epidermal-growth-factor and Staphylococcal-Skin-Infections

Nucleic acid (NA)-based therapy is promising for tissue repair, such as skin and bone defect therapy. However, bacterial infections often occur in the process of tissue healing. The ideal treatment of tissue repair requires both anti-infection and simultaneous tissue healing. The epidermal growth factor (EGF) plays an important role in wound healing processes. In this work, degradable antibacterial gene vectors based on tobramycin (clinically relevant antibiotic) conjugated poly(aspartic acid) (TPT) are proposed as multifunctional delivery nanosystems of plasmid encoding EGF (pEGF) to realize the antibacterial therapy and tissue healing of infected skin defects. TPT has low cytotoxicity and good degradability, which is helpful in the NA delivery process. TPT demonstrates good transfection performances and hemocompatibility, as well as excellent antibacterial activities in vitro. The outstanding pEGF delivery ability of TPT and the bioactivity of expressed EGF facilitate the proliferation of fibroblast cells. The effective in vivo infected skin defect therapy is also demonstrated with TPT/pEGF nanocomplexes, where skin tissue healing is promoted. The present work opens new avenues for the design of multifunctional delivery nanosystems with antibacterial ability to treat infected tissue defect.

Topics: Animals; Anti-Bacterial Agents; Biocompatible Materials; Drug Delivery Systems; Epidermal Growth Factor; Fibroblasts; Humans; Male; Mice; Nanostructures; NIH 3T3 Cells; Peptides; Pseudomonas aeruginosa; Rabbits; Rats, Wistar; Skin; Staphylococcal Skin Infections; Staphylococcus aureus; Tobramycin; Wound Healing

iRHOM2 is a highly conserved, catalytically inactive member of the Rhomboid family, which has recently been shown to regulate the maturation of the multi-substrate ectodomain sheddase enzyme ADAM17 (TACE) in macrophages. Dominant iRHOM2 mutations are the cause of the inherited cutaneous and oesophageal cancer-susceptibility syndrome tylosis with oesophageal cancer (TOC), suggesting a role for this protein in epithelial cells. Here, using tissues derived from TOC patients, we demonstrate that TOC-associated mutations in iRHOM2 cause an increase in the maturation and activity of ADAM17 in epidermal keratinocytes, resulting in significantly upregulated shedding of ADAM17 substrates, including EGF-family growth factors and pro-inflammatory cytokines. This activity is accompanied by increased EGFR activity, increased desmosome processing and the presence of immature epidermal desmosomes, upregulated epidermal transglutaminase activity and heightened resistance to Staphylococcal infection in TOC keratinocytes. Many of these features are consistent with the presence of a constitutive wound-healing-like phenotype in TOC epidermis, which may shed light on a novel pathway in skin repair, regeneration and inflammation.

Topics: ADAM Proteins; ADAM17 Protein; Carrier Proteins; Cytokines; Desmosomes; Epidermal Growth Factor; Epidermis; ErbB Receptors; Esophageal Neoplasms; Female; Gene Expression Regulation; Humans; Intracellular Signaling Peptides and Proteins; Keratinocytes; Keratoderma, Palmoplantar; Male; Mutation; RNA, Small Interfering; Signal Transduction; Staphylococcal Skin Infections; Staphylococcus aureus; Transglutaminases