Hepatic stellate cells relay inflammation signaling from sinusoids to parenchyma in mouse models of immune-mediated hepatitis.

ビタミンAを貯蔵する肝星細胞が肝臓の炎症を制御していた --肝炎、肝硬変、肝癌の予防や治療法開発に期待--. 京都大学プレスリリース. 2015-10-15.Issue published online: 23 MAR 2016Hepatic stellate cells (HSCs) constitute the liver sinusoid with Kupffer cells and liver sinusoidal endothelial cells. While the sinusoid functions as the gateway to liver inflammation, whether HSCs contribute to liver inflammation and, if so, how they exert such functions remain elusive. Here, we found that mouse as well as human HSCs expressed DP1 receptor for prostaglandin D2 selectively in the liver. Pharmacological stimulation of DP1 by BW245C, a DP1-selective agonist, suppressed the activation of cultured HSCs by tumor necrosis factor-α at least in part through down-regulation of nuclear factor kappa-light-chain-enhancer of activated B cells signaling and inhibition of c-Jun N-terminal kinase phosphorylation. DP1 deficiency or BW245C administration in mice significantly enhanced or suppressed concanavalin A (ConA)-induced hepatitis, respectively. ConA injection induced tumor necrosis factor-α and interferon-γ expression in the sinusoid, which was suppressed by administration of BW245C. Coculture of spleen cells and liver nonparenchymal cells showed that ConA first activated spleen cells and that this activation led to activation of nonparenchymal cells to secondarily produce tumor necrosis factor-α and interferon-γ. Microarray analysis revealed ConA-induced expression of endothelin-1, tissue factor, and chemokines in the liver and inducible nitric oxide synthase in hepatocytes, resulting in flow stagnation, leukocyte adherence and migration to the parenchyma, and hepatocyte death. DP1 stimulation inhibits all these events in the liver. Therefore, HSCs mediate amplification of ConA-induced liver inflammation in the sinusoid, causing direct and indirect hepatocyte injury, and DP1 stimulation inhibits this HSC activation

Usefulness of Aerobic Exercise for Home Blood Pressure Control in Patients with Diabetes: Randomized Crossover Trial

Hypertension usually coexists with diabetes mellitus and significantly increases the risk of macrovascular complications. Blood pressure measured at home, especially nocturnal blood pressure, is particularly important because it is more strongly associated with target organ damage than clinical blood pressure measurements. Regular moderate aerobic exercise has been shown to have anti-hypertensive effects. This study aimed to investigate the effects of aerobic exercise on home blood pressure in patients with diabetes. This randomized crossover trial was based on outpatient treatment at a university hospital. In this randomized crossover trial, 124 patients with type 2 diabetes were randomly assigned to two groups over 56 days: an exercise preceding group (exercise intervention for 28 days and then no exercise intervention for the following 28 days) and an exercise lagging group (no exercise intervention for 28 days and then exercise intervention for the following 28 days). The associations between the nocturnal blood pressure and exercise intervention were assessed accordingly. A decrease in blood pressure was observed in the morning and evening, at 2 a.m. and 3 a.m. after exercise intervention; however, there was no significant difference between groups. Moderate exercise was not effective in lowering nocturnal blood pressure in this study

Comprehensive Analysis of Antibodies Induced by Vaccination with 4 Kinds of Avian Influenza H5N1 Pre-Pandemic Vaccines

Four kinds of avian-derived H5N1 influenza virus, A/Vietnam/1194/2004 (Clade 1), A/Indonesia/5/2005 (Clade 2.1), A/Qinghai/1A/2005 (Clade 2.2), and A/Anhui/1/2005 (Clade 2.3), have been stocked in Japan for use as pre-pandemic vaccines. When a pandemic occurs, these viruses would be used as vaccines in the hope of inducing immunity against the pandemic virus. We analyzed the specificity of antibodies (Abs) produced by B lymphocytes present in the blood after immunization with these vaccines. Eighteen volunteers took part in this project. After libraries of Ab-encoding sequences were constructed using blood from subjects vaccinated with these viruses, a large number of clones that encoded Abs that bound to the virus particles used as vaccines were isolated. These clones were classified into two groups according to the hemagglutination inhibition (HI) activity of the encoded Abs. While two-thirds of the clones were HI positive, the encoded Abs exhibited only restricted strain specificity. On the other hand, half of the HI-negative clones encoded Abs that bound not only to the H5N1 virus but also to the H1N1 virus; with a few exceptions, these Abs appeared to be encoded by memory B cells present before vaccination. The HI-negative clones included those encoding broadly cross-reactive Abs, some of which were encoded by non-VH1-69 germline genes. However, although this work shows that various kinds of anti-H5N1 Abs are encoded by volunteers vaccinated with pre-pandemic vaccines, broad cross-reactivity was seen only in a minority of clones, raising concern regarding the utility of these H5N1 vaccine viruses for the prevention of H5N1 pandemics