Effect of Proteasome Inhibitor 1 on Wound Healing: A Potential Scar Prevention Therapy

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Author(s): 
John A. Walker, MD; Gianni Rossini, MS; Michelle E. Thompson, DVM; Joseph C. Wenke, PhD; and David G. Baer, PhD

Index: WOUNDS. 2013;25(2):28–33.

  Abstract: in vitro and in vivo assessments suggest that proteasome inhibitors may be useful for modulating wound healing. Methods. Proteasome Inhibitor I was used to assess the potential utility of proteasome inhibitors in improving wound healing in a standard rat model. Bilateral, 6 cm incisions were made 1 cm lateral to the spine of adult male Sprague Dawley rats. Animals were randomly assigned to 1 of 3 groups: no treatment (n = 15), low concentration (1% w/v, n = 15), or high concentration (5% w/v, n = 15). Treatments were applied to the left side incision at 0 hours, 24 hours, and 48 hours. Right-side incisions received a vehicle, dimethyl sulfoxide, alone and independent of the assigned group, serving as both external and internal controls. Rats were sacrificed at days 7, 14, and 28 (n = 5 per group) and wounds subjected to mechanical testing and histology. Results. No significant intergroup difference existed at 7 and 14 days. On day 28, a dose-dependent increase in tensile strength with increasing Proteasome Inhibitor I was observed. Conclusion. Results suggest dimethyl sulfoxide was not the ideal vehicle and additional improvement may be realized by optimizing the delivery method.

Introduction

  Abnormal scarring is a source of significant morbidity, and thus, is an active area of research. Much of this research is focused on elucidating the normal and pathological processes that differentiate acceptable scars from those that are either excessive or suboptimal.1 A significant insight from this body of work is the importance of inflammation in the progression of wound healing, with such insights having the potential to lead to innovative treatments. Important findings in scarless healing of fetal skin include an altered expression of matrix metalloproteases (MMPs), decreased expression of proinflammatory cytokines, and healing in the presence of reduced inflammation.2-6 The role of TGF-b in scarring has been extensively studied with evidence supporting that high levels of isoforms 1 and 2 play key roles in the scarring process.7-9 However, no pharmaceutical therapy exists for scar prevention, because those currently available either lack sound evidence of benefit, have limited applications, or possess detrimental side effects.10,11

  Recently, proteasome inhibitors (PI) have come under closer investigation as potential antifibrotic therapeutics. Proteasome inhibitors have shown promise as potential anti-fibrotic agents in multiple fibrotic models including renal fibrosis, cardiac fibrosis, myelodysplasia, pulmonary fibrosis, and skin fibrosis.12-15 Proteasome inhibitors exert direct cellular effect via inhibition of the 20S proteasome, a barrel-structured cytosolic enzyme that degrades intracellular proteins tagged for destruction through the ubiquitin pathway. Recent in vitro and in vivo work demonstrate PI can downregulate the inflammatory response through inactivation of nuclear factor (NF)-kB; block antifibrotic effects associated with TGF-b, alter MMP and TIMP expressions; and decrease collagen 1 synthesis.12,16 While most of these cellular effects lack well-delineated pathways and warrant further interrogation, they reflect changes that parallel fetal scarless healing over scarring.

  Proteasome inhibitors have not been explored in wound healing as a potential scar preventive therapy. Thus, the purpose of this study was to qualify proteasome inhibitor 1 (PI1), an aldehyde peptide, for further investigation in a future scar model by first investigating its effects on acute wound healing and further interrogating cellular effects.



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