Soshi Hashimoto

Dysregulation of lung injury and repair in moesin-deficient mice treated with intratracheal bleomycin.

Moesin belongs to the ezrin/radixin/moesin (ERM) protein family and participates in cellular functions, such as morphogenesis and motility, by cross-linking between the actin cytoskeleton and plasma membranes. Although moesin seems necessary for tissue construction and repair, its function at the whole body level remains elusive, perhaps because of redundancy among ERM proteins. To determine the role played by moesin in the modulation of pulmonary alveolar structure associated with lung injury and repair, we examined the morphological changes in the lung and the effect of bleomycin-induced lung injury and fibrosis in moesin-deficient (Msn(-/Y)) and control wild-type mice (Msn(+/Y)). Immunohistochemical analysis revealed that moesin was specifically localized in the distal lung epithelium, where ezrin and radixin were faintly detectable in Msn(+/Y) mice. Compared with Msn(+/Y) mice, Msn(-/Y) mice displayed abnormalities of alveolar architecture and, when treated with bleomycin, developed more prominent lung injury and fibrosis and lower body weight and survival rate. Furthermore, Msn(-/Y) mice had abnormal cytokine and chemokine gene expression as shown by real-time PCR. This is the first report of a functional involvement of moesin in the regulation of lung inflammation and repair. Our observations show that moesin critically regulates the preservation of alveolar structure and lung homeostasis.

The change of plasma endothelin‐1 levels before and after surgery with or without Down syndrome

Background:  The present study aimed to elucidate the pathophysiological roles of endothelin (ET)‐1 in patients with pulmonary hypertension and pulmonary vascular obstructive disease secondary to congenital heart disease and compare the plasma levels of ET‐1 between children with and without Down syndrome.

Disseminated Aspergillosis Following Resolution of Pneumocystis Pneumonia with Sustained Elevation of Beta-Glucan in an Intensive Care Unit: a Case Report

Invasive aspergillosis is a major cause of morbidity and mortality in immunocompromised patients receiving intensive care. The double-sandwich ELISA for galactomannan is reported to have a high sensitivity (96.5%) for the detection of invasive aspergillosis when a cut-off value of 0.8 ng/ml is used. However, we have experienced a case of lethal disseminated aspergillosis in a patient that presented with a negative galactomannan (GM) test and persistent elevation of ß-D glucan (BG) levels. A 63-year-old female was admitted to our Intensive Care Unit (ICU) in acute respiratory failure and elevated BG. She had been receiving medication for Goodpasture syndrome based on anti-glomerular basement membrane antibodies and myeloperoxidase–antineutrophil cytoplasmic antibodies for 9 months and was receiving longterm prednisolone therapy (20 mg/day). On admission, her trachea was immediately intubated, and a PCR analysis of the bronchoalveolar lavage sample revealed Pneumocystis jiroveci. Trimethoprimsulfamethoxazole therapy was started for Pneumocystis pneumonia. The levels of BG remained elevated (> 100 pg/ml) during the treatment period despite the clinical resolution of Pneumocystis pneumonia, raising concerns of another complicated invasive fungal disease; consequently, fosfluconazole was administered empirically. The serum BG levels, however, did not decrease. Blood cultures did not detect a fungal infection. Serum GM levels measured by a double-sandwich ELISA on the 6th, 11th, and 24th days in the ICU were negative (< 0.2 ng/ml). The patient ultimately died of multiple organ failure on the 45th ICU day. Postmortem examination revealed a disseminated fungal infection with aggressive vascular invasion of the lungs, heart, and brain. In situ hybridization with a 568-bp probe of the alkaline proteinase sequence of Aspergillus fumigatus showed specific positive staining within the fungus present in the infected lung tissue, revealing that this patient may have had a systemic infection by A. fumigatus or A. flavus. This is a case of serum GM-negative disseminated aspergillosis pathologically proven by autopsy. Persistent elevated BG levels (> 100 pg/ml) refractory to trimethoprim–sulfamethoxazole and fosfluconazole may suggest possible Aspergillus infection and should prompt the initiation of empiric anti-aspergillosis therapies in patients at risk for fungal infection.

Successful treatment of severe asthma-associated plastic bronchitis with extracorporeal membrane oxygenation

We describe a case of near-fatal asthma requiring extracorporeal membrane oxygenation (ECMO). The patient presented with severe respiratory distress, which was not responsive to conventional pharmacological therapy. The patient also failed to respond to mechanical ventilation and thus was placed on venovenous ECMO for temporary pulmonary support. A fiberoptic bronchoscopy revealed that large amounts of thick bronchial secretions had occluded the main bronchus, which suggested plastic bronchitis secondary to asthma. Aggressive airway hygiene with frequent bronchoscopies and application of biphasic cuirass ventilation for facilitation of secretion clearance were performed to improve the patient’s respiratory status. The patient achieved a full recovery and suffered no neurological sequelae. This case illustrates that aggressive pulmonary hygiene with ECMO is a useful therapy for patients with asthma-associated plastic bronchitis.

Evaluation of semi-quantitative scoring of Gram staining or semi-quantitative culture for the diagnosis of ventilator-associated pneumonia: a retrospective comparison with quantitative culture

BackgroundSemi-quantitative Gram stain and culture methods are still commonly used for diagnosing ventilator-associated pneumonia (VAP), due to its convenience. Only a few studies, however, have assessed the reliability of these methods when compared with quantitative cultures, a current standard for the diagnosis of VAP. The objective of this study was to assess the utility of semi-quantitative scores obtained using Gram stains and cultures of endotracheal aspirates when compared with quantitative cultures in the diagnosis of VAP.MethodsA retrospective chart review of mechanically ventilated patients with clinically suspected VAP in a single intensive care unit was performed. Semi-quantitative scores of Gram stains or culture results were compared with quantitative culture results of endotracheal aspirate for the diagnosis of VAP in 136 samples for 51 patients.ResultsThe semi-quantitative scores of Gram stains and the semi-quantitative culture results significantly correlated with the log value of the quantitative culture results (rs = 0.64 and 0.75). When using a log count ≥6 of quantitative cultures as the reference standard for the diagnosis of VAP, the sensitivity and specificity was 95% and 61% for Gram stain score of ≥1+, and was 42% and 96% for Gram stain score ≥3+, respectively. The sensitivity and specificity was 96% and 40% for the semi-quantitative culture score of ≥2+, and was 59% and 86% for the semi-quantitative culture score of ≥3+, respectively.ConclusionsAbsence of bacteria in semi-quantitative Gram stain and poor growth (≤1+) in semi-quantitative culture method could be utilized to exclude the possibility of VAP, whereas detection of abundant (≥3+) bacteria in semi-quantitative Gram stain could be utilized to strongly suspect VAP.

mTOR signaling controls VGLUT2 expression to maintain pain hypersensitivity after tissue injury.

Mammalian target of rapamycin (mTOR) is a serine-threonine protein kinase that controls protein synthesis in the nervous system. Here, we characterized the role of protein synthesis regulation due to mTOR signaling in rat dorsal root ganglion (DRG) following plantar incision. The number of phosphorylated mTOR (p-mTOR)-positive neurons was increased 2-4days after the incision. Rapamycin inhibited p-mTOR expression in the DRG and thermal hypersensitivity 3days but not 1day after the incision. Vesicular glutamate transporter 2 (VGLUT2) expression was increased after the plantar incision, which was inhibited by rapamycin. These results demonstrated that tissue injury induces phosphorylation of mTOR and increased protein level of VGLUT2 in the DRG neurons. mTOR phosphorylation involves in maintenance of injury-induced thermal hypersensitivity.

Expression of neutral endopeptidase activity during clinical and experimental acute lung injury

BackgroundNeutral endopeptidase (NEP), an enzyme that cleaves inflammatory bioactive peptides, may play a protective role in the pathogenesis of acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). However, its low extracellular activity hinders the precise measurement of changes that take place during ALI/ARDS. The main objective of this study was to clarify the regulation of NEP activity and its expression during ALI/ARDS.MethodsIn a clinical study, we measured plasma NEP activity in patients who developed postoperative ALI/ARDS, using a HPLC fluorometric system. In an experimental study, we induced ALI by intratracheal instillation of hydrochloric acid (HCl) or lipopolysaccharide (LPS) in mice, and similarly measured NEP activity in plasma, lung tissue, and broncho-alveolar lavage fluid (BALF). We also studied the distribution and measured the amounts of NEP protein, using immuno-histochemical and immunoblot analyses, and measured the levels of NEP mRNA, using real-time reverse transcription-polymerase chain reaction, in the lungs of mice with ALI.ResultsThe plasma NEP activity was significantly lower in patients presenting with ALI/ARDS than in controls. Similarly, the NEP activity in plasma and lung tissue was markedly lower, and lung injuries more severe in LPS- than in HCl-treated mice. In contrast, the activity of NEP in the BALF of LPS-treated mice was increased. The intratracheal instillation of LPS decreased the gene expression of NEP in the lung. Immuno-histochemical and Western immunoblot studies in mice confirmed a) the presence of NEP in the alveolar wall, a critical target in ALI/ARDS, and b) a decrease in its expression in HCl- and LPS-induced ALI.ConclusionIn this experimental and clinical study of ALI/ARDS, the activity of NEP was significantly decreased in plasma and increased in the alveolar air space.

Deterioration of Regional Lung Strain and Inflammation during Early Lung Injury

Rationale: The contribution of aeration heterogeneity to lung injury during early mechanical ventilation of uninjured lungs is unknown. Objectives: To test the hypotheses that a strategy consistent with clinical practice does not protect from worsening in lung strains during the first 24 hours of ventilation of initially normal lungs exposed to mild systemic endotoxemia in supine versus prone position, and that local neutrophilic inflammation is associated with local strain and blood volume at global strains below a proposed injurious threshold. Methods: Voxel‐level aeration and tidal strain were assessed by computed tomography in sheep ventilated with low Vt and positive end‐expiratory pressure while receiving intravenous endotoxin. Regional inflammation and blood volume were estimated from 2‐deoxy‐2‐[(18)F]fluoro‐d‐glucose (18F‐FDG) positron emission tomography. Measurements and Main Results: Spatial heterogeneity of aeration and strain increased only in supine lungs (P < 0.001), with higher strains and atelectasis than prone at 24 hours. Absolute strains were lower than those considered globally injurious. Strains redistributed to higher aeration areas as lung injury progressed in supine lungs. At 24 hours, tissue‐normalized 18F‐FDG uptake increased more in atelectatic and moderately high‐aeration regions (>70%) than in normally aerated regions (P < 0.01), with differential mechanistically relevant regional gene expression. 18F‐FDG phosphorylation rate was associated with strain and blood volume. Imaging findings were confirmed in ventilated patients with sepsis. Conclusions: Mechanical ventilation consistent with clinical practice did not generate excessive regional strain in heterogeneously aerated supine lungs. However, it allowed worsening of spatial strain distribution in these lungs, associated with increased inflammation. Our results support the implementation of early aeration homogenization in normal lungs.

Tumor necrosis factor-alpha induces expression of C/EBP-beta in primary afferent neurons following nerve injury.

CCAAT/enhancer binding protein-beta (C/EBP-beta) is a transcription factor that belongs to the C/EBP family. To understand the role of C/EBP-beta in the peripheral nervous system, we investigated the expression of C/EBP-beta in the dorsal root ganglion. C/EBP-beta was weakly detected in nuclei of naive dorsal root ganglion (DRG) neurons. Spinal nerve ligation increased the expression of C/EBP-beta in L4 and L5 DRG neurons. Treatment with anti-TNF-alpha prevented SNL-induced pain hypersensitivity and C/EBP-beta expression in the DRG. Injection of TNF-alpha into the sciatic nerve produced transient pain hypersensitivity and induction of C/EBP-beta expression in the DRG. These results demonstrate that C/EBP-beta is activated in the DRG neurons by a TNF-alpha-dependent manner and might be involved in the activation of primary afferent neurons after nerve injury.

Perioperative respiratory complications: current evidence and strategy discussed in 2017 JA symposium

Respiratory management during general anesthesia aims to safely secure the airway and maintain adequate ventilation to deliver oxygen to the vital organs, maintaining homeostasis even during surgery. Despite its clinical importance, anesthesiologists often encounter difficulties in properly managing respiration during the perioperative period, leading to severe respiratory complications. In this year’s JA symposium, 5 editorial board members of Journal of Anesthesia (JA) who are experts in the field of respiratory management in anesthesia discussed the following topics: quitting smoking before surgery: exposure to passive smoke is damaging to children, ventilator-associated pneumonia, high inspiratory oxygen concentration and lung injury, aspiration pneumonia, and postoperative respiratory management strategy in patients with obstructive sleep apnea. We hope that this special article regarding this year’s JA symposium may be useful for JA readers to manage clinical anesthesia on a daily basis.