GENETIC DELETION OF TRANSLOCATOR PROTEIN EXACERBATES POST-SEPSIS SYNDROME WITH ACTIVATION OF THE C1Q PATHWAY IN SEPTIC MOUSE MODEL.

ABSTRACT: Significant numbers of patients who survive sepsis exhibit psychiatric and cognitive impairments, termed post-sepsis syndrome. Understanding the underlying pathophysiology is essential to develop effective therapies. Translocator protein 18 kDa (TSPO) is a multifaceted mitochondrial protein implicated in inflammation, oxidative stress, and steroidogenesis in the central nervous system. Despite accumulated evidence demonstrating TSPO is a biomarker in psychiatric and neurodegenerative disorders, the role of this protein in post-sepsis syndrome remains elusive. The aim of this study was to investigate the role of TSPO in the long-term impairment of mouse behavior associated with psychiatric and cognitive impairments following sepsis induced by cecal ligation and puncture (CLP) surgery. Animals were divided into three groups: (i) wild type (WT) + sham, (ii) WT + CLP, and (iii) TSPO knock out + CLP. Survival rate and body weight change were assessed up to 17 days after surgeries. Then, we also assessed anxiety-like behavior, depression-like behavior, cognitive function, locomotor activity, and forelimb muscle strength in surviving mice by elevated plus maze, tail suspension test, y-maze, open field test, and grip strength test, respectively. Deletion of the TSPO gene led to high mortality and prolonged weight loss and exacerbated anxiety-like and depressive-like behavior with cognitive impairment 17 days after, but not before, CLP surgery. RNA-seq analysis of the hippocampus revealed the upregulation of genes (C1qb, C1qc, and Tyrobp) in C1q complement pathways correlated significantly with anxiety-like behavior that appeared long after CLP surgery. The expressions of these genes predicted other behavioral traits, including depressive-like behavior in the tail suspension test and grip power impairment, supporting the role of the C1q pathway in post-sepsis syndrome. Because the C1q pathway has recently attracted interest as a tag for pathological synaptic elimination, the current study suggests the C1q pathway is involved in the psychiatric and cognitive impairments observed in post-sepsis syndrome.

Quantification of respiratory sounds by a continuous monitoring system can be used to predict complications after extubation: a pilot study.

To show that quantification of abnormal respiratory sounds by our developed device is useful for predicting respiratory failure and airway problems after extubation. A respiratory sound monitoring system was used to collect respiratory sounds in patients undergoing extubation. The recorded respiratory sounds were subsequently analyzed. We defined the composite poor outcome as requiring any of following medical interventions within 48 h as defined below. This composite outcome includes reintubation, surgical airway management, insertion of airway devices, unscheduled use of noninvasive ventilation or high-flow nasal cannula, unscheduled use of inhaled medications, suctioning of sputum by bronchoscopy and unscheduled imaging studies. The quantitative values (QV) for each abnormal respiratory sound and inspiratory sound volume were compared between composite outcome groups and non-outcome groups. Fifty-seven patients were included in this study. The composite outcome occurred in 18 patients. For neck sounds, the QVs of stridor and rhonchi were significantly higher in the outcome group vs the non-outcome group. For anterior thoracic sounds, the QVs of wheezes, rhonchi, and coarse crackles were significantly higher in the outcome group vs the non-outcome group. For bilateral lateral thoracic sounds, the QV of fine crackles was significantly higher in the outcome group vs the non-outcome group. Cervical inspiratory sounds volume (average of five breaths) immediately after extubation was significantly louder in the outcome group vs non-outcome group (63.3 dB vs 54.3 dB, respectively; p < 0.001). Quantification of abnormal respiratory sounds and respiratory volume may predict respiratory failure and airway problems after extubation.

Regional respiratory sound abnormalities in pneumothorax and pleural effusion detected via respiratory sound visualization and quantification: case report.

Assessment of respiratory sounds by auscultation with a conventional stethoscope is subjective. We developed a continuous monitoring and visualization system that enables objectively and quantitatively visualizing respiratory sounds. We herein present two cases in which the system showed regional differences in the respiratory sounds. We applied our novel continuous monitoring and visualization system to evaluate respiratory abnormalities in patients with acute chest disorders. Respiratory sounds were continuously recorded to assess regional changes in respiratory sound volumes. Because we used this system as a pilot study, the results were not shown in real time and were retrospectively analyzed. Case 1 An 89-year-old woman was admitted to our hospital for sudden-onset respiratory distress and hypoxia. Chest X-rays revealed left pneumothorax; thus, we drained the thorax. After confirming that the pneumothorax had improved, we attached the continuous monitoring and visualization system. Chest X-rays taken the next day showed exacerbation of the pneumothorax. Visual and quantitative findings showed a decreased respiratory volume in the left lung after 3 h. Case 2 A 94-year-old woman was admitted to our hospital for dyspnea. Chest X-rays showed a large amount of pleural effusion on the right side. The continuous monitoring and visualization system visually and quantitatively revealed a decreased respiratory volume in the lower right lung field compared with that in the lower left lung field. Our newly developed continuous monitoring and visualization system enabled quantitatively and visually detecting regional differences in respiratory sounds in patients with pneumothorax and pleural effusion.

A novel system that continuously visualizes and analyzes respiratory sounds to promptly evaluate upper airway abnormalities: a pilot study.

Although respiratory sounds are useful indicators for evaluating abnormalities of the upper airway and lungs, the accuracy of their evaluation may be limited. The continuous evaluation and visualization of respiratory sounds has so far been impossible. To resolve these problems, we developed a novel continuous visualization system for assessing respiratory sounds. Our novel system was used to evaluate respiratory abnormalities in two patients. The results were not known until later. The first patient was a 23-year-old man with chronic granulomatous disease and persistent anorexia. During his hospital stay, he exhibited a consciousness disorder, bradypnea, and hypercapnia requiring tracheal intubation. After the administration of muscle relaxant, he suddenly developed acute airway stenosis. Because we could not intubate and ventilate, we performed cricothyroidotomy. Subsequent review of our novel system revealed mild stridor before the onset of acute airway stenosis, which had not been recognized clinically. The second patient was a 74-year-old woman who had been intubated several days earlier for tracheal burn injury, and was extubated after alleviation of her laryngeal edema. After extubation, she gradually developed inspiratory stridor. We re-intubated her after diagnosing post-extubation laryngeal edema. Subsequent review of our novel system revealed serially increased stridor after the extubation, at an earlier time than was recognized by healthcare providers. This unique continuous monitoring and visualization system for respiratory sounds could be an objective tool for improving patient safety regarding airway complications.

Pharmacological and Genetic Inhibition of Translocator Protein 18 kDa Ameliorated Neuroinflammation in Murine Endotoxemia Model.

ABSTRACT: Sepsis-associated encephalopathy (SAE) is a diffuse brain dysfunction associated with sepsis. The development of an effective strategy for early diagnosis and therapeutic intervention is essential for the prevention of poor prognosis of SAE. Translocator protein 18 kDa (TSPO) is a mitochondrial protein implicated in steroidogenesis and inflammatory responses. Despite accumulating evidence that implicates TSPO in the neuroinflammatory response of the central nervous system, the possible role of TSPO in SAE remains unclear. The aim of this study is to address a role of TSPO in neuroinflammation using mice 24 h after systemic injection of LPS, which consistently demonstrated microglial activation and behavioral inhibition. Quantitative polymerase chain reaction analysis revealed that hippocampal TSPO expression was induced following the systemic LPS injection, associated with an increase in pro-inflammatory cytokines such as tumor necrosis factor-α and interleukin-1ß. Interestingly, pretreatment with the TSPO antagonist, ONO-2952, or germ-line deletion of the TSPO gene exhibited an anti-inflammatory effect with significant suppression of LPS-induced production of those cytokines. These effects demonstrated by the ONO-2952 or TSPO knockout were associated with significant recovery from behavioral inhibition, as shown by improved locomotor activity in the open field analysis. Histological analysis revealed that ONO-2952 pretreatment suppressed the LPS-induced activation of TSPO-expressing microglia in the hippocampus of mice. Collectively, these results suggest that TSPO plays a critical role in the SAE mouse model. Based on this finding, monitoring TSPO activity, as well as the progress of endotoxemia and its sequelae in the animal model, would deepen our understanding of the underlying molecular mechanism of SAE.

Microglial translocator protein and stressor-related disorder.

Despite the prevalence of neuroinflammation in psychiatric disorders, molecular mechanism underlying it remains elusive. Translocator protein 18 kDa (TSPO), also known as peripheral benzodiazepine receptor, is a mitochondrial protein implicated in the synthesis of steroids in a variety of tissues. Multiple reports have shown increased expression of TSPO in the activated microglia in the CNS. Radioactive probes targeting TSPO have been developed and used for imaging assessment in neurological and psychiatric disorders to examine neuroinflammation. Recent studies revealed that the wide range of stressors ranging from psychological to physical insults induced TSPO in human, suggesting that this protein could be an important tool to explore the contribution of microglia in stressor-related disorders. In this review, we first overview the microglial activation with TSPO in a wide range of stressors in human and animal models to discuss prevalent roles of TSPO in response of CNS to stressors. With recent update of the signaling pathway revealing link connecting TSPO with neuroinflammatory effectors such as reactive oxygen species, we discuss TSPO as a therapeutic targeting tool for suppression of adverse effect of stressors on long-lasting changes in animal behaviors and activities. Targeting TSPO which mediates neuroinflammation under the stress might pave the way to develop therapeutic intervention and prophylaxis of stressor-related disorder.