glycans.4 This provisional matrix is later replaced by type III collagen.4 This process is vital for several reasons including wound contraction and strength of new tissue.
As outlined above, the signals carried by cytokines and other molecular mediators are extremely important to proper wound healing. The activity and interactions between these mediators are complex, with many levels of regulation. Our results demonstrate
some significant differences in two cytokines with Bensal HP treatment: IL-6 and TNFα. IL-6 is a pro-inflammatory cytokine released by a variety of cell types including macrophages and fibroblasts.5 Its effects have been shown to have a great impact on wound healing, with in vivo studies demonstrating that exogenous
IL-6 induces persistent leukocyte infiltration and delayed wound healing.6 In contrast, IL-6 knockout mice demonstrated delayed wound healing compared to controls with decreased gene expression of a multitude of pro inflammatory cytokines and cellular adhesion molecules, diminished leukocyte infiltration
and decreased collagen deposition.5 These studies show that while IL-6 is essential to proper wound healing, dysregulation
by either over or underexpression results in delayed wound closure. Our results showed that IL-6 expression was attenuated in Bensal HP-treated wounds, though was not completely extinguished.
The results of this change were more pronounced in the burn wounds, with less inflammatory infiltrate, resulting in dampened wound expansion and increased collagen deposition by the end of the study period.
Similar results were seen when analyzing expression of TNFα, a pro inflammatory cytokine primarily produced by macrophages,
whose overexpression has been observed in a variety of inflammatory disease states.7 TNFα has multiple roles in the wound healing process and is important not only for the recruitment of inflammatory cells and for the release of inflammatory
cytokines (such as IL-6), but also for angiogenesis and the formation of extracellular matrix.4 As with IL-6, overabundance
of TNFα has been linked to delayed wound healing, with persistence of inflammatory infiltrates and decreased collagen deposition.7,8 Furthermore, investigators have shown that knockout of the p55 TNFα receptor results in accelerated wound healing, reduced leukocyte infiltration and enhanced collagen deposition in vivo.9 Results of our study showed decreased
TNFα at both time points investigated for burn wounds with Bensal HP treatement. Again, this correlates well to our findings of decreased inflammatory infiltrates and increased collagen deposition when compared to controls.
These results suggest a role for Bensal HP in burn treatment, especially in the first few days post-injury, when unchecked inflammation
results in wound expansion. Though clinical wound closure was achieved with comparable efficacy to controls, increased
collagen deposition in both burns and excision wounds may represent stronger tensile strength, and higher quality of tissue.
In general, wounds only achieve 80% of the initial strength of the tissue, making a stronger wound bed desirable.10 Furthermore,
given previously described data, we hypothesize that the modulation of cytokine expression seen with Bensal HP treatment
may be beneficial to wound healing, especially in burns which expand due to over exuberant inflammation.
CONCLUSION
Our results have several implications for the role of Bensal HP treatment in the setting of excisional and burn wounds. While Bensal HP treatment resulted in positive histologic and altered immunologic features, the full potential of these effects has yet to be characterized. Additionally, more accurate immunologic studies may help to fully elucidate the mechanism by which Bensal HP exerts its immunologic influence and wound healing efficacy. Further human trials may also be useful in ascertaining the utility of this treatment in human subjects.
DISCLOSURES
The authors acknowledge funding from Valeant Pharmaceuticals,
and no other financial disclosures.
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- Jacobs AM, Tomczak R. Evaluation of Bensal HP for the treatment of diabetic foot ulcers. Adv Skin Wound Care. 2008;21(10):461-465.
- Broughton G, Janis JE, Attinger CE. The basic science of wound healing. Plast Reconstr Surg. 2006;117(7 Suppl):12S-34S.
- Lin Z-Q, Kondo T, Ishida Y, Takayasu T, Mukaida N. Essential involvement of IL-6 in the skin wound-healing process as evidenced by delayed wound healing in IL-6-deficient mice. J Leukoc Biol Suppl. 2003;73(6):713-721.
- Saba AA, Kaidi AA, Godziachvili V, et al. Effects of interleukin-6 and its neutralizing antibodies on peritoneal adhesion formation and wound healing. The American surgeon. 1996;62(7):569-572.
- Buck M, Houglum K, Chojkier M. Tumor necrosis factor-alpha inhibits collagen alpha1 (I) gene expression and wound healing in a murine model of cachexia. Am J Patho. 1996;149(1):195.
- Siwik DA, Chang DL-F, Colucci WS. Interleukin-1β and tumor necrosis factor-α decrease collagen synthesis and increase matrix metalloproteinase activity in cardiac fibroblasts in vitro. Circ Res. 2000;86(12):1259-1265.
- Mori R, Kondo T, Ohshima T, Ishida Y, Mukaida N. Accelerated wound healing in tumor necrosis factor receptor p55-deficient mice with reduced leukocyte infiltration. FASEBÂ J. 2002;16(9):963-974.
- Levenson SM, Geever EF, Crowley LV, Oates JF, Berard CW, Rosen H. Healing of Rat Skin Wounds. Ann Surg. 1965;161(2):293-308.
AUTHOR CORRESPONDENCE
Adam J. Friedman MD……............................... Ajfriedman@mfa.gwu.edu
