Hyperglycaemia augments lipopolysaccharide-induced reduction in rat and human macrophage phagocytosis via the endoplasmic stress-C/EBP homologous protein pathway.

BACKGROUND: Macrophage phagocytosis constitutes an essential part of the host defence against microbes and the resolution of inflammation. Hyperglycaemia during sepsis is reported to reduce macrophage function, and thus, potentiate inflammatory deterioration. We investigated whether high-glucose concentrations augment lipopolysaccharide-induced reduction in macrophage phagocytosis via the endoplasmic stress-C/EBP homologous protein (CHOP) pathway using animal and laboratory investigations. METHODS: Peritoneal macrophages of artificially ventilated male Wistar rats, divided into four groups based on target blood glucose concentrations achieved by glucose administration with or without lipopolysaccharide, were obtained after 24 h. Human macrophages were also cultured in normal or high glucose with or without lipopolysaccharide exposure for 72 h. Changes in the phagocytic activity, intranuclear CHOP expression, and intracellular Akt phosphorylation status of macrophages were evaluated. These changes were also evaluated in human macrophages after genetic knock-down of CHOP by specific siRNA transfection or resolvin D2 treatment. RESULTS: Lipopolysaccharide impaired phagocytosis, increased intranuclear expression of CHOP, and inhibited Akt phosphorylation in both rat peritoneal and human macrophages. Hyperglycaemic glucose concentrations augmented these changes. Genetic knock-down of CHOP restored phagocytic ability and Akt phosphorylation in human macrophages. Furthermore, resolvin D2 co-incubation restored the inhibited phagocytosis and Akt phosphorylation along with the inhibition of intranuclear CHOP expression in human macrophages. CONCLUSIONS: These findings imply that controlling endoplasmic reticulum stress might provide new strategies for restoring reduced macrophage phagocytosis in sepsis-induced hyperglycaemia.

Diet and Japanese herbal medicine for recalcitrant atopic dermatitis: efficacy and safety.

We have been utilizing Kampo, a Japanese herbal medicine, together with lifestyle advice, for recalcitrant atopic dermatitis. To estimate the safety and efficacy of the treatment, we administered Kampo formulas to patients in whom conventional treatment failed to improve symptoms, along with dietary advice recommending traditional Japanese food. The therapeutic effects of Kampo formulas were assessed in 95 patients with recalcitrant atopic dermatitis who consulted our clinic from January to June, 2000. The overall result was 'markedly effective" in 19 patients (20%), "moderately effective" in 33 (35%), "slightly effective" in 36 (38%) and "ineffective" in four (4%). Three patients dropped out of the study. No adverse reactions in laboratory data were noted in examined patients. The most commonly used formula was Hochu-ekki-to containing Astragalus root, liquorice, jujube, ginseng, white Atractylodes rhizome, fresh ginger and Chinese Angelica root. Diet and Japanese herbal medicine are thought to be useful as an alternative therapy of intractable atopic dermatitis.

The effects of Hochu-ekki-to in patients with atopic dermatitis resistant to conventional treatment.

Hochu-ekki-to is one of Kampo formulas containing Astragalus root, liquorice, jujube, ginseng, white Atractylodes rhizome, fresh ginger and Chinese angelica root. This formula has been identified as an effective drug to improve the function of digestive systems and to strengthen defensive systems against many kinds of infections. We examined serum IgE levels and eosinophils before and after the administration of Hochu-ekki-to in patients with recalcitrant atopic dermatitis. The increased numbers of eosinophils was statistically decreased after 3 months' use of this formula. Serum IgE levels showed a tendency to decrease after the administration of this substance.

Hochu-ekki-to suppresses development of dermatitis and elevation of serum IgE level in NC/Nga mice.

The Japanese herbal medicine Hochu-ekki-to (Chinese name: Bu-Zhong-Yi-Qi-tang) is composed of ten species of medical plants and is used for many therapeutic purposes such as recovery from weakness, dysfunction of the digestive system and fatigue. In certain groups of patients with intractable atopic dermatitis this prescription has shown clinical effectiveness. We examined the ability of Hochu-ekki-to to inhibit dermatitis and IgE production in atopic NC/Nga mice. Oral administration of Hochu-ekki-to suppressed spontaneous dermatitis and serum IgE levels in NC/Nga mice. This finding provides evidence that Hochu-ekki-to may have immunological effects in atopic dermatitis.

Induction of cutaneous delayed hypersensitivity reactions in mice sensitized with intragastrically administered hapten: activation of Langerhans cells in the sensitization and elicitation phases.

BACKGROUND: As seen in atopic dermatitis, allergic diseases often produce lesions both in the gastrointestinal tract and the skin, suggesting the involvement of an immunological relationship between the two organs in the pathogenesis. OBJECTIVES: To study the role of gastric and epidermal Langerhans cells (LCs) in the sensitization and elicitation phases, respectively, of cutaneous delayed-type hypersensitivity (DTH) reactions to intragastrically administered hapten. METHODS: BALB/c mice, which were subjected to intragastric administration of trinitrochlorobenzene 5 days previously, received an elicitative challenge of the same hapten to the ear skin. Sections of the ear were immunostained for CD4 and CD8. Epidermal sheets of the ear and epithelial sheets of the forestomach were immunostained for I-A and observed under a confocal laser scanning microscope. RESULTS: Cutaneous DTH reactions were induced in mice, as demonstrated by an increase in ear thickness and a prominent infiltration of CD4+ and CD8+ lymphocytes at 24-36 h after the elicitative challenge. In the elicitation phase, epidermal LCs showed a significant increase in size, indicating in vivo activation, at 24 h. In the sensitization phase, gastric LCs increased in size at 2 h, became round at 6 h, and decreased in number at 24 h, possibly representing the sequential events of LC activation and migration from the epithelium. CONCLUSIONS: The present study demonstrated that gastric LCs and epidermal LCs were activated in vivo in the sensitization and elicitation phases, respectively, of cutaneous DTH reactions in orally sensitized mice.

Inflammatory vitiligo in Vogt-Koyanagi-Harada disease.

Vogt-Koyanagi-Harada disease is a rare disease characterized by uveitis, meningitis, dysacusis, alopecia, poliosis, and vitiligo. We describe a 48-year-old patient with Vogt-Koyanagi-Harada disease associated with thin inflammatory raised erythema and plaque-type inflammatory erythema superimposed on vitiligo. Interestingly, inflammatory raised erythema was separated from the perfect vitiligo, and the incomplete vitiligo lay between them initially. Thereafter, incomplete vitiligo became completely depigmented with diminution of inflammatory raised erythema. This is the second case of vitiligo with inflammatory raised borders associated with Vogt-Koyanagi-Harada disease. Our results of immunohistochemical and electron microscopic studies suggested the involvement of T-cell-mediated cytotoxicity and apoptosis in the development of skin lesions.

In vivo activation of langerhans cells and dendritic epidermal T cells in the elicitation phase of murine contact hypersensitivity.

Langerhans cells (LCs) and dendritic epidermal T cells (DETCs) constitute the skin immune system. To demonstrate the kinetics of in vivo activation of murine LCs and DETCs in the elicitation phase of contact hypersensitivity, we measured the cell area positively stained for I-A and gammadeltaT-cell receptor (or Thy-1.2), respectively, under a fluorescence microscope at various time intervals after topical application of dinitrofluorobenzene. The fluorescence-positive area of LCs increased in parallel with that of DETCs at 1 h and 24 h, indicating the biphasic activation of LCs and DETCs. Early activation was hapten-specific and often exhibited close LC-to-DETC apposition. Experiments with in vivo administration of neutralizing anticytokine antibodies revealed that none of interferon (IFN)-gamma, tumour necrosis factor (TNF)-alpha and interleukin (IL)-1beta were involved in the induction of early activation of LCs and DETCs, while TNF-alpha and IL-1beta mediated late activation of LCs, and IFN-gamma and IL-1beta mediated that of DETCs. Our results indicate that LCs and DETCs are synchronously and biphasically activated in the epidermis during the elicitation phase of contact hypersensitivity and suggest that different mechanisms may control early and late activation.

Morphometric and ultrastructural analyses of in vivo-activated murine Langerhans cells induced by administration of a streptococcal preparation (OK-432).

Langerhans cells (LCs) are activated in the epidermis by external and internal stimuli, such as antigens and cytokines, respectively. To reveal the morphologic and functional properties of in vivo-activated LCs during inflammation, we injected the streptococcal preparation OK-432 intradermally into the earskin of mice and performed time-course analyses by immunofluorescence and electron microscopy. Cellular infiltrate appeared in the dermis at 6 h after OK-432 injection and had progressively extended to the dermoepidermal junction at 12 and 24 h. Immunostaining for class II antigen revealed that LCs were enlarged and extended long dendrites during inflammation. Acidic compartments such as lysosomes and multivesicular bodies also increased in number and Golgi apparatuses developed as demonstrated by electron microscopy and morphometric analysis. Birbeck granules, although not showing numerical changes, were translocated from the Golgi area to the subplasmalemmal area. After epicutaneous application of cationic ferritin, LCs often contained endosomes as the result of engulfment by the cytoplasmic projections. The present results indicate that nonspecifically induced dermal inflammation is capable of inducing activation of LCs in vivo, and that in vivo-activated LCs have the capacity for active endocytosis and intracellular digestion or processing.

Fixed drug eruption due to colchicine.

A case of fixed drug eruption due to colchicine was reported. A 31-year-old man developed a dark purplish-red round macule on the glans penis 5 h after taking 2.5 mg of colchicine. An oral challenge test with 0.5 mg of colchicine provoked flare-up of the eruption.