The suppressive effects of Mer inhibition on inflammatory responses in the pathogenesis of LPS-induced ALI/ARDS

The pathogenesis of sepsis-induced acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) has not yet been fully elucidated. Growth arrest-specific 6 (Gas6) has marked effects on hemostasis and reduces inflammation through its interaction with receptor tyrosine kinases of the TAM family: Tyro3, Axl, and Mer. Here, we found that plasma concentrations of Gas6 and soluble Mer were greater in patients with severe sepsis or septic ALI/ARDS compared with those in normal healthy donors. To determine whether the Gas6-Mer axis was critical in the pathogenesis of ALI/ARDS, we investigated the effects of intravenous administration of the selective Mer inhibitor UNC2250 on lipopolysaccharide (LPS)-induced ALI in mouse models subjected to inhalation of LPS. UNC2250 markedly inhibited the infiltration into the lungs of neutrophils and monocytes with increased amounts of Gas6 and Mer proteins, severe lung damage, and increased amounts of reactive oxygen species (ROS) in LPS-induced ALI in mice. In human pulmonary aortic endothelial cells, LPS induced decreases in the amounts of endothelial nitric oxide synthase, thrombomodulin, and vascular endothelial-cadherin, which was blocked by treatment with UNC2250. UNC2250 also inhibited the LPS-dependent increases in cell proliferation and enhanced apoptosis in HL-60 cells, a human neutrophil-like cell line, and RAW264.7 cells, a mouse monocyte/macrophage cell line. These data provide insights into the potential multiple beneficial effects of the Mer inhibitor UNC2250 as a therapeutic reagent to treat inflammatory responses in ALI/ARDS

Comparison of overall survival between before and after the disaster.

<p>Survival curves were plotted to compare the mortality of each group using the Kaplan-Meier method. The dotted and solid lines indicate the time-to-events of participants before and after the disaster, respectively. The notches within the line represent the censors. The numbers at risk are illustrated below the chart. Overall survival was significantly worse in the group after the disaster (<i>P</i> = 0.029 by log rank test).</p

The influence of the Great East Japan earthquake on microscopic polyangiitis: A retrospective observational study

<div><p>Background</p><p>Antineutrophil cytoplasmic antibody-associated vasculitis is triggered by environmental factors, including silica dust exposure. Repeated tsunami waves brought a large volume of silica-containing sludge inland after the Great East Japan earthquake in 2011. We aimed to determine if the serious disaster influenced the clinical features of the microscopic polyangiitis.</p><p>Methods</p><p>This is an observational retrospective study conducted in a single institute. A total of 43 patients were included based on the CHCC2012 criteria for microscopic polyangiitis from 2007 to 2015. We used the Poisson regression model to determine the incidence of microscopic polyangiitis within the annual population of the medical district. The participants were selected during a 3-year period from before (N = 13) to after the disaster (N = 20). The differences of parameters and the overall survival between the groups were analyzed.</p><p>Results</p><p>The incidence of microscopic polyangiitis increased after the disaster (λ = 17.4/million/year [95%CI: 7.66–39.6] before the disaster and λ = 33.1/million/year [17.7–61.7] after the disaster, <i>P</i> = 0.044). A high Birmingham Activity Score was associated with a high incidence of microscopic polyangiitis after the disaster. The overall survival of the patients with microscopic polyangiitis declined significantly after the disaster.</p><p>Conclusions</p><p>The Great East Japan earthquake influenced the development of the microscopic polyangiitis in our restricted area. The patients who developed after the disaster had severe symptoms and a high mortality rate.</p></div

Change in the annual incidence of microscopic polyangiitis (MPA) in the Ishinomaki medical area.

<p>The incident cases were divided by the population at risk in the restricted medical area and plotted according to annual intervals. The white and black bars represent the incidence per 1 million people before and after the disaster, respectively. The mean incidence of MPA was 17.4 /million/year [95% Confidence Interval (CI): 7.66 to 39.61] before the disaster and 33.1 /million/year [95% CI: 17.73 to 61.74] after the disaster. The dashed line indicates the mean annual incidence of MPA in Japan. The incidence ratio and <i>P</i>-value were obtained using Poisson regression analysis (<i>P</i> = 0.044).</p

Baseline characteristics of 43 MPA patients in this study.

<p>Baseline characteristics of 43 MPA patients in this study.</p

Comparison of factors before and after the GEJE.

<p>Comparison of factors before and after the GEJE.</p

Flow diagram of screening for participants in this study.

<p>The crude number of patients with microscopic polyangiitis was counted on the basis of ICD-10 codes from medical records in our hospital. Each of the patients was diagnosed with MPA based on the CHCC2012 criteria. Drug-induced and recurrent cases were excluded. Abbreviations: ICD, international classification of diseases; RPGN, rapidly progressive glomerulonephritis; GPA, granulomatosis with polyangiitis; EGPA, eosinophilic granulomatosis with polyangiitis, CHCC; Chapel Hill Consensus Conference, MPA; microscopic polyangiitis.</p

Efficacy and safety in mice of repeated, lifelong administration of an ANGPTL3 vaccine

Abstract Previously, we reported that an ANGPTL3 vaccine is a hopeful therapeutic option against dyslipidemia. In our current study, we assess durability and booster effects of that vaccine over a period representing a mouse’s lifespan. The vaccine remained effective for over one year, and booster vaccination maintained suppression of circulating triglyceride levels thereafter without major adverse effects on lungs, kidneys, or liver, suggesting vaccine efficacy and safety