Mechanistic Effects of Long-Term Ultraviolet B Irradiation Induce Epidermal and Dermal Changes in Human Skin Xenografts

UVB irradiation has been reported to induce photoaging and suppress systemic immune function that could lead to photocarcinogenesis. However, because of the paucity of an UVB-induced photodamaged skin model, precise and temporal mechanism(s) underlying the deleterious effects of long-term UVB exposure on human skin have yet to be delineated. In this study, we established a model using human skin xenografted onto severe combined immunodeficient mice, which were subsequently challenged by repeated UVB irradiation for 6 weeks. Three-dimensional optical image analysis of skin replicas and noninvasive biophysical measurements illustrated a significant increase in skin surface roughness, similar to premature photoaging, and a significant loss of skin elasticity after long-term UVB exposure. Resembling authentically aged skin, UVB-exposed samples exhibited significant increases in epithelial keratins (K6, K16, K17), elastins, and matrix metalloproteinases (MMP-1, MMP-9, MMP-12) as well as degradation of collagens (I, IV, VII). The UVB-induced deterioration of fibrous keratin intermediate filaments was also observed in the stratum corneum. Additionally, similarities in gene expression patterns between our model and chronologically aged skin substantiated the plausible relationship between photodamage and chronological age. Furthermore, severe skin photodamage was observed when neutralizing antibodies against TIMP-1, an endogenous inhibitor of MMPs, were administered during the UVB exposure regimen. Taken together, these findings suggest that our skin xenograft model recapitulates premature photoaged skin and provides a comprehensive tool with which to assess the deleterious effects of UVB irradiation.Morphological changes in the skin, such as wrinkling and sagging, are often found in photoaged skin caused by chronic UV irradiation.^1,2,3 Skin photodamage is physiologically correlated with several alterations including the increase and disorganization of elastic fibers and the reduction of collagens in the dermal extracellular matrix^{4,5,6,7,8,9,10,11} and the increase of keratin contents and the deterioration of keratin intermediate filaments (KIFs) in the epidermis.^12,13,14Elastic fibers are age-dependent-decreasing dermal extracellular matrix that respond primarily to the fibrous mechanism controlling cutaneous elasticity.^4,5,15,16 The accumulation of dystrophic elastotic material in the reticular dermis, referred to as solar elastosis, is commonly observed in photoaged skin.^17,18,19 Reported in both in vivo and in vitro, UVB irradiation induces tropoelastin gene and protein expression in fibroblasts and keratinocytes, resulting in an aberrant accumulation of dermal elastic fibers and elastin content.^5,8,10,11,20 On the other hand, it has been reported that the degeneration of these fibers in chronologically and/or photoaged skin stems from an increase in matrix metalloproteinase-12 (MMP-12) and/or elastase, an elastin-degrading enzyme that is produced and secreted by dermal fibroblasts.^21,22,23,24 To date, the mechanisms underlying the alteration of elastin fibers in photoaged skin including their production, accumulation, and degradation are not fully understood.As the main constituent of the dermal matrix, collagen fibers are responsible in regulating the mechanical properties of the skin (ie, skin resilience and skin elasticity). In photoaged skin, the concomitant reductions of collagen I and III occur as procollagen synthesis subsides and the existed dermal collagen degrades because of the disproportionate expression of MMP-1.^25,26,27,28 The reduction of collagens VII and IV at the dermo-epidermal junction has been also reported in the pronounced wrinkling skin.²⁹ In hairless mouse, repetitive UVB exposure has been reported to escalate the degradation of collagens VII and IV by up-regulating MMP-2 and MMP-9 expression.^30,31In addition to the alterations in the dermal compartment, the changes in several epithelial keratins have been well documented in photoaged skin. In healthy skin, keratins compose up to 85% of a fully differentiated keratinocyte and orderly form the epithelial-specific intermediate filament composed of acidic type I (K9 to K20)-basic type II (K1 to K8) coiled-coil heterodimer in healthy skin.^{32,33,34,35,36,37} The existence of keratin fibers strengthening the viscoelastic properties in the stratum corneum (SC) provides a semi-impermeable membrane that is tough and resilient.^38,39,40,41 In hairless mice, a repeated low-dose UV exposure has been reported to deteriorate KIFs and induce the expression of epithelial keratins (K1, K5, and K10), resulting in the loss of skin elasticity and eventually initiating wrinkled skin, consistent with previous reports demonstrating no causal relationship between wrinkle formation and dermal changes.^{12,13,14,42,43}Many studies of skin photoaging have been conducted using animal models and human skin substitute. The results may be misleading because of inferior architecture, such as the relative thin epidermal layer and compromised barrier function.⁴⁴ The use of actual human skin or human skin xenografts to study skin photoaging is more appropriate.^45,46,47 The reversible hyperproliferation and differentiation of human epidermis after acute UVB exposure has been successfully demonstrated using human skin grafted onto congenitally athymic nude mice.⁴⁸ Although the lack of inflammatory cells, T and B cells, in athymic and severe combined immunodeficient (SCID) mice allows the implantation of human skin without rejection, it may pose a problematic interpretation of immune function and UV response. A result from a clinical study suggested that T lymphocytes are involved in collagen degradation by the activation of MMP-1.⁴⁹ To date, the detail mechanisms of premature photoaging because of long-term UVB exposure on actual human skin had not been assessed. Therefore, it is of particular interest to establish a chimeric model with human skin xenograft on SCID mice to examine the mechanism(s) of photodamaged skin after long-term UVB irradiation. Here we report for the first time that repeated UVB irradiation in combination with the repetitive motion of the human skin xenograft represents a photodamaged skin model reflecting the documented changes in both the epidermis and the dermis. In addition, we also suggest new insights for the involvement of K6 and its partners in this process.     

Comparative clinicopathological study of primary CNS diffuse large B-cell lymphoma and intravascular large B-cell lymphoma

Primary CNS diffuse large B-cell lymphoma (CNS DLBCL) is confined to the CNS, and constitutes a distinct entity. In the present study a series of 40 Japanese patients with CNS DLBCL who presented with neurological, but not systemic symptoms, was reviewed. Median survival was 18.7 months. CD5, CD10, Bcl-6, MUM-1, and Bcl-2 were positive in 30%, 10%, 84%, 100%, and 93% of patients, respectively. All CD10-negative patients had non-germinal center B-cell type. There was no significant difference in survival among the immunophenotypic subgroups. CNS DLBCL appeared to be homogenous as a group, which prompted the comparison with another distinct extranodal entity, intravascular large B-cell lymphoma (IVLBCL) in Japanese patients. CNS DLBCL patients did not differ in age, sex, or immunophenotype, including CD5 positivity, from IVLBCL patients, but were significantly less likely to have poor prognostic parameters than IVLBCL patients: the international prognostic index score was low or low–intermediate in 86% of CNS DLBCL patients and high or high–intermediate in 98% of IVLBCL patients. Notably, despite this difference, their survival curves almost overlapped. The present study highlights the issue of clinical distinctiveness of aggressive extranodal lymphomas, the peculiar migration and localization of which should be further clarified.     

A delayed splenic rupture after transcatheter arterial embolization required total splenectomy in a patient with an implantable left ventricular assist device

We successfully managed a splenic injury and delayed splenic rupture in a patient with an implantable left ventricular assist device (iLVAD). A 42-year-old man with an iLVAD for idiopathic dilated cardiomyopathy was admitted to our department complaining of dizziness. Laboratory data showed severe anemia, and computed tomography demonstrated a traumatic splenic injury. Following conservative treatment, partial splenic embolization was performed. Fifteen days after the intervention, the patient went into hemorrhagic shock due to delayed splenic rupture. Emergency total splenic embolization was performed, and total splenectomy was conducted later to prevent re-bleeding or abscess formation. His postoperative course was uneventful, and he was discharged on postoperative day 22. Finally, he underwent orthotropic heart transplantation without post-splenectomy sepsis or thrombotic complications 472 days after splenectomy. Splenic injury should be considered as a possible complication of iLVAD. In addition, careful follow-up after transcatheter arterial embolization for splenic injury is essential for managing delayed splenic rupture.     

Human heme oxygenase-1 deficiency presenting with hemolysis, nephritis, and asplenia

Heme oxygenase-1 (HO-1) is a stress-induced enzyme that catalyses the oxidation of heme to biliverdin. The primary deficiency of this enzyme has been shown in HO-1 knockout mice, and is characterized by intrauterine death and chronic inflammation. The first case of human HO-1 deficiency was reported in 1999. Human HO-1 deficiency has been observed to involve the endothelial cells more severely, resulting in hemolysis and disseminated intravascular coagulation. We report another case of human HO-1 deficiency in a young girl with congenital asplenia, who presented with severe hemolysis, inflammation, nephritis, which was refractory to therapy with corticosteroids, cyclophosphamide, and rituximab.     

The Structures of the E22Δ Mutant-Type Amyloid-β Alloforms and the Impact of E22Δ Mutation on the Structures of the Wild-Type Amyloid-β Alloforms

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Orthognathic treatment with maxillary and mandibular anterior segmental osteotomy

This case report presents a case that underwent orthognathic treatment with anterior segmental osteotomies on both jaws. The patient was a 26-year-old female with maxillary protrusion, lip incompetence with an everted vermilion border. The overbite was +1.0 mm, overjet +1.0 mm. The pre-surgical orthodontic treatment included the extraction of the four first premolars and a multi-bracket treatment was started. After 12 months of pre-surgical orthodontic treatment, both the anterior maxillary and the anterior mandibular segments were retracted surgically by 5.5 mm. The total treatment period was 18 months. An anterior segmental osteotomy can induce the remarkable structural changes for bimaxillary lip protrusion patients.     

Hodgkin's disease of the thoracic vertebrae

Background contextHodgkin's disease rarely occurs in the spine, which is usually a setting for the advanced form of the disease.PurposeTo describe an unusual case of isolated, primary spinal Hodgkin's disease and to draw attention to this disease as a possible diagnosis in patients with mixed inflammatory cell infiltrate lesions located in the thoracic spine.Study design/settingA case report of a 28-year-old woman who presented with back pain and progressive weakness in the lower extremities as a result of spinal cord compression from Hodgkin's disease of the thoracic vertebrae.MethodsWe report a new case of spinal cord compression resulting from Hodgkin's disease of the thoracic vertebrae. Decompression surgery was performed in the patient, followed by antibiotic treatment.ResultsAntibiotic therapy temporarily improved inflammation and fever. However, magnetic resonance imaging (MRI) evaluation showed that the inflammatory reaction in the lesion was not completely resolved. The disease progressed and later investigations revealed Hodgkin's disease, which improved with a course of chemotherapy and radiation.ConclusionsHodgkin's disease should be considered in the differential diagnosis of spinal neoplastic lesions with clinical features similar to spondylitis. Because MRI evaluation showed that the vertebral disc was maintained in this case, the presence of a tumor rather than inflammation should have been suspected.     

Association of head trauma with cervical spine injury, spinal cord injury, or both

BACKGROUND: Links between cervical spine and/or spinal cord injuries and head trauma have not been reported in detail. METHODS: 188 patients with cervical spine and/or spinal cord injury were divided into two groups, i.e., with upper cervical and mid-lower cervical injury, and compared for head injury. RESULTS: Associated head trauma was investigated in 188 patients with cervical spine and/or spinal cord injuries; 35% had moderate or severe injuries. Brain damage was more frequently observed in patients with upper cervical injury than in those with mid to lower cervical injury. Those patients with upper cervical injury appeared to have an elevated risk of suffering skull base fractures, traumatic subarachnoid hemorrhage, and contusional hemotoma. CONCLUSIONS: Approximately one third of patients with cervical spine and/or spinal cord injuries had moderate or severe head injuries. Brain damage was more frequently associated with upper cervical injury. Those patients with upper cervical injury are at greater risk of suffering from skull base fractures and severe intracranial hematomas than those with mid to lower cervical injury.     

Progressive bilateral sensorineural hearing loss induced by an antithyroid drug

We report a patient with antithyroid drug-induced progressive bilateral sensorineural hearing loss associated with myeloperoxidase-antineutrophil cytoplasmic antibodies (MPO-ANCA). While antithyroid drugs have been linked to MPO-ANCA-associated small-vessel vasculitis, sensorineural hearing loss rarely was noted. A 36-year-old man treated for hyperthyroidism with propylthiouracil (PTU) developed progressive bilateral sensorineural hearing loss accompanied by fever and arthritis. MPO-ANCA were demonstrated in serum. Distortion product otoacoustic emissions test results suggested dysfunction of outer hair cells of the organ of Corti. Inner ear blood flow impairment from ANCA-associated small-vessel vasculitis presumably caused cochlear dysfunction. PTU withdrawal and high-dose methylprednisolone administration greatly improved hearing on both sides.