Mutsuko Yamada

Redox-Active Protein Thioredoxin-1 Administration Ameliorates Influenza A Virus (H1N1)-Induced Acute Lung Injury in Mice

Objectives:Influenza virus infections can cause severe acute lung injury leading to significant morbidity and mortality. Thioredoxin-1 is a redox-active defensive protein induced in response to stress conditions. Animal experiments have revealed that thioredoxin-1 has protective effects against various severe disorders. This study was undertaken to evaluate the protective effects of recombinant human thioredoxin-1 administration on influenza A virus (H1N1)-induced acute lung injury in mice. Design:Prospective animal trial. Setting:Research laboratory. Subjects:Nine-week-old male C57BL/6 mice inoculated with H1N1. Intervention:The mice were divided into a vehicle-treated group and recombinant human thioredoxin-1-treated group. For survival rate analysis, the vehicle or recombinant human thioredoxin-1 was administered intraperitoneally every second day from day –1 to day 13. For lung lavage and pathological analyses, vehicle or recombinant human thioredoxin-1 was administered intraperitoneally on days –1, 1, and 3. Measurements and Main Results:Lung lavage and pathological analyses were performed at 24, 72, and 120 hrs after inoculation. The recombinant human thioredoxin-1 treatment significantly improved the survival rate of H1N1-inoculated mice, although the treatment did not affect virus propagation in the lung. The treatment significantly attenuated the histological changes and neutrophil infiltration in the lung of H1N1-inoculated mice. The treatment significantly attenuated the production of tumor necrosis factor-&agr; and chemokine (C-X-C motif) ligand 1 in the lung and oxidative stress enhancement, which were observed in H1N1-inoculated mice. H1N1 induced expressions of tumor necrosis factor-&agr; and chemokine (C-X-C motif) ligand 1 in murine lung epithelial cells MLE-12, which were inhibited by the addition of recombinant human thioredoxin-1. The recombinant human thioredoxin-1 treatment started 30 mins after H1N1 inoculation also significantly improved the survival of the mice. Conclusions:Exogenous administration of recombinant human thioredoxin-1 significantly improved the survival rate and attenuated lung histological changes in the murine model of influenza pneumonia. The protective mechanism of thioredoxin-1 might be explained by its potent antioxidative and anti-inflammatory actions. Consequently, recombinant human thioredoxin-1 might be a possible pharmacological strategy for severe influenza virus infection in humans.

Thioredoxin-1 and oxidative stress status in pregnant women at early third trimester of pregnancy: relation to maternal and neonatal characteristics

This study examined the clinical and biological importance of thioredoxin-1, a redox-active defensive protein that controls multiple biological functions, in pregnant women. We measured serum concentrations of thioredoxin-1, total hydroperoxides, and redox potential in 60 pregnant women at the early third trimester: gestational age of 27–29 weeks. The thioredoxin-1 concentration (mean ± SD) was 90 ± 42 ng/ml. Total hydroperoxides was 471 ± 105 U.CARR (1 U.CARR = 0.08 mg/dl H2O2). Redox potential was 2142 ± 273 µmol/l. The total hydroperoxides: redox potential ratio (oxidative stress index) was 0.23 ± 0.08. Thioredoxin-1, total hydroperoxides, and oxidative stress index were higher and redox potential was lower than in blood of healthy adults. Total hydroperoxides and redox potential were mutually correlated significantly and negatively. Thioredoxin-1 correlated significantly and negatively and redox potential correlated significantly and positively with body weight and body mass index. Thioredoxin-1 and redox potential correlated significantly and positively with uric acid and albumin, respectively. Thioredoxin-1 and oxidative stress index correlated significantly and negatively and redox potential significantly and positively with neonatal birth weight. These results suggest that high concentrations of thioredoxin-1 are linked to high oxidative stress status in pregnant women and that neonatal birth weight is affected by the maternal oxidative condition during later pregnancy.

Prognostic value of brain injury biomarkers in acute encephalitis/encephalopathy

Acute encephalitis/encephalopathy (AEE) is a devastating cause of severe neurodevelopmental sequelae or death in children. Assessing ongoing brain injury and predicting outcomes using bedside point‐of‐care testing is expected to be extremely valuable.

Transient myeloproliferative disorder with partial trisomy 21.

Myeloid malignancy with Down syndrome (ML‐DS) is estimated to have a step‐wise leukemogenesis including GATA1 mutation. Trisomy 21 is essential for ML‐DS; however, we do not know exactly which gene or genes located on chromosome 21 are necessary for the ML‐DS. We report a female infant with transient myeloproliferative disorder (TMD) and partial trisomy 21. SNP array analysis showed 10 Mb amplification of 21q22.12–21q22.3, which included DYRK1A, ERG, and ETS but not the RUNX1 gene. With two other reported TMD cases having partial trisomy 21, DYRK1A, ERG, and ETS were the most likely genes involved in collaboration with the GATA1 mutation. Pediatr Blood Cancer

Anti-high mobility group box-1 monoclonal antibody treatment of brain edema induced by influenza infection and lipopolysaccharide

Encephalopathy is a major cause of influenza‐associated child death and severe neurological sequelae in Japan, highlighting the urgent need for new therapeutic strategies. In this study, we evaluated the effects of anti‐high mobility group box‐1 monoclonal antibody (α‐HMGB1) treatment on brain edema induced by influenza A virus (IAV) and lipopolysaccharide in 4‐week‐old BALB/c female mice. The results showed that administration of 7.5 mg/kg α‐HMGB1 1 h after IAV (A/Puerto Rico/8/34) inoculation significantly alleviated brain edema at 48 h after IAV inoculation, as confirmed by the suppression of Evans Blue dye leakage and matrix metallopeptidase‐9 mRNA expression in the brain. Moreover, we also observed suppression of oxidative stress and different cytokines in IAV‐inoculated mice. The expression of plasminogen activator inhibitor‐1 was also attenuated following treatment with α‐HMGB1. Notably, α‐HMGB1 treatment had no effect on virus propagation in the lung. In summary, anti‐HMGB1 treatment may improve the prognosis in cases with influenza‐associated encephalopathy by attenuating brain edema and reducing the inflammatory responses induced by HMGB1.

Combined effect of anti-high-mobility group box-1 monoclonal antibody and peramivir against influenza A virus-induced pneumonia in mice: HATAYAMA et al.

Human pandemic H1N1 2009 influenza virus causes significant morbidity and mortality with severe acute lung injury due to the excessive inflammatory reaction, even with neuraminidase inhibitor use. The anti‐inflammatory effect of anti‐high‐mobility group box‐1 (HMGB1) monoclonal antibody (mAb) against influenza pneumonia has been reported. In this study, we evaluated the combined effect of anti‐HMGB1 mAb and peramivir against pneumonia induced by influenza A (H1N1) virus in mice. Nine‐week‐old male C57BL/6 mice were inoculated with H1N1 and treated with intramuscularly administered peramivir at 2 and 3 days post‐infection (dpi). The anti‐HMGB1 mAb or a control mAb was administered at 2, 3, and 4 dpi. Survival rates were assessed, and lung lavage and pathological analyses were conducted at 5 and 7 dpi. The combination of peramivir with the anti‐HMGB1 mAb significantly improved survival rate whereas the anti‐HMGB1 mAb alone did not affect virus proliferation in the lungs. This combination therapy also significantly ameliorated histopathological changes, neutrophil infiltration, and macrophage aggregation by inhibiting HMGB1, inflammatory cytokines, and oxidative stress. Fluorescence immunostaining showed that the anti‐HMGB1 mAb inhibited HMGB1 translocation from type I alveolar epithelial cells. In summary, combining anti‐HMGB1 with conventional anti‐influenza therapy might be useful against severe influenza virus infection.

Serum Procalcitonin Levels in Acute Encephalopathy with Biphasic Seizures and Late Reduced Diffusion

Procalcitonin (PCT) is used as a biomarker in severe infections. Here, we retrospectively investigated levels of serum PCT, C-reactive protein (CRP), and inflammatory cytokines (IL-6, TNF-α, and IFN-γ) in the second phase of patients with acute encephalopathy with biphasic seizures and late reduced diffusion (AESD). Nine AESD pediatric patients (4 men, 5 women; AESD group) admitted to Okayama University Hospital from 2010 to 2016 were compared with 10 control patients with febrile seizures (FS) (3 men, 7 women; FS group). Mean PCT concentrations (ng/mL) in the AESD and FS groups were significantly different, at 9.8 ± 6.7 and 0.8 ± 0.9, respectively (p = 0.0006). CRP (mg/dL) were 0.79 ± 0.89 and 1.4 ± 1.0 (p = 0.94), respectively; IL-6 (pg/mL) were 449.7 ± 705.0 and 118.3 ± 145.4 (p = 0.20), respectively; TNF-α (pg/mL) were 18.6 ± 12.5 and 16.6 ± 6.0 (p = 0.67), respectively; and IFN-γ (pg/mL) were 79.6 ± 158.5 and 41.9 ± 63.7 (p = 0.56), respectively. Ratios of PCT to CRP were 27.5 ± 34.2 and 3.2 ± 6.8 (p < 0.0001), respectively. The sensitivity and specificity in the diagnosis of AESD using a cutoff of PCT/CRP ratio of 1.0 were 79% and 100%, respectively. These results suggest that PCT and the PCT/CRP ratio are useful in auxiliary diagnosis of the second stage of AESD, and in AESD, PCT is likely to increase through a different mechanism.

Local and Systemic Immune Responses to Influenza A Virus Infection in Pneumonia and Encephalitis Mouse Models

Objective To compare local and systemic profiles between different disease pathologies (pneumonia and encephalitis) induced by influenza A virus (IAV). Methods An IAV pneumonia model was created by intranasal inoculation of C57BL/6 mice with influenza A/WSN/33 (H1N1) virus. Lung lavage and blood collection were performed on day 3 after IAV inoculation. Similarly, an IAV encephalitis mouse model was created by direct intracranial IAV inoculation. Cerebrospinal fluid (CSF) and blood collection were conducted according to the same schedule. Cytokine/chemokine profiles were produced for each collected sample. Then the data were compared visually using radar charts. Results Serum cytokine profiles were similar in pneumonia and encephalitis models, but local responses between the bronchoalveolar lavage fluid (BALF) in the pneumonia model and CSF in the encephalitis model differed. Moreover, to varying degrees, the profiles of local cytokines/chemokines differed from those of serum in both the pneumonia and encephalitis models. Conclusion Investigating local samples such as BALF and CSF is important for evaluating local immune responses, providing insight into pathology at the primary loci of infection. Serum data alone might be insufficient to elucidate local immune responses and might not enable clinicians to devise the most appropriate treatment strategies.