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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 murine wound healing of IDR-1018 compared to LL-37 and HB-107.On day 0, mice were wounded on two dorsolateral areas. Treatments were administered every 48 hours for 14 days with either 15 µl of vehicle control (PBS; wound one) or 200 µg/ml (3 µg/dose) of the indicated peptides (wound two). Re-epithelialization was measured every second day. The bars represent standard error of the mean wound closure (*  = p<0.05; **  = p<0.01; ***  = p<0.005 compared to vehicle control).
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pone-0039373-g003: Efficacy in murine wound healing of IDR-1018 compared to LL-37 and HB-107.On day 0, mice were wounded on two dorsolateral areas. Treatments were administered every 48 hours for 14 days with either 15 µl of vehicle control (PBS; wound one) or 200 µg/ml (3 µg/dose) of the indicated peptides (wound two). Re-epithelialization was measured every second day. The bars represent standard error of the mean wound closure (*  = p<0.05; **  = p<0.01; ***  = p<0.005 compared to vehicle control).

Mentions: To further characterize the wound healing activities of IDR-1018, we compared it to two peptides with previously characterized wound healing activities, the human cathelicidin LL-37 and the synthetic peptide HB-107. At the 200 µg/ml (3 µg/dose) level, treatment of wounds with IDR-1018 led to significantly higher rates of re-epithelialization in non-diabetic mice as compared to LL-37 and HB-107. By day 2, a significantly faster wound closure was measured in IDR-1018 treated wounds compared to untreated wounds (14%, p<0.0001). Further, IDR-1018 treated wounds were 28% smaller than control wounds on day 8 (d8, p = 0.0018). In contrast, neither HB-107 (which led to a slight but non-significant decrease in the rate of wound healing; p = 0.0577–0.4415 from day 2–14; Fig. 3) nor LL-37 (p = 0.1586–0.9243; day 2 14) improved re-epithelialization compared to carrier control treated wounds in diabetic mice. Although there was a tendency towards better re-epithelialization with LL-37 on day 4 (p = 0.1586 respectively) this tendency was lost over time (Fig. 3).


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 murine wound healing of IDR-1018 compared to LL-37 and HB-107.On day 0, mice were wounded on two dorsolateral areas. Treatments were administered every 48 hours for 14 days with either 15 µl of vehicle control (PBS; wound one) or 200 µg/ml (3 µg/dose) of the indicated peptides (wound two). Re-epithelialization was measured every second day. The bars represent standard error of the mean wound closure (*  = p<0.05; **  = p<0.01; ***  = p<0.005 compared to vehicle control).
© Copyright Policy
Related In: Results  -  Collection

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

pone-0039373-g003: Efficacy in murine wound healing of IDR-1018 compared to LL-37 and HB-107.On day 0, mice were wounded on two dorsolateral areas. Treatments were administered every 48 hours for 14 days with either 15 µl of vehicle control (PBS; wound one) or 200 µg/ml (3 µg/dose) of the indicated peptides (wound two). Re-epithelialization was measured every second day. The bars represent standard error of the mean wound closure (*  = p<0.05; **  = p<0.01; ***  = p<0.005 compared to vehicle control).
Mentions: To further characterize the wound healing activities of IDR-1018, we compared it to two peptides with previously characterized wound healing activities, the human cathelicidin LL-37 and the synthetic peptide HB-107. At the 200 µg/ml (3 µg/dose) level, treatment of wounds with IDR-1018 led to significantly higher rates of re-epithelialization in non-diabetic mice as compared to LL-37 and HB-107. By day 2, a significantly faster wound closure was measured in IDR-1018 treated wounds compared to untreated wounds (14%, p<0.0001). Further, IDR-1018 treated wounds were 28% smaller than control wounds on day 8 (d8, p = 0.0018). In contrast, neither HB-107 (which led to a slight but non-significant decrease in the rate of wound healing; p = 0.0577–0.4415 from day 2–14; Fig. 3) nor LL-37 (p = 0.1586–0.9243; day 2 14) improved re-epithelialization compared to carrier control treated wounds in diabetic mice. Although there was a tendency towards better re-epithelialization with LL-37 on day 4 (p = 0.1586 respectively) this tendency was lost over time (Fig. 3).

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