Elizabeth Lebrun

Cortisol Synthesis in Epidermis Is Induced by IL-1 and Tissue Injury

Glucocorticoids (GCs) are known inhibitors of wound healing. In this study we report the novel finding that both keratinocytes in vitro and epidermis in vivo synthesize cortisol and how this synthesis regulates wound healing. We show that epidermis expresses enzymes essential for cortisol synthesis, including steroid 11 β-hydroxylase (CYP11B1), and an enzyme that controls negative feedback mechanism, 11β-hydroxysteroid dehydrogenase 2 (11βHSD2). We also found that cortisol synthesis in keratinocytes and skin can be stimulated by ACTH and inhibited by metyrapone (CYP11B1 enzyme inhibitor). Interestingly, IL-1β, the first epidermal signal of tissue injury, induces the expression of CYP11B1 and increases cortisol production by keratinocytes. Additionally, we found induction of CYP11B1 increased production of cortisol and activation of GR pathway during wound healing ex vivo and in vivo using human and porcine wound models, respectively. Conversely, inhibition of cortisol synthesis during wound healing increases IL-1β production, suggesting that cortisol synthesis in epidermis may serve as a local negative feedback to proinflammatory cytokines. Local GCs synthesis, therefore, may provide control of the initial proinflammatory response, preventing excessive inflammation upon tissue injury. Inhibition of GC synthesis accelerated wound closure in vivo, providing the evidence that modulation of cortisol synthesis in epidermis may be an important regulatory mechanism during wound healing.

Induction of Specific MicroRNAs Inhibits Cutaneous Wound Healing

Background: Venous ulcers (VUs) are a major health problem, but their molecular pathology remains unknown. Results: A specific set of miRNAs induced in VUs targets signaling molecules and inhibits healing. Conclusion: Induction of miRNAs in VUs leads to inhibition of epithelialization and granulation tissue formation. Significance: This new discovery will enable miRNA use as diagnostic/therapeutic targets in VUs. Chronic nonhealing wounds, such as venous ulcers (VUs), are a widespread and serious medical problem with high morbidity and mortality. The molecular pathology of VUs remains poorly understood, impeding the development of effective treatment strategies. Using mRNA expression profiling of VUs biopsies and computational analysis, we identified a candidate set of microRNAs with lowered target gene expression. Among these candidates, miR-16, -20a, -21, -106a -130a, and -203 were confirmed to be aberrantly overexpressed in a cohort study of 10 VU patients by quantitative PCR and in situ hybridizations. These microRNAs were predicted to target multiple genes important for wound healing, including early growth response factor 3, vinculin, and leptin receptor (LepR). Overexpression of the top up-regulated miRNAs, miR-21 and miR-130a, in primary human keratinocytes down-regulated expression of the endogenous LepR and early growth response factor 3. The luciferase reporter assay verified LepR as a direct target for miR-21 and miR-130a. Both miR-21 and miR-130a delayed epithelialization in an acute human skin wound model. Furthermore, in vivo overexpression of miR-21 inhibited epithelialization and granulation tissue formation in a rat wound model. Our results identify a novel mechanism in which overexpression of specific set of microRNAs inhibits wound healing, resulting in new potential molecular markers and targets for therapeutic intervention.

The role of surgical debridement in healing of diabetic foot ulcers

An estimated 15% of patients with diabetes mellitus will develop a foot ulcer during their lifetime. Debridement is included in multiple guidelines and algorithms for the care of patients with diabetic neuropathic foot ulcers, and it has long been considered an essential step in the protocol for treating diabetic foot ulcers. In addition to altering the environment of the chronic wound, debridement is a technique aimed at removing nonviable and necrotic tissue, thought to be detrimental to healing. This is accomplished by removing abnormal wound bed and wound edge tissue, such as hyperkeratotic epidermis (callus) and necrotic dermal tissue, foreign debris, and bacteria elements known to have an inhibitory effect on wound healing. While the rationale for surgical debridement seems logical, the evidence for its role in enhancing healing is deficient. In this paper, we systematically review five published clinical trials, which met the criteria and investigated surgical debridement of diabetic foot ulcers to enhance healing. Most existing studies are not randomized clinical trials optimized to test the relationship between debridement of diabetic foot ulcers and wound healing. Therefore, a focused, well‐designed study is needed to elucidate the effect of surgical debridement on the healing status of chronic wounds.

Frequent Debridement for Healing of Chronic Wounds

Chronic wounds, such as from diabetes and vascular disease, affect almost 7 million Americans annually, cost nearly

Post-kala-azar dermal leishmaniasis in HIV-infected patients with AIDS: a report of two cases diagnosed in the USA

25 billion annually, and are associated with increased mortality.1 Standard care for the treatment of chronic wounds includes debridement, with best evidence existing for diabetic foot ulcers, where secondary analysis of randomized trials suggests centers with higher frequency of debridement have superior healing rates.2 The rationale for debridement is to remove tissue and debris that inhibit healing, which at times is obvious, for example, when necrotic eschar or excessive callus is present, but at other times is less obvious, for example, when trying to remove bacterial biofilms or abnormal host cells that may also contribute to slow healing. For example, keratinocytes adjacent to chronic wounds have a diminished ability to migrate and respond to growth factors and contribute to a pathogenic phenotype that inhibits healing.2 Wilcox et al3 found more frequent debridement, performed weekly, was associated with faster healing times (P < .001). One explanation is that chronic wounds provide an environment conducive for inhibitors of healing, such as biofilms, to rapidly form and require a consistent approach to removal. Alternatively, the wound centers studied often see patients on a routine basis and use evidenced-based algorithms for care that include debridement, with this constellation of care resulting in improved outcomes. In either case, these data provide a best-practice approach, to which most dermatologists likely do not adhere, and as such represent a practice gap. Because of a lack of either appreciation of the need for a consistent approach or understanding of the importance of debridement, many are likely not performing debridement enough. To overcome this gap, medical professionals need to be educated about the types of debridement; the goals and importance of debridement, such as attending wound sessions at the American Academy of Dermatology or at wound healing meetings (www.sawc.org); and the systematic approaches to evaluation and management, including, but not limited to, debridement, such as from the evidenced-based guidelines for chronic wounds (www.woundheal.org/index.php?option=com _content&view=article&id=180). For example, excisional debridement of the wound bed and edges with a scalpel is often performed initially to remove all inhibitors to healing, and thereafter maintenance debridement is performed on a regular (weekly or every second week) basis using either surgical or nonsurgical (enzymatic or autolytic debridement among others) techniques. Training for dermatology residents should include experience with debridement and managing wounds. However, education is not limited to physicians because general staff members need training to make debridement and care of patients with a wound efficient to fit the flow of dermatology practice. To ensure wounds are improving, close tracking of wound size reduction by measurements or photographs is needed, and the use of templates for patient care and procedures can be incorporated into electronic medical records, which can serve as a resource to ensure all elements of evaluation and management are performed. This can also include alerts when advanced therapies are needed (typically if standard care fails to reduce wound size by 40%-50% in 4 weeks) and/or when referral to wound experts should be initiated.

The role of surgical debridement in healing of diabetic foot ulcers.

Post‐kala‐azar dermal leishmaniasis (PKDL) is an uncommon complication of visceral leishmaniasis (VL) but is emerging as an increasingly frequent and serious complication of acquired immunodeficiency syndrome (AIDS). It manifests as a macular, morbilliform, or nodular eruption in a patient who has recovered from VL.