with the indicated concentrations of IDR-1018 or PBS (negative control). Re-epithelialization/wound closure was measured every second day. Standard deviation was assessed as SEM (Superscript symbols *, +, and ∼ represent 15 µl doses of 3, 0.3 and 0.03 µg respectively; *,+,∼  = p<0.05; **,++,∼∼  = p<0.01; ***,+++,∼∼∼  = p<0.005 compared to vehicle control).
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pone-0039373-g002: Efficacy in wound healing of IDR-1018 peptide in a murine dose-response model.Peptides were administered every 48 hours with the indicated concentrations of IDR-1018 or PBS (negative control). Re-epithelialization/wound closure was measured every second day. Standard deviation was assessed as SEM (Superscript symbols *, +, and ∼ represent 15 µl doses of 3, 0.3 and 0.03 µg respectively; *,+,∼  = p<0.05; **,++,∼∼  = p<0.01; ***,+++,∼∼∼  = p<0.005 compared to vehicle control).

Mentions: To analyze the effects of IDR-1018 in the complex process of wound healing we performed a dose response study using a splint-model in non-diabetic mice (n = 5 for each group). The application of IDR-1018 led to significant increase in wound closure in a dose-dependent manner as compared to vehicle control (Fig. 2). Treatment with the highest dose of IDR-1018 (200 µg/ml) resulted in the greatest acceleration of wound closure. This dosage of IDR-1018 also resulted in the most significant difference in wound closure as compared to vehicle control. Wound closure in IDR-1018 treated animals led to 14 28% smaller wound areas as compared to controls from days 2–8 (p<0.0001 to p = 0.0087; IDR-1018 treated wounds vs. untreated wounds). Moreover, although the rate of wound closure was slower in animals treated with lower doses, even small amounts of IDR-1018 (2 µg/ml) improved wound closure on days 8–10 (Fig 2).


Innate defense regulator peptide 1018 in wound healing and wound infection.

Steinstraesser L, Hirsch T, Schulte M, Kueckelhaus M, Jacobsen F, Mersch EA, Stricker I, Afacan N, Jenssen H, Hancock RE, Kindrachuk J - PLoS ONE (2012)

Efficacy in wound healing of IDR-1018 peptide in a murine dose-response model.Peptides were administered every 48 hours with the indicated concentrations of IDR-1018 or PBS (negative control). Re-epithelialization/wound closure was measured every second day. Standard deviation was assessed as SEM (Superscript symbols *, +, and ∼ represent 15 µl doses of 3, 0.3 and 0.03 µg respectively; *,+,∼  = p<0.05; **,++,∼∼  = p<0.01; ***,+++,∼∼∼  = p<0.005 compared to vehicle control).
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3412849&req=5

pone-0039373-g002: Efficacy in wound healing of IDR-1018 peptide in a murine dose-response model.Peptides were administered every 48 hours with the indicated concentrations of IDR-1018 or PBS (negative control). Re-epithelialization/wound closure was measured every second day. Standard deviation was assessed as SEM (Superscript symbols *, +, and ∼ represent 15 µl doses of 3, 0.3 and 0.03 µg respectively; *,+,∼  = p<0.05; **,++,∼∼  = p<0.01; ***,+++,∼∼∼  = p<0.005 compared to vehicle control).
Mentions: To analyze the effects of IDR-1018 in the complex process of wound healing we performed a dose response study using a splint-model in non-diabetic mice (n = 5 for each group). The application of IDR-1018 led to significant increase in wound closure in a dose-dependent manner as compared to vehicle control (Fig. 2). Treatment with the highest dose of IDR-1018 (200 µg/ml) resulted in the greatest acceleration of wound closure. This dosage of IDR-1018 also resulted in the most significant difference in wound closure as compared to vehicle control. Wound closure in IDR-1018 treated animals led to 14 28% smaller wound areas as compared to controls from days 2–8 (p<0.0001 to p = 0.0087; IDR-1018 treated wounds vs. untreated wounds). Moreover, although the rate of wound closure was slower in animals treated with lower doses, even small amounts of IDR-1018 (2 µg/ml) improved wound closure on days 8–10 (Fig 2).

Bottom Line: IDR-1018 was significantly less cytotoxic in vitro as compared to either LL-37 or HB-107.Furthermore, administration of IDR-1018 resulted in a dose-dependent increase in fibroblast cellular respiration.However, no significant differences in bacterial colonization were observed.

View Article: PubMed Central - PubMed

Affiliation: Department of Plastic Surgery, BG University Hospital Bergmannsheil, Ruhr University Bochum, Bochum, Germany. lars.steinstraesser@ruhr-uni-bochum.de

ABSTRACT
Innate defense regulators (IDRs) are synthetic immunomodulatory versions of natural host defense peptides (HDP). IDRs mediate protection against bacterial challenge in the absence of direct antimicrobial activity, representing a novel approach to anti-infective and anti-inflammatory therapy. Previously, we reported that IDR-1018 selectively induced chemokine responses and suppressed pro-inflammatory responses. As there has been an increasing appreciation for the ability of HDPs to modulate complex immune processes, including wound healing, we characterized the wound healing activities of IDR-1018 in vitro. Further, we investigated the efficacy of IDR-1018 in diabetic and non-diabetic wound healing models. In all experiments, IDR-1018 was compared to the human HDP LL-37 and HDP-derived wound healing peptide HB-107. IDR-1018 was significantly less cytotoxic in vitro as compared to either LL-37 or HB-107. Furthermore, administration of IDR-1018 resulted in a dose-dependent increase in fibroblast cellular respiration. In vivo, IDR-1018 demonstrated significantly accelerated wound healing in S. aureus infected porcine and non-diabetic but not in diabetic murine wounds. However, no significant differences in bacterial colonization were observed. Our investigation demonstrates that in addition to previously reported immunomodulatory activities IDR-1018 promotes wound healing independent of direct antibacterial activity. Interestingly, these effects were not observed in diabetic wounds. It is anticipated that the wound healing activities of IDR-1018 can be attributed to modulation of host immune pathways that are suppressed in diabetic wounds and provide further evidence of the multiple immunomodulatory activities of IDR-1018.

Show MeSH
Related in: MedlinePlus