Osamu Norisugi

Macrophage Migration Inhibitory Factor Is Essential for Eosinophil Recruitment in Allergen-Induced Skin Inflammation

Macrophage migration inhibitory factor (MIF) is a pluripotent cytokine that has an essential role in the pathophysiology of experimental allergic inflammation. Recent findings suggest that MIF is involved in several allergic disorders, including atopic dermatitis (AD). In this study, the role of MIF in allergic skin inflammation was examined using a murine model of AD elicited by epicutaneous sensitization with ovalbumin (OVA). We observed the number of skin-infiltrating eosinophils to significantly increase in OVA-sensitized MIF transgenic (Tg) mice compared with their wild-type (WT) littermates. On the other hand, eosinophils were virtually absent from the skin of MIF knockout (KO) mice and failed to infiltrate their skin after repeated epicutaneous sensitization with OVA. The mRNA expression levels of eotaxin and IL-5 were significantly increased in OVA-sensitized skin sites of MIF Tg mice, but were significantly decreased in MIF KO mice in comparison with the levels in WT littermates. Eotaxin expression was induced by IL-4 stimulation in fibroblasts in MIF Tg mice, but not in MIF KO mice. These findings indicate that MIF can induce eosinophil accumulation in the skin. Therefore, the targeted inhibition of MIF might be a promising new therapeutic strategy for allergic skin diseases.

UV-B radiation induces macrophage migration inhibitory factor-mediated melanogenesis through activation of protease-activated receptor-2 and stem cell factor in keratinocytes.

UV radiation indirectly regulates melanogenesis in melanocytes through a paracrine regulatory mechanism involving keratinocytes. Protease-activated receptor (PAR)-2 activation induces melanosome transfer by increasing phagocytosis of melanosomes by keratinocytes. This study demonstrated that macrophage migration inhibitory factor (MIF) stimulated PAR-2 expression in human keratinocytes. In addition, we showed that MIF stimulated stem cell factor (SCF) release in keratinocytes; however, MIF had no effect on the release of endothelin-1 or prostaglandin E2 in keratinocytes. In addition, MIF had no direct effect on melanin and tyrosinase synthesis in cultured human melanocytes. The effect of MIF on melanogenesis was also examined using a three-dimensional reconstituted human epidermal culture model, which is a novel, commercially available, cultured human epidermis containing functional melanocytes. Migration inhibitory factor induced an increase in melanin content in the epidermis after a 9-day culture period. Moreover, melanin synthesis induced by UV-B stimulation was significantly down-regulated by anti-MIF antibody treatment. An in vivo study showed that the back skin of MIF transgenic mice had a higher melanin content than that of wild-type mice after 12 weeks of UV-B exposure. Therefore, MIF-mediated melanogenesis occurs mainly through the activation of PAR-2 and SCF expression in keratinocytes after exposure to UV-B radiation.

Macrophage migration inhibitory factor ameliorates UV-induced photokeratitis in mice.

Acute ultraviolet (UV) exposure causes photokeratitis, and induces apoptosis in corneal cells of the eye. Macrophage migration inhibitory factor (MIF) was originally identified as a lymphokine. Today, MIF is considered as an integral component of the host antimicrobial alarm system and stress response that promotes the proinflammatory functions of immune cells. Also, MIF is considered to contribute the wound healing process. The aim of the present study is to determine the effects of MIF expression on UV irradiated corneal damage. MIF transgenic (MIF-Tg), wild type (WT), and MIF deficient (MIF KO) mice were UVB-irradiated of 400mJ/cm2 to induce acute UV-photokeratitis. MIF Tg mice constitutively produce high levels of MIF. Morphological changes were most severe in MIF KO mice, and WT and MIF Tg mice were following. Corneal basement membrane of MIF-Tg was well preserved. Prominent higher level of MIF was observed in MIF-Tg than WT after UVB irradiation in cornea. TUNEL staining showed a significantly smaller number of TUNEL positive nuclei in MIF-Tgm (6.2+/-4.3 cells/section, p<0.01 compared with WT) than WT (30.7+/-9.1) and MIF KO mice (32.1+/-12.7) 24h after UV exposure. The number of c-Jun positive nuclei was significantly higher in MIF Tg (p<0.01) than in WT and MIF KO mice. Serial observation revealed that BrdU incorporation was significantly upregulated in MIF Tg (p<0.01), but downregulated in MIF KO (p<0.01) than WT mice. MIF expression may thus be related to the amelioration of UVB-caused corneal injury, and this association was attributable to the upregulation of cell proliferation after acute UV-induced corneal damage, which involves the c-Jun dependent pathway. In conclusion, UV-damaged cornea is recoverable without MIF, however it takes longer time than normal condition. Cornea is less damaged and can make a quick recovery when ocular tissue is enough supplied with MIF.

Desmoplastic fibroblastoma (collagenous fibroma)

Desmoplastic fibroblastoma (DF) is a rare fibrotic tumor that has a wide anatomic distribution and it can appear in deep sections of the subcutis, in fascia, in aponeurosis or in skeletal muscles. This report describes a case of DF that appeared on the left side of the neck of a 55‐year‐old male as a 3.5‐cm solitary, firm nodule. Histologically, it was composed of stellate or bland spindle‐shaped cells embedded in a loose collagenous stroma. The entrapment of fat and muscle tissues was focally identified at the edges of the tumor. The stellate and multinucleated cells in the lesion were strongly positive for vimentin but negative for cytokeratin, smooth muscle actin, desmin, S‐100, CD34, factor XIIIa, and CD68. These findings suggest that the stellate and multinucleated cells in the lesion were of fibroblastic origin and this neoplasm was pathologically benign.

Successful treatment of lichen amyloidosis using a CO2 surgical laser

Lichen amyloidosis (LA) is a type of primary localized cutaneous amyloidosis characterized by multiple pruritic discrete hyperkeratotic papules with amyloid deposition in the papillary dermis. Two patients with LA had been treated with topical corticosteroids, but with no effect on the eruptions. The present authors then started treating the affected area by superficial ablation using a CO2 surgical laser (LASER 30C, Lumenis Inc., Yokneum, Israel) at a setting of 10–15 watts with a 0.12‐second pulse duration, 0.36‐second rest duration, and 5‐mm laser spot size. The present authors treated the patients twice a month with the CO2 laser. The papules on the legs had flattened in both patients, with a great improvement in the severe itching after 6 months in Case 1 and after 10 months in Case 2. These cases indicate that the CO2 laser led to a good response in terms of the clinical manifestations, and may be useful for the treatment of LA.

Involvement of MIF in Basement Membrane Damage in Chronically UVB-Exposed Skin in Mice

Solar ultraviolet (UV) B radiation is known to induce matrix metalloproteinases (MMPs) that degrade collagen in the basement membrane. Macrophage migration inhibitory factor (MIF) is a pluripotent cytokine that plays an essential role in the pathophysiology of skin inflammation induced by UV irradiation. This study examined the effects of MIF on basement membrane damage following chronic UVB irradiation in mice. The back skin of MIF transgenic (Tg) and wild-type (WT) mice was exposed to UVB three times a week for 10 weeks. There was a decrease in intact protein levels of type IV collagen and increased basement membrane damage in the exposed skin of the MIF Tg mice compared to that observed in the WT mice. Moreover, the skin of the MIF Tg mice exhibited higher MIF, MMP-2 and MMP-9 expression and protein levels than those observed in the WT mice. We also found that chronic UVB exposure in MIF Tg mice resulted in higher levels of neutrophil infiltration in the dermis compared with that observed in the WT mice. In vitro experiments revealed that MIF induced increases in the MMPs expression, including that of MMP-9 in keratinocytes and MMP-2 in fibroblasts. Cultured neutrophils also secreted MMP-9 stimulated by MIF. Therefore, MIF-mediated basement membrane damage occurs primarily through MMPs activation and neutrophil influx in murine skin following chronic UVB irradiation.

Primary cutaneous Ewing sarcoma following metastasis to the bone and lymph nodes

nomenclature of these three syndromes. However, avoidance of eponyms has become the public tendency in recent years and an acronym is preferred which summarizes information of the disease. Nevertheless, the acronyms JMP and CANDLE seem to represent only limited aspects of this disease, the advanced phenotypes and the pathological features, respectively. Indeed, Online Mendelian Inheritance in Man (OMIM) #256040, in which the designation ‘Nakajo syndrome’ has long been registered until recently, now includes all three syndromes under the new designation ‘autoinflammation, lipodystrophy and dermatosis (ALDD) syndrome’. Furthermore, a new conceptual acronym ‘proteasome-associated autoinflammatory syndromes (PRAAS)’ has recently been proposed as the umbrella term for these three syndromes. However, to apply this designation, proteasome dysfunction due to the novel mutation should be evident. Collectively, we believe that it would be both appropriate and desirable to discuss the distinction of these syndromes from the genetic and clinical aspects and, if they are really included in the same entity, to select the most suitable designation for the definition.

Effective treatment of angiosarcoma on the nose by combination treatment with electron beam irradiation, recombinant interleukin‐2 and docetaxel

Angiosarcoma is an uncommon malignant vascular neoplasm. It commonly develops on the head and neck, but it rarely affects the nose. Complete surgical excision of angiosarcoma on the nose is difficult because of cosmetic and functional issues. We describe a patient with angiosarcoma on the nose, which was treated by combination therapy including the administration of docetaxel. A 71-year-old man presented with an 8-month history of an ill-defined, painful, erythematous plaque on his nose and right cheek (Fig. 1a). He had injured his nose in a traffic accident 40 years previously. Histological examination of a skin biopsy taken from the lesion revealed infiltration of spindle-shaped cells to the dermis, and numerous unusual vascular spaces lined by atypical endothelial cells (Fig. 1b,c). Immunohistochemical staining found that the atypical cells were positive for CD31 and CD34 (Fig. 1d), and the mindbomb homologue (MIB)-1 index for the atypical cells was 50%. These histological findings indicated a diagnosis of angiosarcoma. Computed tomography (CT) of the patient s neck and chest and gallium scintigraphy found no evidence of metastasis. Results of all laboratory tests were normal. Owing to the extensive facial involvement, surgical excision was excluded as a treatment option. The patient was initially treated with 50 Gy of electron-beam irradiation to the tumour, followed by subcutaneous injection of recombinant interleukin (IL)-2 (4 · 10 U ⁄ day). These treatments yielded a partial response; however, the tumour gradually redeveloped on the nose and lung metastases were confirmed by CT 18 months later (Fig. 2a).

Synthesis and characterization of high-quality skin-cooling sheets containing thermosensitive poly(N-isopropylacrylamid)

Poly(N-isopropylacrylamide) (PNIPAAm) is the most popular thermosensitive polymer, and exhibits a low critical solution temperature of approximately 32°C. This study aimed to examine the usefulness of new cooling sheets, which are manufactured using a thermosensitive poly(N-isopropylacrylamide) (PNIPAAm) material. We prepared cooling-hydrogel sheets containing PNIPAAm (PNIPAAm sheet). We measured the skin temperature on the arms of the subjects using a thermograph and compared the usefulness of the PNIPAAm sheet and a control cooling-hydrogel sheet that did not contain the PNIPAAm mixture. Thermographic measurements obtained 40 min after the treatment with the cooling sheets showed the skin temperature of the subjects treated with the 3.% (w/w) PNIPAAm sheets to be significantly lower than that of the subjects treated with the control cooling-hydrogel sheet (p < 0.005). Compared with the control sheet, the cooling effect of the new PNIPAAm sheet also persisted for a longer duration (up to 100 min). The PNIPAAm sheets exhibited excellent cooling effects. This sheet may therefore be useful for lowering the body temperature of patients with high-grade fever, such as fever due to influenza infection.

Hailey-Hailey disease diagnosed based on an exacerbation of contact dermatitis with topical crotamiton

Hailey-Hailey disease (HHD; OMIM #169600), also known as benign familial chronic pemphigus, is a rare hereditary condition characterized by the formation of blisters at sites of friction. HHD is caused by mutations in the ATP2C1 gene. We herein describe a patient with HHD who was diagnosed following the exacerbation of skin lesions resulting from contact dermatitis induced by crotamiton. A 67-year-old female was admitted with complaints of itchy eruptions on the right sole, groin and trunk. She had [...]