Keiichi Hiramoto

Skin disruption is associated with indomethacin‐induced small intestinal injury in mice

One mechanism by which non‐steroidal anti‐inflammatory drugs (NSAIDs) cause intestinal injury is by inducing matrix metalloproteinases (MMPs) that degrade and remodel the extracellular matrix. In addition to the intestinal mucosa, MMPs are expressed in the skin and can be activated by mast cell‐secreted tryptase. We therefore investigated whether intestinal injury resulting from treatment with the NSAID indomethacin induced MMPs in the skin of mice and caused an associated disruption of skin function. Hairless mice and mast cell‐deficient mice were administered indomethacin, after which damage to the jejuna and skin was assessed with immunohistochemistry and Western blotting. The plasma concentration of inflammatory mediators was assessed to evaluate potential pathways for signalling skin disruption in response to intestinal injury. In hairless mice with intestinal injury, transepidermal water loss (TEWL) was higher and skin hydration was lower than in control mice. The expression levels of mast cells, tryptase, MMP‐1 and MMP‐9 were also increased, with concurrent degradation of types I and IV collagen. In contrast, no changes in skin TEWL or skin hydration were observed in mast cell‐deficient mice with indomethacin‐induced intestinal injury. In all mice evaluated, the plasma concentrations of IgE, IgA, histamine and TNF‐α were increased in response to indomethacin treatment. Skin disruption was strongly associated with indomethacin‐induced small intestinal injury, and the activation of mast cells and induction of tryptase, MMP‐1 and MMP‐9 are critical to this association.

The amelioration effect of tranexamic acid in wrinkles induced by skin dryness.

Tranexamic acid (trans-4-aminomethylcyclohexanecarboxylic acid) is a medical amino acid widely used as an anti-inflammatory and a whitening agent. This study examined the effect of tranexamic acid administration in wrinkle formation following skin dryness. We administered tranexamic acid (750mg/kg/day) orally for 20 consecutive days to Naruto Research Institute Otsuka Atrichia (NOA) mice, which naturally develop skin dryness. In these NOA mice, deterioration of transepidermal water loss (TEWL), generation of wrinkles, decrease of collagen type I, and increases in mast cell proliferation and tryptase and matrix metalloproteinase (MMP-1) release were observed. However, these symptoms were improved by tranexamic acid treatment. Moreover, the increase in the β-endorphin level in the blood and the expression of μ-opioid receptor on the surface of fibroblasts increased by tranexamic acid treatment. In addition, when the fibroblasts induced by tranexamic acid treatment were removed, the amelioration effect by tranexamic acid treatment was halved. On the other hand, tranexamic acid treated NOA mice and mast cell removal in tranexamic acid treated NOA mice did not result in changes in the wrinkle amelioration effect. Additionally, the amelioration effect of mast cell deficient NOA mice was half that of tranexamic acid treated NOA mice. These results indicate that tranexamic acid decreased the proliferation of mast cells and increases the proliferation of fibroblasts, subsequently improving wrinkles caused by skin dryness.

The Effects of Ultraviolet Eye Irradiation on Dextran Sodium Sulfate-Induced Ulcerative Colitis in Mice.

Ultraviolet (UV) eye irradiation denatures the cells of the intestine. This study examined the action of UVA and UVB on dextran sodium sulfate (DSS)‐induced ulcerative colitis. We produced a mouse model of ulcerative colitis by administering DSS for 5 days and irradiated the eye with UVB or UVA for each day of the DSS treatment period. DSS‐induced ulcerative colitis was deteriorated by the UVB eye irradiation. Conversely, the symptoms improved with UVA eye irradiation. The levels of adrenocorticotropic hormone (ACTH), corticotropin‐releasing hormone (CRH), urocortin 2, interleukin (IL)‐18, IL‐6 and histamine in the blood increased after the UVB eye irradiation of DSS‐treated mice (UVB/DSS‐treated mice). In contrast, the β‐endorphin level in the blood of the UVA/DSS‐treated mice increased and the levels of urocortin 2, tumor necrosis factor (TNF)‐α and histamine decreased. Furthermore, in the colon, the expression of melanocortin‐2 receptors (MC2R) increased in the UVB/DSS‐treated mice, while the expression of μ‐opioid receptors increased in the UVA/DSS‐treated mice. When an ACTH inhibitor was administered, UVB eye irradiation caused the deterioration of DSS‐treated ulcerative colitis, while the effect of UV eye irradiation disappeared with a μ‐opioid receptor antagonist. These results suggested that UV eye irradiation plays an important role in DSS‐induced ulcerative colitis.

Impairment of skin barrier function via cholinergic signal transduction in a dextran sulphate sodium-induced colitis mouse model.

Dry skin has been clinically associated with visceral diseases, including liver disease, as well as for our previously reported small intestinal injury mouse model, which have abnormalities in skin barrier function. To clarify this disease‐induced skin disruption, we used a dextran sulphate sodium (DSS)‐induced colitis mouse model. Following treatment with DSS, damage to the colon and skin was monitored using histological and protein analysis methods as well as the detection of inflammatory mediators in the plasma. Notably, transepidermal water loss was higher, and skin hydration was lower in DSS‐treated mice compared to controls. Tumor necrosis factor‐alpha (TNF‐α), interleukin 6 and NO2−/NO3− levels were also upregulated in the plasma, and a decrease in body weight and colon length was observed in DSS‐treated mice. However, when administered TNF‐α antibody or an iNOS inhibitor, no change in skin condition was observed, indicating that another signalling mechanism is utilized. Interestingly, the number of tryptase‐expressing mast cells, known for their role in immune function via cholinergic signal transduction, was elevated. To evaluate the function of cholinergic signalling in this context, atropine (a muscarinic cholinoceptor antagonist) or hexamethonium (a nicotinic cholinergic ganglion‐blocking agent) was administered to DSS‐treated mice. Our data indicate that muscarinic acetylcholine receptors (mAChRs) are the primary receptors functioning in colon‐to‐skin signal transduction, as DSS‐induced skin disruption was suppressed by atropine. Thus, skin disruption is likely associated with DSS‐induced colitis, and the activation of mast cells via mAChRs is critical to this association.

Impaired Skin Barrier Function in Mice with Colon Carcinoma Induced by Azoxymethane and Dextran Sodium Sulfate

We have previously reported that impaired skin barrier function was induced by small intestinal injury in mice. Therefore, we postulated that other intestinal diseases might also influence skin barrier function. In this study, we evaluated the skin barrier function of hairless mice with colon carcinoma that was induced by azoxymethane (AOM) and dextran sodium sulfate (DSS). In mice treated with these drugs, we observed elevated transepidermal water loss and reduced skin hydration levels, compared to those in the control mice. In addition, plasma nitrogen di/trioxide (NO2(-)/NO3(-)) levels were significantly elevated, and expression of type I collagen was significantly reduced in the treated mice, compared to those in control. These results suggest that impaired skin barrier function occurs in mice when colon carcinoma is present.

Immunosuppression by ultraviolet B rays via eyes in mice

Abstract Irradiation by ultraviolet B (UV-B; 280–320 nm) initiates suppression of contact hypersensitivity. Immunosuppression was induced in C57BL/6N Crj mice by exposure of the dorsal skin or the eyes to a 10 kJ/m 2 dose of UV-B radiation from 20SE sunlamps, followed by sensitization with 0.5% fluorescein isothiocyanate (FITC). The degree of immunosuppression induced by UV-B eye irradiation was equal to that induced by UV-B skin irradiation. When mice were irradiated with UV-B into the eyes after the optic nerve had been cut, systemic immunosuppression was not induced.

Stress-Induced Glucocorticoid Release Upregulates Uncoupling Protein-2 Expression and Enhances Resistance to Endotoxin-Induced Lethality

Objective: Although psychological and/or physiological stress has been well documented to influence immune responses, the precise mechanism for immunomodulation remains to be elucidated. The present work describes the role of the hypothalamic-pituitary-adrenal (HPA) axis in the mechanism of stress-mediated enhanced-resistance to lethality after lipopolysaccharide (LPS) injection. Methods/Results: Preconditioning with restraint stress (RS) resulted in enhanced activation of the HPA axis in response to LPS injection and suppressed LPS-induced release of proinflammatory cytokines and nitric oxide metabolites. Melanocortin 2 receptor-deficient mice (MC2R-/-) failed to increase plasma levels of glucocorticoids in response to LPS injection, and exhibited high sensitivity to LPS-induced lethality with enhanced release of proinflammatory cytokines as compared with MC2R+/- mice. Real-time PCR analysis revealed that RS induced upregulation of uncoupling protein-2 (UCP2) in macrophages in the lung and the liver of MC2R+/-, but not of MC2R-/-, mice. In addition, RS increased UCP2-dependent uncoupling activity of isolated mitochondria from the liver of MC2R+/-, but not of MC2R-/-, mice. In vitro study revealed that corticosterone and dexamethasone directly increased UCP2 expression in mouse RAW 264.7 macrophages and suppressed the generation of LPS-induced mitochondrial reactive oxygen species (ROS) and TNF-α production. Knockdown of UCP2 by small interfering RNA blunted the dexamethasone action for suppressing LPS-induced mitochondrial ROS and TNF-α production. Conclusion: The present work suggests that RS enhances activation of the HPA axis to release glucocorticoids and upregulation of UCP2 in macrophages, thereby increasing the resistance to endotoxin-induced systemic inflammation and death.

Chronic liver injury in mice promotes impairment of skin barrier function via tumor necrosis factor-alpha

Abstract Context: Alcohol is frequently used to induce chronic liver injury in laboratory animals. Alcohol causes oxidative stress in the liver and increases the expression of inflammatory mediators that cause hepatocellular damage. However, during chronic liver injury, it is unclear if/how these liver-derived factors affect distal tissues, such as the skin. Objective: The purpose of this study was to evaluate skin barrier function during chronic liver injury. Materials and methods: Hairless mice were administered 5% or 10% ethanol for 8 weeks, and damages to the liver and skin were assessed using histological and protein-analysis methods, as well as by detecting inflammatory mediators in the plasma. Results: After alcohol administration, the plasma concentration of the aspartate and alanine aminotransferases increased, while albumin levels decreased. In mice with alcohol-induced liver injury, transepidermal water loss was significantly increased, and skin hydration decreased concurrent with ceramide and type I collagen degradation. The plasma concentrations of / and tumor necrosis factor-alpha (TNF-α) were significantly increased in mice with induced liver injury. TNF receptor (TNFR) 2 expression was upregulated in the skin of alcohol-administered mice, while TNFR1 levels remained constant. Interestingly, the impairment of skin barrier function in mice administered with 10% ethanol was ameliorated by administering an anti-TNF-α antibody. Conclusions: We propose a novel mechanism whereby plasma TNF-α, via TNFR2 alone or with TNFR1, plays an important role in skin barrier function during chronic liver disease in these mouse models.

Ultraviolet A eye irradiation ameliorates colon carcinoma induced by azoxymethane and dextran sodium sulfate through β‐endorphin and methionine‐enkephalin

We previously reported that ultraviolet (UV) A eye irradiation reduces the ulcerative colitis induced by dextran sodium sulfate (DSS). This study examined the effects of UVA on colon carcinoma induced by azoxymethane (AOM) and DSS.

The gender differences in the inhibitory action of UVB-induced melanocyte activation by the administration of tranexamic acid.

Tranexamic acid has an inhibitory action on ultraviolet (UV) B‐induced melanocyte activation. This study examined the sex differences in the inhibitory action of tranexamic acid on UVB‐induced melanocyte activation.