Lung Surfactant Accelerates Skin Wound Healing: A Translational Study with a Randomized Clinical Phase I Study.

Lung surfactants are used for reducing alveolar surface tension in preterm infants to ease breathing. Phospholipid films with surfactant proteins regulate the activity of alveolar macrophages and reduce inflammation. Aberrant skin wound healing is characterized by persistent inflammation. The aim of the study was to investigate if lung surfactant can promote wound healing. Preclinical wound models, e.g. cell scratch assays and full-thickness excisional wounds in mice, and a randomized, phase I clinical trial in healthy human volunteers using a suction blister model were used to study the effect of the commercially available bovine lung surfactant on skin wound repair. Lung surfactant increased migration of keratinocytes in a concentration-dependent manner with no effect on fibroblasts. Significantly reduced expression levels were found for pro-inflammatory and pro-fibrotic genes in murine wounds. Because of these beneficial effects in preclinical experiments, a clinical phase I study was initiated to monitor safety and tolerability of surfactant when applied topically onto human wounds and normal skin. No adverse effects were observed. Subepidermal wounds healed significantly faster with surfactant compared to control. Our study provides lung surfactant as a strong candidate for innovative treatment of chronic skin wounds and as additive for treatment of burn wounds to reduce inflammation and prevent excessive scarring.

Mirastschijski U ，Schwab I ，Coger V ，Zier U ，Rianna C ，He W ，Maedler K ，Kelm S ，Radtke A ，Belge G ，Lindner P ，Stahl F ，Scharpenberg M ，Lasota L ，Timm J ... -  《Scientific Reports》

Extracellular matrix/stromal vascular fraction gel conditioned medium accelerates wound healing in a murine model.

Conditioned medium (CM) is a new treatment modality in regenerative medicine and has shown a successful outcome in wound healing. We recently introduced extracellular matrix/stromal vascular fraction gel (ECM/SVF-gel), an adipose-derived stem cell and adipose native extracellular matrix-enriched product for cytotherapy. This study aimed to evaluate the effect of CM from ECM/SVF-gel (Gel-CM) on wound healing compared with the conventional CM from adipose tissue (Adi-CM) and stem cell (SVF-CM). In vitro wound healing effect of three CMs on keratinocytes and fibroblasts was evaluated in terms of proliferation property, migratory property, and extracellular matrix production. In vivo, two full-thickness wounds were created on the back of each mice. The wounds were randomly divided to receive Gel-CM, Adi-CM, SVF-CM, and PBS injection. Histologic observations and collagen content of wound skin were made. Growth factors concentration in three CMs was further quantified. In vitro, Gel-CM promoted the proliferation and migration of keratinocytes and fibroblasts and enhanced collagen I synthesis in fibroblasts compared to Adi-CM and SVF-CM. In vivo, wound closure was faster, and dermal and epidermal regeneration was improved in the Gel-CM-treated mice compared to that in Adi-CM and SVF-CM-treated mice. Moreover, The growth factors concentration (i.e., vascular endothelial growth factor, basic fibroblast growth factor, hepatocyte growth factor, and transforming growth factor-β) in Gel-CM were significantly higher than those in Adi-CM and SVF-CM. Gel-CM generated under serum free conditions significantly enhanced wound healing effect compared to Adi-CM and SVF-CM by accelerating cell proliferation, migration, and production of ECM. This improved trophic effect may be attributed to the higher growth factors concentration in Gel-CM. Gel-CM shows potential as a novel and promising alternative to skin wound healing treatment. But limitations include the safety and immunogenicity studies of Gel-CM still remain to be clearly clarified and more data on mechanism study are needed.

Deng C ，He Y ，Feng J ，Dong Z ，Yao Y ，Mok H ，Lin M ，Feng L ... -  《-》

The effects of artocarpin on wound healing: in vitro and in vivo studies.

The skin protects the body against harmful substances and microorganisms. When the skin is damaged, wound healing must be finely regulated to restore the normal function of skin tissue. Artocarpin (ARTO), a prenylated flavonoid purified from the plant Artocarpus communis, has been reported to have anti-inflammatory and anti-cancer properties. The aim of the present study was to evaluate the wound healing potential and therapeutic mechanism of ARTO. Immunohistochemical staining of neutrophils and macrophages and mouse cytokine array analysis demonstrated that ARTO accelerates inflammatory progression and subsequently decreases persistent inflammation. ARTO increases collagen production and increases human fibroblast proliferation and migration by activating the P38 and JNK pathways. Moreover, ARTO increases the proliferation and migration of human keratinocytes through the ERK and P38 pathways and augments human endothelial cell proliferation and tube formation through the Akt and P38 pathways. Together, our data suggested that ARTO enhances skin wound healing, possibly by accelerating the inflammatory phase and by increasing myofibroblast differentiation, proliferation and migration of fibroblasts and keratinocytes, collagen synthesis and maturation, re-epithelialization, and angiogenesis. These findings indicate that ARTO has potential as a potent therapeutic agent for the treatment of skin wounds.

Yeh CJ ，Chen CC ，Leu YL ，Lin MW ，Chiu MM ，Wang SH ... -  《Scientific Reports》

Effect of herbal mixture composed of Alchemilla vulgaris and Mimosa on wound healing process.

Alchemilla vulgaris and Mimosa tenuiflora (Mimosa) have been used to treat cutaneous wounds as a traditional remedy due to their various biological activities. But, there are only a few studies about the effects of these herbs on wound healing. The purpose of this study is to investigate the wound healing effect of the herbal mixture, consisting of A. vulgaris and Mimosa, in mice and to determine the activity of the extract in vitro. In present study, application of an ointment containing the herbal mixture on the dorsal skin wounds of mice showed that the wound healing process was faster than treatment of Fusidic acid. Histological analysis demonstrated the herbal mixture promoted re-epithelialization, collagen synthesis, and especially the regeneration of skin appendages such as hair follicles. Immunohistochemical analysis revealed the herbal mixture improved angiogenesis and the stabilization of blood vessels, as well as accelerated the formation of granulation tissue. In addition, we demonstrated that herbal mixture enhanced the migration of HaCaT, fibroblasts, and HUVECs on a two-dimensional wound, and promoted the proliferation of macrophages and lymphatic vessels. Our results demonstrated that herbal mixture can promote the migration of keratinocytes, fibroblasts, and endothelial cells, and the proliferation of macrophages and lymphatic vessels. Furthermore, it showed that herbal mixture accelerates wound healing. Therefore, we suggest that herbal mixture may have a potential for therapeutic use for treatment and management of cutaneous wound.

Choi J ，Park YG ，Yun MS ，Seol JW ... -  《-》

A synthetic leukotriene B(4) receptor type 2 agonist accelerates the cutaneous wound healing process in diabetic rats by indirect stimulation of fibroblasts and direct stimulation of keratinocytes.

The synthetic leukotriene B receptor type 2 (BLT2) agonist CAY10583 (CAY) accelerates wound healing in diabetic mice by promoting keratinocyte migration. However, its effects on fibroblast activity and granulation are unknown. We investigated the mechanisms by which CAY promotes wound healing. CAY was applied to wounds on streptozotocin-induced diabetic rats, and wound closure, granulation thickness, and epithelialization gaps were analyzed. BLT2 expression was examined by RT-PCR. Migration and proliferation were studied by scratch assays and MTS assays. Keratinocyte supernatants with CAY were applied to fibroblasts, and cytokines were measured by enzyme-linked immunosorbent assays. CAY significantly accelerated wound healing in diabetic rats (CAY, 78.05±12.22% vs. control, 59.84±11.09%; p=0.0222), with increased re-epithelialization and granulation compared to controls. BLT2 was expressed in keratinocytes, but not in fibroblasts. Keratinocyte treatment with the CAY supernatant enhanced fibroblast proliferation and migration (fibroblast scratch closure: CAY, 75.95±4.09% vs. control, 49.69±4.49%; p<0.0001). CAY-treated keratinocytes exhibited increased TGF-β1 and bFGF expression. CAY directly promotes keratinocyte migration and indirectly enhances fibroblast proliferation by increasing keratinocyte production of TGF-β1 and bFGF, accelerating wound closure. CAY is a promising pharmaceutical agent for diabetic wounds.

Luo L ，Tanaka R ，Kanazawa S ，Lu F ，Hayashi A ，Yokomizo T ，Mizuno H ... -  《-》