Epithelial to Mesenchymal Transition in Human Skin Wound Healing Is Induced by Tumor Necrosis Factor-α through Bone Morphogenic Protein-2

Epithelial-mesenchymal transition (EMT), characterized by loss of epithelial adhesion and gain of mesenchymal features, is an important mechanism to empower epithelial cells into the motility that occurs during embryonic development and recurs in cancer and fibrosis. Whether and how EMT occurs in wound healing and fibrosis in human skin remains unknown. In this study we found that migrating epithelial cells in wound margins and deep epithelial ridges had gained mesenchymal features such as vimentin and FSP1 expression. In hypertrophic scars, EMT-related genes were elevated along with inflammatory cytokines, indicating a causal relationship. To reconstitute EMT in vitro, normal human skin and primary keratinocytes were exposed to cytokines such as tumor necrosis factor-α (TNF-α), resulting in expression of vimentin, FSP1, and matrix metalloproteinases. Moreover, TNF-α–induced EMT was impaired by antagonists against bone morphogen proteins (BMP) 2/4, suggesting that BMP mediates the TNF-α–induced EMT in human skin. Indeed, TNF-α could induce BMP-2 and its receptor (BMPR1A) in human skin and primary keratinocytes, and BMP2 could induce EMT features in skin explants and primary keratinocytes. In summary, we uncovered EMT features in both acute and fibrotic cutaneous wound healing of human skin. Moreover, we propose that the mesenchymal induction in wound healing is motivated by TNF-α, in part, through induction of BMP.Epithelial to mesenchymal transition (EMT) was originally described as a mechanism to form primary mesenchymal cells in mesoderm from primitive epithelium during gastrulation in the early embryo.¹ Then, the concept was substantially expanded to phenotypic alternations or plasticity of epithelial lineages in adult tissues, resulting in loss of cell–cell adhesion and apical–basal polarity, and gain of mesenchymal features including enhanced motility and cytoskeletal rearrangement.² Growing evidence in clinical observations and animal models has exhibited widespread relevance of EMT in the chronic diseases such as fibrosis and tumor progression.³ The common features among these chronic diseases are that the transformed or activated epithelial cells are detached, produce matrix-degrading proteolytic enzymes, and even exhibit fibroblasts-like characteristics.^4,5The essence of cutaneous wound healing is to restore the epidermal barrier to the external environment during a process called re-epithelialization.⁶ A key feature of re-epithelialization is movement or migration of the epithelial sheets under stimulation of injury signals.⁷ We speculated that stationary keratinocytes in human skin may be activated and mobilized in wound healing in a manner that is reminiscent of EMT, which is orchestrated by injury signals such as inflammatory cytokines. Whether and how EMT contributes to normal and fibrotic skin wound healing in humans is still elusive. To investigate these possibilities, we examined acute wounds at the phase of re-epithelialization and hypertrophic scars in the growth phase for those epithelial cells having attained mesenchymal markers. The EMT characteristics were tightly associated with persistent inflammation, indicating a possible causative induction. This led us to test a panel of cytokines for their capacities to induce EMT in explanted human skin and primary human keratinocyte cultures. Based on this rationale we uncovered that tumor necrosis factor-α (TNF-α)–induced EMT in human skin is mediated, in part, by induction of bone morphogen protein (BMP) 2.     

Medication errors in community pharmacy: an investigation into the types and potential causes

Objectives To establish the nature of medication errors occurring within community pharmacy and analyse common error patterns. To identify factors which influence the occurrence of medication errors and near misses, with the intention of designing systems or strategies to reduce the occurrence of these events. Setting Fifteen community pharmacies situated within Brighton and Hove City Primary Care Trust, East Sussex, between January and March 2004. Method A self‐reporting form was designed, piloted and administered to pharmacists, which gathered information on the detection of an error or near miss in the dispensing process. Key findings One‐hundred and thirteen near misses and thirty‐two medication errors were reported. The majority of near misses were detected by the pharmacist at the final check, and the majority of medication errors were detected by the patient or patient's representative. Selection errors were most common, with similar drug names and packaging cited as the main contributory factors. ‘Business’ was frequently cited as the circumstance surrounding the error. Conclusion This study demonstrates that pharmacists do have an important part to play and the positive impact of community pharmacists in preventing, detecting and correcting errors and thus preventing harm to patients in the primary care setting. However, medication errors do occur, and therefore a multifactorial approach by manufacturers, marketing and packaging personnel, in addition to input from pharmacists, may be an effective permanent solution in reducing the errors made.