ABSTRACT
In vivo wound healing models are predictive preclinical tests for therapeutics that enhance skin repair or limit scarring. Large animals, such as swine, heal in a manner similar to humans, but testing is impractical and expensive. Experiments in mice are more economic, but may be less translatable as this species heals primarily through contraction, not by the processes of epithelialization and granulation tissue formation as seen in human wounds. Here, we describe a murine model of thermal burn injury that closely mimics human healing, resulting in a large, hypertrophic-like scar. This practical, reproducible model is ideal for testing promising wound-healing therapies, such as virus-derived growth factors and immune-modulatory proteins.
Subject(s)
Burns/pathology , Cicatrix/prevention & control , Disease Models, Animal , Re-Epithelialization/genetics , Animals , Burns/genetics , Burns/therapy , Cicatrix/genetics , Cicatrix/pathology , Female , Gene Expression , Hot Temperature , Humans , Immunologic Factors/biosynthesis , Immunologic Factors/genetics , Immunologic Factors/pharmacology , Intercellular Signaling Peptides and Proteins/biosynthesis , Intercellular Signaling Peptides and Proteins/genetics , Intercellular Signaling Peptides and Proteins/pharmacology , Mice , Mice, Inbred C57BL , Re-Epithelialization/drug effects , Skin/drug effects , Skin/injuries , Transgenes , Viruses/geneticsABSTRACT
Orf virus (OV) is a zoonotic parapoxvirus that causes highly proliferative skin lesions which resolve with minimal inflammation and scarring. OV encodes two immunomodulators, vascular endothelial growth factor (VEGF)-E and interleukin-10 (ovIL-10), which individually modulate skin repair and inflammation. This study examined the effects of the VEGF-E and ovIL-10 combination on healing processes in a murine wound model. Treatments with viral proteins, individually and in combination, were compared to a mammalian VEGF-A and IL-10 combination. Wound biopsies were harvested to measure re-epithelialisation and scarring (histology), inflammation, fibrosis and angiogenesis (immunofluorescence), and gene expression (quantitative polymerase chain reaction). VEGF-E and ovIL-10 showed additive effects on wound closure and re-epithelialisation, and suppressed M1 macrophage and myofibroblast infiltration, while allowing M2 macrophage recruitment. The viral combination also increased endothelial cell density and pericyte coverage, and improved collagen deposition while reducing the scar area. The mammalian combination showed equivalent effects on wound closure, re-epithelialisation and fibrosis, but did not promote blood vessel stabilisation or collagen remodeling. The combination treatments also differentially altered the expression of transforming growth factor beta isoforms, Tgfß1 and Tgfß3. These findings show that the OV proteins synergistically enhance skin repair, and act in a complimentary fashion to improve scar quality.
ABSTRACT
Bronchopleural fistula is a well-recognized complication of pneumonectomy, which presents a difficult challenge to the thoracic surgeon. We report the successful treatment of a bronchopleural fistula after right pneumonectomy for lung cancer, using a covered esophageal stent.
