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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 porcine wound healing of IDR-1018 compared to LL-37.(A) Efficacy in an infected porcine model of wound healing by IDR-1018. Digital photographic overview of porcine wounds treated with IDR-1018 (20 or 200 µg/ml every 48 hours) compared to LL-37 (200 µg/ml, positive control) and PBS (carrier control). (B) Quantification of re-epithelialization in wounds treated with IDR-1018. Re- epithelialization was assessed with IDR-1018 (20 and 200 µg/ml), LL-37 (200 µg/ml) or PBS. For day 0 to day 6 each value was calculated as mean out of six wounds while values of day 8 and 10 were calculated out of three different wounds. The bars represent standard error of the mean wound closure (*,+  = p<0.05; **,++  = p<0.01 (*IDR-1018 200 µg/ml; +IDR-1018 20 µg/ml) compared to vehicle control).
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pone-0039373-g004: Efficacy in porcine wound healing of IDR-1018 compared to LL-37.(A) Efficacy in an infected porcine model of wound healing by IDR-1018. Digital photographic overview of porcine wounds treated with IDR-1018 (20 or 200 µg/ml every 48 hours) compared to LL-37 (200 µg/ml, positive control) and PBS (carrier control). (B) Quantification of re-epithelialization in wounds treated with IDR-1018. Re- epithelialization was assessed with IDR-1018 (20 and 200 µg/ml), LL-37 (200 µg/ml) or PBS. For day 0 to day 6 each value was calculated as mean out of six wounds while values of day 8 and 10 were calculated out of three different wounds. The bars represent standard error of the mean wound closure (*,+  = p<0.05; **,++  = p<0.01 (*IDR-1018 200 µg/ml; +IDR-1018 20 µg/ml) compared to vehicle control).

Mentions: On day 1 post-infection, all wounds showed clinical signs of inflammation including swelling and redness (Fig 4a). By day 4 the wound fluid was cloudy and a fibrinous- purulent wound clot formed on top of the wounds. In all groups, representative cross-sectional biopsies were taken on days 6 and 10 after surgery and demonstrated that the high dose of IDR-1018 resulted in almost complete healing by day 10.


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 porcine wound healing of IDR-1018 compared to LL-37.(A) Efficacy in an infected porcine model of wound healing by IDR-1018. Digital photographic overview of porcine wounds treated with IDR-1018 (20 or 200 µg/ml every 48 hours) compared to LL-37 (200 µg/ml, positive control) and PBS (carrier control). (B) Quantification of re-epithelialization in wounds treated with IDR-1018. Re- epithelialization was assessed with IDR-1018 (20 and 200 µg/ml), LL-37 (200 µg/ml) or PBS. For day 0 to day 6 each value was calculated as mean out of six wounds while values of day 8 and 10 were calculated out of three different wounds. The bars represent standard error of the mean wound closure (*,+  = p<0.05; **,++  = p<0.01 (*IDR-1018 200 µg/ml; +IDR-1018 20 µg/ml) compared to vehicle control).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3412849&req=5

pone-0039373-g004: Efficacy in porcine wound healing of IDR-1018 compared to LL-37.(A) Efficacy in an infected porcine model of wound healing by IDR-1018. Digital photographic overview of porcine wounds treated with IDR-1018 (20 or 200 µg/ml every 48 hours) compared to LL-37 (200 µg/ml, positive control) and PBS (carrier control). (B) Quantification of re-epithelialization in wounds treated with IDR-1018. Re- epithelialization was assessed with IDR-1018 (20 and 200 µg/ml), LL-37 (200 µg/ml) or PBS. For day 0 to day 6 each value was calculated as mean out of six wounds while values of day 8 and 10 were calculated out of three different wounds. The bars represent standard error of the mean wound closure (*,+  = p<0.05; **,++  = p<0.01 (*IDR-1018 200 µg/ml; +IDR-1018 20 µg/ml) compared to vehicle control).
Mentions: On day 1 post-infection, all wounds showed clinical signs of inflammation including swelling and redness (Fig 4a). By day 4 the wound fluid was cloudy and a fibrinous- purulent wound clot formed on top of the wounds. In all groups, representative cross-sectional biopsies were taken on days 6 and 10 after surgery and demonstrated that the high dose of IDR-1018 resulted in almost complete healing by day 10.

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