Skin Tissue Damage Research Articles

HucMSC Exosome-Delivered 14-3-3ζ Orchestrates Self-Control of the Wnt Response via Modulation of YAP During Cutaneous Regeneration.

Numerous studies showed that mesenchymal stem cells derived exosome (MSC-Ex) markedly enhanced tissue regeneration, however, the issue of whether MSC-Ex could control stem cells expansion after a regenerative response to prevent tissue from overcrowding and dysplasia remains to be established. Herein, we found that human umbilical cord MSC (hucMSC)-exosomal14-3-3ζ mediated the binding of YAP and p-LATS by forming a complex to promote the phosphorylation of YAP, which orchestrate exosomal Wnt4 signal in cutaneous regeneration. First, we assessed deep second-degree burn rats treated with hucMSC-Ex and discovered that hucMSC-Ex promoting self-regulation of Wnt/β-catenin signaling at the remodeling phase of cutaneous regeneration. HucMSC-Ex restricted excessive skin cell expansion and collagen deposition at 4 weeks. Under high cell density conditions, hucMSC-Ex inhibited Wnt/β-catenin signaling through induction of YAP phosphorylation. Second, hucMSC-Ex proteomic analysis revealed that 14-3-3 proteins could be transported by exosome. Using gain- and loss-of-function studies, our results showed that hucMSC-exosomal 14-3-3ζ controlled YAP activities and phosphorylation at Ser127 site, and were required for the binding of YAP and p-LATS. Further studies revealed that 14-3-3ζ recruited YAP and p-LATS to form a complex under high cells density status and 14-3-3ζ other than YAP or p-LATS was the key regulatory molecule of this complex. These findings collectively indicate that hucMSC-Ex functions not only as an "accelerator" of the Wnt/β-catenin signal to repair damaged skin tissue but also as a "brake" of the signal by modulating YAP to orchestrate controlled cutaneous regeneration. Stem Cells 2016;34:2485-2500.

Effect of Acetone on Reactive Oxygen Species to Mice Skin

Acetone is one of the organic solvents that causes skin barrier disruption such as eczema and dermatitis, ichthyosis and xerosis, and ROS (reactive oxygen species) paly a role of skin toxicity. This study is focused on investigating the effect of ROS of applied acetone. Acetone was applied to mice skin (0.25ml/㎠) four times (6h, 12h, 18h, 24h) every day for two or four days. Increased activity of acid phosphatase (ACP) and increased content of lipid peroxide (LPO) in acetone was determined in the applied group for four days(4ACE) compared with the acetone applied group for two days (2ACE). As for the ROS generating enzymes, one of them, xanthine oxidase (XO) showed no differences between control and 2ACE despite the significantly different 4ACE. There were some differences between 2ACE and 4ACE on the activities of cytochrome P450 dependent aniline hydroxylase (CYPdAH), which seemed to be the increased rates of acetone metabolites. There were more decreased rates of the activities of ROS scavenging enzymes, glutathione peroxidase (GPx), catalase (CAT), superoxide dismutae (SOD), glutathione S-transferase (GST), and glutathione (GSH) contents in 4ACE compared with 2ACE. The results indicate that the damaged skin tissue could cause unbalance of the ROS generating system and scavenging system by the frequent exposure of acetone application.

Advances Toward Forming Synthetic Mimetic Tendon

ABSTRACTCollagen is the most abundant protein present in the human body and found in connective tissues, bone, and tendon. It is also known as a natural resource for healing damaged skin tissues [1]. In this study, under specific microenvironment conditions, mimetic collagen gels were successfully formed synthetically from reconstituted Bovine type I collagen monomers. This was achieved by controlling ionic strength, temperature and pH, allowing fibrils with native mimetic D periodic banding structure to assemble spontaneously within the gels. In addition, by providing appropriate aging temperatures and times, mature collagen fibril growth is also realized in the gels in vitro. Mimetic gels were subsequently formed into fibers through a wet-spinning process. These spun fibers were found to preserve the native mimetic D periodic banding and fibrillar structure formed in the initial gels. As a result, the synthetic fibers resemble native tendon. Here structural development within the gel samples and fibers as a function of processing was analyzed by scanning electron microscopy (SEM). Results in this study also show a potentially new route for the fabrication of synthetic collagen fibers mimicking tendon, which may find applications as engineered tissues or scaffolding materials.

Chondroitin sulfate-based biomaterials for tissue engineering

Chondroitin sulfate (CS) is a sulfated glycosaminoglycan (GAG) that is usually found attached to proteins as part of a proteoglycan. The use of CS-based biomaterials in the field of tissue engineering applications has been intensively growing over the past decades because CS is a biopolymer with the major advantages of being biodegradable, biocompatible, easily available, and highly versatile. In vitro and in vivo studies have shown that CS-based biomaterials upregulate cartilage-specific gene expression in chondrocytes and mesenchymal stem cells and also support osteogenic differentiation by increasing the effectiveness of bone anabolic growth factors. Chondroitin sulfate proteoglycan plays a key role during the acute recovery stage after spinal cord injury by activating microglia/macrophages and modulating neurotrophic factor secretion. In addition, CS-based materials promote the wound-healing process and stimulate the regeneration of skin defects. Moreover, CS can be used to construct high toughness gels by having a double network structure. Taken together, CS-based biomaterials would be a useful material for successful replacement and regeneration of damaged cartilage, bone, skin, and neural tissues.

Enlightenment and deliberation after treatment for extraordinary injuries

With the development of modern society, the range of disease spectrum is changing, and risk factors leading to human trauma and damage are also in the shift. In addition to the extraordinary burns in the traditional sense, we also call extraordinary injury as damage induced by some of extraordinary insults in the past. In recent years, damage to skin and soft tissue caused by an extraordinary injury showed a gradually increasing trend. Manifestations of the wound of an extraordinary injury are various and its clinical treatment is very difficult, often requiring exceptional systemic comprehensive treatments. Currently, it is the duty of colleagues in the burn unit to actively deliberate about their realities regarding the following aspects: to accurately define the concept and scope of extraordinary injury, to include it into the range of clinical research and treatment of burns, to fully use professional skills of burn surgeons in dealing with wounds, and to effectively treat the patients through learning and mastering treatment skills of other clinical disciplines for treatment of extraordinary injury.

Skin Damage Mechanisms Related to Airborne Particulate Matter Exposure.

Epidemiological studies suggest a correlation between increased airborne particulate matter (PM) and adverse health effects. The mechanisms of PM-health effects are believed to involve oxidative stress and inflammation. To evaluate the ability of PM promoting skin tissue damage, one of the main organs exposed to outdoor pollutants, we analyzed the effect of concentrated ambient particles (CAPs) in a reconstructed human epidermis (RHE) model. RHE tissues were exposed to 25 or 100 µg/ml CAPs for 24 or 48 h. Data showed that RHE seems to be more susceptible to CAPs-induced toxicity after 48 h exposure than after 24 h. We found a local reactive O(2) species (ROS) production increase generated from metals present on the particle, which contributes to lipids oxidation. Furthermore, as a consequence of altered redox status, NFkB nucleus translocation was increase upon CAPs exposure, as well as cyclooxygenase 2 and cytochrome P450 levels, which may be involved in the inflammatory response initiated by PM. CAPs also triggered an apoptotic process in skin. Surprisingly, by transition electron microscopy analysis we showed that CAPs were able to penetrate skin tissues. These findings contribute to the understanding of the cutaneous pathophysiological mechanisms initiated by CAPs exposure, where oxidative stress and inflammation may play predominant roles.

Review of AlloDerm Acellular Human Dermis Regenerative Tissue Matrix in Multiple Types of Oculofacial Plastic and Reconstructive Surgery.

AlloDerm acellular human dermis is used for repair or replacement of damaged or inadequate skin tissue. It has been used successfully in multiple types of surgeries, including abdominal wall reconstruction, breast reconstruction, and head and neck reconstruction. Its application to ophthalmic plastic and reconstructive surgery is less well described. This study seeks to evaluate the efficacy and factors influencing surgical outcomes using Alloderm in multiple types of oculofacial plastic surgery. Institutional Review Board-approved retrospective review of 84 patients who underwent surgical procedures using Alloderm. Preoperative demographic data, comorbidities, smoking, clinical etiology, surgical methods, Alloderm type, and outcome (cosmetic and functional) were evaluated. This study included 84 patients, accounting for a total of 98 procedures. Mean age was 52.5 years (3-93 years). Etiologies necessitating surgery included malignancy in 26 patients (31.0%), trauma in 19 patients (22.6%), congenital lesions in 15 patients (17.9%), and senile change in 11 patients (13.1%). Surgical procedures included lower eyelid posterior lamella elongation, socket and fornix reconstruction, scar repair, patch grafts, and filler. Mean duration of follow up was 530 days. Overall, 92.8% of patients had favorable outcomes. Factors associated with significantly worse outcomes included smoking, congenital anomaly etiologies, and previous graft/flaps in the same area (p = 0.03, p = 0.029, and p = 0.007, respectively). This study suggests that Alloderm acellular human dermis can be used safely and effectively in multiple types of oculofacial procedures. Smoking, congenital anomaly etiologies, and previous graft/flap were associated with poor cosmetic and functional outcomes.

Pilon fractures

Pilon fractures are articular fractures of the distal tibia which involve the weight bearing part of the ankle joint. Assessment of the fracture is carried out with computed tomography and evaluation of the skin and soft tissue damage. In joint-preserving surgical reconstruction, treatment of the soft tissue damage has priority. The surgical approaches are preferably local and when necessary multiple (up to three) and performed simultaneously but the localization also depends on the trauma-induced damage. The surgical strategy includes joint distraction, sequential joint reconstruction and joint axis correction as well as early non-weight bearing joint mobilization.

Suramin attenuated inflammation and reversed skin tissue damage in experimentally induced atopic dermatitis in mice.

Atopic dermatitis (AD) is a skin disease that is characterized by inflammation. Skin barrier dysfunction is commonly seen in AD leading to commonly seen infectious lesions in the skin of AD. Most people develop the skin inflammation condition first, before any skin lesions become visible. Suramin is potent competitive inhibitor of reverse transcriptase and blocks the infectivity and cytopathic effects. Therefore, the following study was performed to illustrate if suramin could produce protection against AD in-vivo. AD like symptoms were introduced in mice by epicutaneous application of DNCB on shaved dorsal skin and ears. 20 mg/kg suramin was taken by intra-peritoneal injection twice weekly for 3 weeks to assess their anti-pruritic effects. Serum levels of inflammatory cytokine, interleukin (IL)-1β, IL-6 and tumor necrosis factor (TNF)-αwere assessed by using ELISA kits. We found that suramin alleviated DNCB-induced AD-like symptoms as quantified by skin lesion, dermatitis score, ear thickness and scratching behavior. Levels of reactive oxygen species in the suramin group were significantly inhibited as compared with that in the DNCB group. In parallel, suramin blocked DNCB-induced elevation in serum TNF-α, IL-1β, IL-6 and IgE. The collective results indicate that suramin suppresses DNCB-induced AD in mice via reduction of inflammatory mediators.

In vitro analysis of the effect of alkyl-chain length of anionic surfactants on the skin by using a reconstructed human epidermal model.

We investigated the effect of the alkyl-chain length of anionic surfactants on the skin using an in vitro model. The evaluated anionic surfactants were sodium alkyl sulfate (AS) and sodium fatty acid methyl ester sulfonate (MES), which had different alkyl-chain lengths (C8-C14). Skin tissue damage and permeability were examined using a reconstructed human epidermal model, LabCyte EPI-MODEL24. Skin tissue damage was examined by measuring cytotoxicity with an MTT assay. Liquid chromatography/tandem mass spectrometry (LC/MS-MS) and liquid chromatography/mass spectrometry (LC/MS) were used to detect surfactants that permeated into the assay medium through an epidermal model. To assess the permeation mechanism and cell damage caused by the surfactants through the epidermis, we evaluated the structural changes of Bovine Serum Albumin (BSA), used as a simple model protein, and the fluidity of 1,2-dipalmitoyl-sn-glycero-3-phosphpcholine (DPPC) liposome, which serves as one of the most abundant phospholipid models of living cell membranes in the epidermis. The effects of the surfactants on the proteins were measured using Circular Dichroism (CD) spectroscopy, while the effects on membrane fluidity were investigated by electron spin resonance (ESR) spectroscopy. ET50 (the 50% median effective time) increased as follows: C10 < C12 < C8 < C14 in AS and C8, C10 < C12 < C14 in MES. The order of permeation through the LabCyte EPI-MODEL24 was C10 > C12 > C14, for both AS and MES. For both AS and MES, the order parameter, which is the criteria for the microscopic viscosity of lipid bilayers, increased as follows: C10 < C12 < C14, which means the membrane fluidity is C10 > C12 > C14. It was determined that the difference in skin tissue damage in the LabCyte EPI-MODEL24 with C10 to C14 AS and MES was caused by the difference in permeation and cell membrane fluidity through the lipid bilayer path in the epidermis.

Basal Cell Carcinoma Presenting as a Hypertrophic Scar

Basal Cell Carcinoma Presenting as a Hypertrophic Scar

Role of the aryl hydrocarbon receptor in tobacco smoke extract–induced matrix metalloproteinase‐1 expression

Findings from large epidemiologic studies indicate that there is a link between smoking and extrinsic skin ageing. We previously reported that matrix metalloproteinases (MMPs) mediate connective tissue damage in skin exposed to tobacco smoke extracts. Tobacco smoke contains more than 3800 constituents, including numerous water-insoluble polycyclic aromatic hydrocarbons (PAHs) that trigger aryl hydrocarbon receptor (AhR) signalling pathways. To analyse the molecular mechanisms involved in tobacco smoke-induced skin ageing, we exposed primary human fibroblasts and keratinocytes to tobacco smoke extracts. Hexane- and water-soluble tobacco smoke extracts significantly induced MMP-1 mRNA in both human cultured fibroblasts and keratinocytes in a dose-dependent manner. To clarify the involvement of the AhR pathway, we used a stable AhR-knockdown HaCaT cell line. AhR knockdown abolished the increased transcription of the AhR-dependent genes CYP1A1/CYP1B1 and MMP-1 induced by either of the tobacco smoke extracts. Furthermore, the tobacco smoke extracts induced 7-ethoxyresorufin-O-deethylase activity, which was almost completely abolished by AhR knockdown. Likewise, treating fibroblasts with AhR pathway inhibitors, that is, the flavonoids 3-methoxy-4-nitroflavone and α-naphthoflavone, blocked the expression of CYP1B1 and MMP-1. These findings suggest that the tobacco smoke extracts induce MMP-1 expression in human fibroblasts and keratinocytes via activation of the AhR pathway. Thus, the AhR pathway may be pathogenetically involved in extrinsic skin ageing.

Antioxidative Action of Citrus limonum Essential Oil on Skin

Aims: The purpose of this study was to investigate the action of Citrus limonum essential oil to control free radical-induced lipid peroxidation and preventing tissue damage in skin. Place and Duration of Study: Department of Internal Medicine (University of Roma “Tor Vergata) and A.R.P.A (Aging Research, Prevention and Therapy Association, www.antiaging.it), between January 2010 and June 2011. Methodology: The essential oil was subjected to GC-MS analysis. The superoxide anion scavenging activity of essential oil was evaluated by the enzymatic hypoxanthine/xanthine oxidase system. The same oil diluted in DMSO or grape-seed oil was spread on the face of human volunteers after UV exposition. A sample of skin lipids was collected and the presence of peroxyl radicals was detected based on the measurement of light emitted (chemiluminescence) when the excited carbonyl and singlet oxygen decay to ground state. Research Article European Journal of Medicinal Plants, 3(1): 1-9, 2013 2 Results: Our data demonstrate that the lemon essential oil is more active than tocopherol against O2 and peroxide free radical inhibition at 1:100 dilution. A protocol for controlling free radical-induced lipid peroxidation in human skin was thus proposed. Conclusion: The scavenging action of lemon essential oil could have a practical application for treating human skin against oxidative damage.

Nonsurgical Treatment of a Massive Substance Loss

Traumatic wounds are caused by severe trauma, resulting in lesions with extensive skin and subcutaneous tissue loss and damage to tissue viability. A “difficult wound” is a solution of continuity that does not heal spontaneously within three months. The factors that determine it may be as follows: a massive loss of substance, an infection, the presence of foreign bodies, or the clinical condition of the patient. We report a case of a 25-year-old man that presents a skin lesion on the anterior region of the left arm with extensive necrosis of skin and subcutaneous plants that involve the underlying muscle planes, caused by a trauma due to a car accident. In most of the lesions of such size and position, there is always a need for surgery. But in this case, considering the young age and the regenerative capacity of the patient, a quick and targeted antibiotic therapy was chosen, combined with debridement and worked with collagenase ointment.

T-Bet Is Critical for the Development of Acute Graft-Versus-Host Disease Through Controlling T Cell Differentiation and Function

Abstract 452 Background:Allogeneic hematopoietic cell transplantation (HCT) offers great promise for the treatment of hematologic malignancies. However, HCT benefits are frequently offset by graft-versus-host disease (GVHD). Donor T cells can differentiate into Th1 or Th17 subset that contribute to GVHD. The T-box transcription factor T-bet is important for promoting the differentiation of naïve CD4+T cells into Th1 phenotype, while simultaneously inhibiting Th2 and Th17 lineage commitment. Published data indicate that donor T cells deficient for IFN-γ induce exacerbated GVHD. In contrast, our recent study showed that T cells deficient for T-bet were impaired in the induction of GVHD. Given T-bet is a master regulator for the differentiation into Th1 cells that produce IFN-γ, the underlining mechanisms accounted for the distinct outcomes caused by T-bet- versus IFN-γ-deficient donor T cells are not clear. Method:We evaluated the roles of T-bet and IFN-γ in acute GVHD induced by naïve CD4+ T cells or polarized Th17 cells using murine allogeneic bone marrow transplantation (allo-BMT) model. WT, T-bet knockout (KO) and IFN-γ KO mice on C57BL/6 (B6) background were used as donors, and lethally irradiated BALB/c mice were used as recipients. Pathologic analysis and serum cytokine detection were done 14 days after adoptive transfer of WT, T-bet–/–, and IFN-γ–/– CD4+ T cells. Using microarray technology, gene expression profile on donor T cells was analyzed 7 days after adoptive transfer by sorting donor-derived CD4+ T cells from the recipients of WT, T-bet–/– or IFN-γ–/– CD4+ T cells. Results:We compared the ability of WT, T-bet–/–, and IFN-γ–/– CD4 T cells in the induction of acute GVHD. In the comparison with WT cells, IFN-γ–/– CD4 T cells caused similar or even more severe GVHD as expected. In sharp contrast, T-bet–/– CD4 T cells induced much ameliorated GVHD, as significantly higher survival and less body weight loss were observed in the recipients of T-bet–/–T cells. Pathology study on GVHD target organs showed that recipients of T-bet–/– donor T cells had markedly reduced T cell infiltration and tissue damage in liver, gut, and skin, when compared with those of WT or IFN-γ–/– T cells. Reduced GVHD in the recipients of T-bet–/– T cells was consistent with significantly lower levels of pathogenic cytokines IFN-γ, TNF-α, and IL-2 but higher IL-10 (anti-inflammatory), IL-6 (Th17 related) and IL-4 (Th2 related) in serum as compared with those in the recipients of WT T cells. Mechanistic studies in vitro revealed that T-bet–/– CD4 T cells expressed significantly lower levels of IFN-γ, CXCR3 (Th1 specific chemokine receptor) and CD122 (T cell activation marker), but higher levels of IL-17 (Th17 cytokine) and CCR6 (Th17 specific chemokine receptor) compared with WT CD4 T cells, indicating that T-bet–/– T cells impaired in differentiating into Th1 cells and instead into Th17 cells. Given Th17 subset only is capable of causing GVHD and T-bet–/– T cells are prone to Th17-differentiation, we assessed the role of T-bet or IFN-γ in the development of GVHD by comparing the pathogenicity of in vitro polarized WT, T-bet–/– and IFN-γ–/– Th17 cells. While IFN-γ–/– Th17 cells had a comparable ability to cause GVHD compared with WT Th17 cells, T-bet–/– Th17 cells had reduced pathogenicity, and caused ameliorated GVHD. Furthermore, microarray analysis identified genes that are regulated by T-bet but independent of IFN-γ, including Cxcr3, Ccr5, Ccl3, Ccl4, Klrc1, Klrd1, Nkg7 and Pdcd1, which may explain the compromised ability of T-bet−/− not IFN-γ–/–T cells in the induction of GVHD. Conclusions:We conclude that T-bet is required for Th1 differentiation and optimal function of Th17 cells, and it can also control T cell infiltration into GVHD target organs by regulating chemokines and their receptors. Thus, failure in Th1 generation, migration and reduced activity of polarized Th17 cells are likely accounted for impaired ability of T-bet−/− CD4 T cells in the induction of acute GVHD. The current study suggests that targeting T-bet or regulating its downstream effectors independent of IFN-γ may be a promising strategy to control GVHD after allogeneic HCT in clinic. Disclosures:No relevant conflicts of interest to declare.

Sacral pressure ulcer successfully treated with traction, resulting in a reduction of wound deformity

Sacral pressure ulcer successfully treated with traction, resulting in a reduction of wound deformity

Composite poly-l-lactic acid/poly-(α,β)-dl-aspartic acid/collagen nanofibrous scaffolds for dermal tissue regeneration

Tissue engineering scaffolds for skin tissue regeneration is an ever expounding area of research, as the products that meet the necessary requirements are far and elite. The nanofibrous poly-l-lactic acid/poly-(α,β)-dl-aspartic acid/Collagen (PLLA/PAA/Col I&III) scaffolds were fabricated by electrospinning and characterized by SEM, contact angle and FTIR analysis for skin tissue regeneration. The cell-scaffold interactions were analyzed by cell proliferation and their morphology observed in SEM. The results showed that the cell proliferation was significantly increased (p≤0.05) in PLLA/PAA/Col I&III scaffolds compared to PLLA and PLLA/PAA nanofibrous scaffolds. The abundance and accessibility of adipose derived stem cells (ADSCs) may prove to be novel cell therapeutics for dermal tissue regeneration. The differentiation of ADSCs was confirmed using collagen expression and their morphology by CMFDA dye extrusion technique. The current study focuses on the application of PLLA/PAA/Col I&III nanofibrous scaffolds for skin tissue engineering and their potential use as substrate for the culture and differentiation of ADSCs. The objective for inclusion of a novel cell binding moiety like PAA was to replace damaged extracellular matrix and to guide new cells directly into the wound bed with enhanced proliferation and overall organization. This combinatorial epitome of PLLA/PAA/Col I&III nanofibrous scaffold with stem cell therapy to induce the necessary paracrine signalling effect would favour faster regeneration of the damaged skin tissues.

Shikonin enhances efficacy of a gene-based cancer vaccine via induction of RANTES

BackgroundShikonin, a phytochemical purified from Lithospermum erythrorhizon, has been shown to confer diverse pharmacological activities, including accelerating granuloma formation, wound healing, anti-inflammation and others, and is explored for immune-modifier activities for vaccination in this study. Transdermal gene-based vaccine is an attractive approach for delivery of DNA transgenes encoding specific tumor antigens to host skin tissues. Skin dendritic cells (DCs), a potent antigen-presenting cell type, is known to play a critical role in transmitting and orchestrating tumor antigen-specific immunities against cancers. The present study hence employs these various components for experimentation.MethodThe mRNA and protein expression of RANTES were detected by RT-PCR and ELISA, respectively. The regional expression of RANTES and tissue damage in test skin were evaluated via immunohistochemistry assay. Fluorescein isothiocyanate sensitization assay was performed to trace the trafficking of DCs from the skin vaccination site to draining lymph nodes. Adjuvantic effect of shikonin on gene gun-delivered human gp100 (hgp100) DNA cancer vaccine was studied in a human gp100-transfected B16 (B16/hgp100) tumor model.ResultsAmong various phytochemicals tested, shikonin induced the highest level of expression of RANTES in normal skin tissues. In comparison, mouse RANTES cDNA gene transfection induced a higher level of mRANTES expression for a longer period, but caused more extensive skin damage. Topical application of shikonin onto the immunization site before gene gun-mediated vaccination augmented the population of skin DCs migrating into the draining lymph nodes. A hgp100 cDNA gene vaccination regimen with shikonin pretreatment as an adjuvant in a B16/hgp100 tumor model increased cytotoxic T lymphocyte activities in splenocytes and lymph node cells on target tumor cells.ConclusionTogether, our findings suggest that shikonin can effectively enhance anti-tumor potency of a gene-based cancer vaccine via the induction of RANTES expression at the skin immunization site.

The IL-17 Differentiation Pathway and Its Role in Transplant Outcome

The limitations of allogeneic transplantation are graft-versus-host disease (both acute and chronic), infection, and relapse. Acute GVHD has traditionally been thought of as a Th1-mediated disease with inflammatory cytokines (eg, interferon [IFN]-γ and tumor necrosis factor [TNF]) and cellular cytolysis mediating apoptotic target tissue damage in skin, gut, and liver. Chronic GVHD has not fit neatly into either Th1 or Th2 (eg, IL-4, IL-13) paradigms. Increasingly, the Th17 pathway of differentiation has been shown to play important roles in acute and chronic GVHD (aGVHD, cGVHD), particularly in relation to skin and lung disease. Here we discuss the IL-17 pathway of T cell differentiation and the accumulating evidence suggesting it represents an important new target for the control of deleterious alloimmune responses.

Autocrine Regulation of Re-Epithelialization After Wounding by Chemokine Receptors CCR1, CCR10, CXCR1, CXCR2, and CXCR3

This study identifies chemokine receptors involved in an autocrine regulation of re-epithelialization after skin tissue damage. We determined which receptors, from a panel of 13, are expressed in healthy human epidermis and which monospecific chemokine ligands, secreted by keratinocytes, were able to stimulate migration and proliferation. A reconstructed epidermis cryo(freeze)-wound model was used to assess chemokine secretion after wounding and the effect of pertussis toxin (chemokine receptor blocker) on re-epithelialization and differentiation. Chemokine receptors CCR1, CCR3, CCR4, CCR6, CCR10, CXCR1, CXCR2, CXCR3, and CXCR4 were expressed in epidermis. No expression of CCR2, CCR5, CCR7, and CCR8 was observed by either immunostaining or flow cytometry. Five chemokine receptors (CCR1, CCR10, CXCR1, CXCR2, and CXCR3) were identified, the corresponding monospecific ligands (CCL14, CCL27, CXCL8, CXCL1, CXCL10, respectively) of which were not only able to stimulate keratinocyte migration and/or proliferation but were also secreted by keratinocytes after introducing cryo-wounds into epidermal equivalents. Blocking of receptor-ligand interactions with pertussis toxin delayed re-epithelialization, but did not influence differentiation (as assessed by formation of basal layer, spinous layer, granular layer, and stratum corneum) after cryo-wounding. Taken together, these results confirm that an autocrine positive-feedback loop of epithelialization exists in order to stimulate wound closure after skin injury.