Oestrogen inhibits psoriasis-like dermatitis induced by imiquimod in mice in relation to increased IL-10 producing cells despite elevated expression of IL-22, IL-23, IL-17 mRNA.

Sex hormones influence the development and natural course of psoriasis. Here, we examined the effects of female sex hormones, particularly oestrogen, on psoriasis-like dermatitis induced using topical imiquimod in mice that underwent either sham operation (Sham) or ovariectomy (OVX), with (hormone replacement treatment: HRT) or without 17ß-oestradiol targeting the maximum physiological levels. The number of neutrophils in the skin was higher in the order of OVX-, Sham-, and HRT-treated mice. However, no significant difference was detected in the clinical scores among the three groups due to severe erythema and scale in a few mice out of HRT-treated mice in a set of experiments. OVX- and HRT-treated mice showed increased mRNA levels of interleukin (IL)-22 and IL-23 compared with Sham-treated mice; increased IL-10 mRNA levels were found in HRT-treated mice, possibly due to an increased proportion of forkhead box P3 (Foxp3)- and IL-10 positive large cells (possibly macrophages). In addition, HRT-treated mice had a more compact stratum corneum with higher expression of loricrin and involucrin than OVX- and Sham-treated mice. This study suggests that oestrogen has a dual potential in the pathogenesis of psoriasis: suppression of inflammation by enhancing IL-10 production and enhancement of inflammation by induction of IL-22 and IL-23 expression.

Possible involvement of type 2 cytokines in alloknesis in mouse models of menopause and dry skin.

Alloknesis, an abnormal itch sensation induced by innocuous stimuli, is a key phenomenon in the vicious itch-scratch cycle in patients with atopic dermatitis. Dry skin and pruritus, including alloknesis, are major health problems in peri- and post-menopausal women. We recently reported permeability barrier dysfunction in ovariectomized (OVX) mice-a model of menopause-and found that the dysfunction was related to dry skin. However, the mechanism of the itch remains unknown. Therefore, we examined touch- and pruritogen-evoked alloknesis and epidermal innervation in OVX mice and acetone, diethyl ether and water (AEW)-treated mice, for the experimental dry skin model. Both alloknesis and epidermal innervation were comparable in OVX and AEW mice. Neutralizing antibodies against IL-4 and IL-13 inhibited alloknesis in both OVX and AEW mice as early as 30 min after intradermal administration. Comparable values close to the measurement limit of IL-4 were found in the skin of HRT and Sham mice as well as AEW and the control mice, but the levels of IL-4 were within the measurement limit in OVX mice. We could not detect mRNAs of IL-4 or IL-13 in any groups of mice. On the other hand, the number of eosinophils and basophils was increased in OVX and AEW mice. These results suggest that impaired barrier function in cooperation with type 2 cytokines derived from eosinophils and basophils in the skin or with endogenous type 2 cytokine may trigger the development of alloknesis, and thus, these cytokines could be a therapeutic target for sensitive skin.

Morphological changes in synovial mesenchymal stem cells during their adhesion to the meniscus.

Synovial mesenchymal stem cells (MSCs) are an attractive cell source for transplantation because of their high chondrogenic potential, especially in areas like the meniscus of the knee. A synovial MSC suspension placed onto the meniscus for 10 min promoted healing of repaired meniscal tears that generally do not heal. Here, we quantified the proportion of human synovial MSCs that adhered to a porcine abraded meniscus, clarified their morphological changes, and revealed the mechanism by which the synovial MSCs adhered to the meniscus. The numbers of adhering cells at immediately after 10, 60 min and 6, 24 h after suspension placement were calculated. The meniscus surface was examined by scanning electron microscopy, and 50 cells were randomly selected at each time period, classified, and quantified for each of the six donors. Approximately 28% of the synovial MSCs immediately adhered to the meniscus after placement and the proportion of adhered cells increased further with time. All cells maintained a round shape for 60 min, and then transformed to a mixture of round and semi-flattened cells. By 24 h, flattened cells covered the meniscus. Microspikes were observed in 36% of the floating synovial MSCs and in 76% of the cells on the meniscus shortly after placement on the meniscus, then the proportion of cells with pseudopodia increased. The bleb-dominant cell proportion significantly decreased, and the smooth-dominant cell proportion increased within 60 min. Microspikes or the bodies of synovial MSCs were trapped by meniscal fibers immediately after placement. The proportion of adhered cells increased with time, and the cell morphology changed dynamically for 24 h as the synovial MSCs adhered to the meniscus. The MSCs in the round morphological state had a heterogeneous morphology. The microspikes, and the subsequent development of pseudopodia, may play an important role in adhesion onto the meniscus.

Projected Cartilage Area Ratio Determined by 3-Dimensional MRI Analysis: Validation of a Novel Technique to Evaluate Articular Cartilage.

We have developed 3-dimensional (3D) magnetic resonance imaging (MRI) analysis software that allows measurement of the projected cartilage area ratio with a particular thickness intended to allow quantitation of the cartilage in the knee. Our aims in this study were to validate the projected cartilage area ratio in both pig and human knees and to examine the ratio in patients reporting knee pain. METHODS: After 3D MRI reconstruction, the femoral cartilage was projected onto a flat surface. The projected cartilage area was determined in pig knees using our 3D MRI analysis software, and was compared with the area obtained with other software. The projected cartilage area ratio (for cartilage thickness ≥1.5 mm) at 4 segments was also validated in human knees. Finally, changes in the projected cartilage area ratio were examined in 8 patients with knee pain who had undergone 2 MR images at 3 to 21-month intervals. RESULTS: The projected cartilage areas determined with our 3D MRI analysis software were validated in pig knees. The projected cartilage area ratio at each segment in human knees had an intraclass correlation coefficient (ICC) of 0.87 to 0.99 (n = 16) between readers and 0.76 to 0.99 (n = 20) between measurements on repeat MR images. The projected cartilage area ratio (for cartilage thickness ≥1.5 mm) at the most affected segment in 8 human patients significantly decreased between the pairs of MR images obtained at intervals of 3 to 21 months. CONCLUSIONS: We proposed a novel evaluation method using 3D MRI to quantify the amount of cartilage in the knee. This method had a low measurement error in both pig and human knees. CLINICAL RELEVANCE: The projected cartilage area ratio based on a particular thickness may serve as a sensitive method for assessing changes in cartilage over time.

Specific role of the truncated betaIV-spectrin Sigma6 in sodium channel clustering at axon initial segments and nodes of ranvier.

At axon initial segments and nodes of Ranvier in neurons, the spectrin membrane skeleton plays roles in physically stabilizing the plasma membrane integrity and in clustering voltage-gated sodium channels for proper conduction of the action potential. betaIV-Spectrin, an essential component of the membrane skeleton at these sites, has an N-terminal-truncated isoform, Sigma6, which is expressed at much higher levels than the full-length isoform Sigma1. To investigate the role of betaIV-spectrin Sigma6, we generated Sigma1-deficient mice with a normal level of Sigma6 expression (Sigma1(-/-) mice), and compared their phenotypes with those of previously generated mice lacking both Sigma1 and Sigma6(Sigma1Sigma6(-/-) mice). The gross neurological defects observed in Sigma1Sigma6(-/-) mice, such as hindleg contraction, were apparently ameliorated in Sigma1(-/-) mice. At cellular levels, Sigma1Sigma6(-/-) and Sigma1(-/-) neurons similarly exhibited waving and swelling of the plasma membrane at axon initial segments and nodes of Ranvier. By contrast, the levels of ankyrin G and voltage-gated sodium channels at these sites, which are significantly reduced in Sigma1Sigma6(-/-) mice, were substantially recovered in Sigma1(-/-) mice. We conclude that the truncated betaIV-spectrin isoform Sigma6 plays a specific role in clustering voltage-gated sodium channels, whereas it is dispensable for membrane stabilization at axon initial segments and nodes of Ranvier.

Effect of core body temperature on ventilator-induced lung injury.

OBJECTIVE: Ventilator-induced lung injury is a risk in patients requiring elevated ventilatory support pressures. We hypothesized that thermal stress modulates the development of ventilator-induced lung injury. DESIGN: Experimental study. SETTING: University laboratory. SUBJECTS: Anesthetized rabbits. INTERVENTIONS: Two experimental studies were designed to determine the role of temperature as a cofactor in ventilator-induced lung injury. In the first study, three groups of anesthetized rabbits were randomized to be ventilated for 2 hrs at core body temperatures of 33, 37, or 41 degrees C while ventilated with pressure control ventilation of 15/3 cm H2O (noninjurious settings-control) or 35/3 cm H2O (potentially injurious settings-experimental). To exclude effects arising from cardiac output fluctuations or from extrapulmonary organs, an isolated lung model was used for the second study, perfused at a fixed rate and studied at either 33 degrees C or 41 degrees C. MEASUREMENTS AND MAIN RESULTS: In the first study, the hyperthermic group compared with the hypothermic animals had significantly reduced mean PaO2 (-114 vs. + 14 mm Hg, p <.05), increased lung edema formation (mean wet weight/dry weight ratio of 8.1 vs. 5.7), and altered pressure-volume curves. The hyperthermic isolated, perfused lungs had an increased ultrafiltration coefficient, formed more edema, and experienced greater alveolar hemorrhage than hypothermic lungs. CONCLUSIONS: In two studies of ventilator-induced lung injury in rabbits, maintaining hyperthermia compared with hypothermia augmented the development of lung injury. Similar results from both the in vivo and isolated, perfused lung studies suggest that the observed effects were not due to cardiovascular factors or consequences of heating nonpulmonary organs.