Zinc deficiency exacerbates pressure ulcers by increasing oxidative stress and ATP in the skin.

BACKGROUND: Zinc deficiency is believed to be a predisposing factor for the development and intractable healing of pressure ulcers (PUs); however, the mechanisms of this association have not been elucidated. OBJECTIVE: Objective was to elucidate the mechanisms of the formation of severe and prolonged PUs under the zinc deficiency condition. METHODS: We assessed PUs formation after cutaneous ischemia-reperfusion (I/R) injury in mice fed with a zinc-adequate (ZA) or a zinc-deficient (ZD) diet from 2 weeks before I/R injury. Wound size, vascular damage, apoptotic cells, adenosine triphosphate (ATP) amount, and the number of Langerhans cells (LCs) in I/R area were analyzed. We evaluated the extent of oxidative stress in I/R area in OKD48 mice through bioluminescence detection. RESULTS: We found that dietary zinc deficiency caused the formation of severe and prolonged PUs in mice. Zinc deficiency increased the vascular disorder, oxidative stress, and apoptosis induced by cutaneous I/R injury. I/R injury-induced oxidative stress signals were significantly higher in ZD OKD48 mice than in ZA OKD48 mice. Additionally, zinc deficiency reduced the number of LCs and increased the amount of ATP in cutaneous I/R-injured skin. Oral supplementation of zinc improved zinc deficiency-associated PUs. CONCLUSION: Zinc deficiency might increase cutaneous I/R injury-induced vascular damages, oxidative stress, and apoptosis, as well as ATP amount in I/R area due to the loss of LCs. These mechanisms might partly account for zinc deficiency-induced formation of severe and prolonged PUs. Oral supplementation of zinc might be a reasonable therapeutic choice for patients with PUs and zinc deficiency.

Severe dermatitis with loss of epidermal Langerhans cells in human and mouse zinc deficiency.

Zinc deficiency can be an inherited disorder, in which case it is known as acrodermatitis enteropathica (AE), or an acquired disorder caused by low dietary intake of zinc. Even though zinc deficiency diminishes cellular and humoral immunity, patients develop immunostimulating skin inflammation. Here, we have demonstrated that despite diminished allergic contact dermatitis in mice fed a zinc-deficient (ZD) diet, irritant contact dermatitis (ICD) in these mice was more severe and prolonged than that in controls. Further, histological examination of ICD lesions in ZD mice revealed subcorneal vacuolization and epidermal pallor, histological features of AE. Consistent with the fact that ATP release from chemically injured keratinocytes serves as a causative mediator of ICD, we found that the severe ICD response in ZD mice was attenuated by local injection of soluble nucleoside triphosphate diphosphohydrolase. In addition, skin tissue from ZD mice with ICD showed increased levels of ATP, as did cultured wild-type keratinocytes treated with chemical irritants and the zinc-chelating reagent TPEN. Interestingly, numbers of epidermal Langerhans cells (LCs), which play a protective role against ATP-mediated inflammatory signals, were decreased in ZD mice as well as samples from ZD patients. These findings suggest that upon exposure to irritants, aberrant ATP release from keratinocytes and impaired LC-dependent hydrolysis of nucleotides may be important in the pathogenesis of AE.

Heat immunotherapy using magnetic nanoparticles and dendritic cells for T-lymphoma.

Dendritic cells (DCs) are potent antigen-presenting cells that play important roles in regulating immune responses in cancer. Immunotherapy using these immunocytes has become an accepted therapeutic modality. We previously reported that hyperthermia using magnetic nanoparticles induces antitumor immunity, which could be activated by adjuvant including cytokines. In the present study, we investigated the therapeutic effects of hyperthermia combined with DC immunotherapy on mouse EL4 T-lymphoma. Magnetite cationic liposomes (MCLs) have a positive surface charge and generate heat in an alternating magnetic field (AMF) due to hysteresis loss. MCLs were injected into an EL4 nodule in C57BL/6 mice, which were subjected to AMF for 30 min. The temperature at the surface of the tumor reached 45 degrees C and was maintained by controlling the magnetic field intensity. Hyperthermia treatment was repeated twice with 24 h intervals. After hyperthermia, immature DCs were directly injected into the EL4 nodule. As a result, complete regression of tumors in 75% (6/8) of the mice was observed, while the percentage of complete regression of tumors was 12.5% (1/8) in the case of mice treated by hyperthermia alone. This novel cancer therapy, which we have termed "heat immunotherapy", may be applicable to patients with advanced malignancies.

Intratumoral injection of immature dendritic cells enhances antitumor effect of hyperthermia using magnetic nanoparticles.

Dendritic cells (DCs) are potent antigen-presenting cells that play a pivotal role in regulating immune responses in cancer and have recently been shown to be activated by heat shock proteins (HSPs). We previously reported that HSP70 expression after hyperthermia induces antitumor immunity. Our hyperthermia system using magnetite cationic liposomes (MCLs) induced necrotic cell death that was correlated with HSP70 release. In the present study, we investigated the therapeutic effects of DC therapy combined with MCL-induced hyperthermia on mouse melanoma. In an in vitro study, when immature DCs were pulsed with mouse B16 melanoma cells heated at 43 degrees C, major histocompatibility complex (MHC) class I/II, costimulatory molecules CD80/CD86 and CCR7 in the DCs were upregulated, thus resulting in DC maturation. C57BL/6 mice bearing a melanoma nodule were subjected to combination therapy using hyperthermia and DC immunotherapy in vivo by means of tumor-specific hyperthermia using MCLs and directly injected immature DCs. Mice were divided into 4 groups: group I (control), group II (hyperthermia), group III (DC therapy) and group IV (hyperthermia + DC therapy). Complete regression of tumors was observed in 60% of mice in group IV, while no tumor regression was seen among mice in the other groups. Increased cytotoxic T lymphocyte (CTL) and natural killer (NK) activity was observed on in vitro cytotoxicity assay using splenocytes in the cured mice treated with combination therapy, and the cured mice rejected a second challenge of B16 melanoma cells. This study has important implications for the application of MCL-induced hyperthermia plus DC therapy in patients with advanced malignancies as a novel cancer therapy.