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The thymic stromal lymphopoietin (TSLP) in the central nervous system is highly expressed in response to inflammation but the function of TSLP is still unclear. Using the LPS-stimulated microglia model, we measured oxidative stress, microglial activation markers, and inflammatory indexes to examine the direct impact of TSLP on LPS-stimulated microglia activation as well as the underlying mechanism. The results demonstrated that TSLP treatment decreased LPS-induced oxidative stress, inflammation, and the expression of M1-type markers in microglia by increasing TSLP receptor expression. The results also showed that TSLP treatment could control the differentiation of microglia toward M2 type by preventing the activation of microglia in the JAK2/STAT5 pathway with the presence of LPS, even though TSLP may directly promote the expression of pro-inflammatory cytokines without the presence of LPS. These findings support the hypothesis that TSLP reduces neuroinflammation and blocks the JAK2/STAT5 pathway induced by LPS, revealing the regulatory role of TSLP in the central nervous system and presenting a novel strategy for the control of the inflammatory response in the central nervous system.

Acute lung injury (ALI) usually causes acute respiratory distress syndrome (ARDS), or even death in critical ill patients. Immune cell infiltration in inflamed lungs is an important hallmark of ARDS. Macrophages are a type of immune cell that participate in the entire pathogenic trajectory of ARDS and most prominently via their interactions with lung alveolar epithelial cells (AECs). In the early stage of ARDS, classically activated macrophages secrete pro-inflammatory cytokines to clearance of the pathogens which may damage alveolar AECs cell structure and result in cell death. Paradoxically, in late stage of ARDS, anti-inflammatory cytokines secreted by alternatively activated macrophages dampen the inflammation response and promote epithelial regeneration and alveolar structure remodeling. In this review, we discuss the important role of macrophages and AECs in the progression of ARDS.

Younian Xu,1 Yangyang Ge,1 Miaomiao Zhou,2 Zongze Zhang2 1Anesthesiology Department, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China; 2Anesthesiology Department, Zhongnan Hospital of Wuhan University, Wuhan, People’s Republic of ChinaCorrespondence: Miaomiao ZhouAnesthesiology Department, Zhongnan Hospital of Wuhan University, No. 169 Donghu Road, Wuchang District, Wuhan, 430071, Hubei Province, People’s Republic of ChinaTel/Fax +86 027-67812903Email 879475227@qq.comBackground: Large ischemic stroke provokes an inflammatory response, promoting the release of norepinephrine (NE) by intensifying the sympathetic nervous system. This augmented sympathetic outflow was deemed to act on β 2-adrenergic receptors (β 2-ARs) expressed by immune cells, rendering organisms to post-stroke infections, like pneumonia. To clarify this issue, we introduced selective β 2-ARs agonist clenbuterol (CLEN) to stroke mice to investigate how β 2-adrenergic signaling augmentation after stroke affects immune response and post-stroke outcomes, including central and peripheral.Methods: We developed a middle cerebral artery occlusion (MCAO) stroke model in mice to induce large ischemic stroke and administered CLEN 24 h after the onset of MCAO stroke. First, we assessed infarct volume and NE levels in plasma and spleen 3ds later. Next, the immune state was identified by analyzing the spleen index, immune cell populations, and immune cytokines. Finally, peripheral outcomes were assessed by measuring signs of pneumonia, such as pathology, bacterial burden, and lung cytokines.Results: We report that CLEN treatment 24 h after MCAO stroke causes an enlarged infarct volume and a decrease in NE levels at 3ds after stroke. Consistent with a reduction of total T cells, T helper cells, and increase of cytotoxic T cells, the immune milieu after CLEN treatment presents an anti-inflammatory landscape, showing raised expression of anti-inflammatory cytokines: IL-4, IL-10, and TGF-β 1, and decreased expression of pro-inflammatory cytokines, such as TNF-α, IL-1β, and IFN-γ, with a dramatically reduced percentage of Gr-1+ neutrophils and B cells but an increased percentage of NK cells. In our study, CLEN treatment results in no higher risk of pneumonia but relieves bacterial burden, inhibits or limits pneumonia, and diminishes TNF-α expression in lung tissues after MCAO.Conclusion: We identified increased β 2-adrenergic signaling after MCAO stroke, inhibits or limits post-stroke pneumonia but enlarges stroke volume in MCAO mice. Thus, careful consideration must be taken to improve post-stroke outcomes by manipulation over β 2-adrenergic receptors.Keywords: ischemic stroke, β 2-adrenergic receptor, infarct, pneumonia, immunity, sympathetic

Graphical abstract, Background Acute respiratory distress syndrome is associated with a mortality of 45%. The authors investigated the possible mechanisms and effect of vascular endothelial growth factor on alveolar epithelial barrier permeability in acute respiratory distress syndrome mice model. Methods Eighty Male BALB/c mice were randomly assigned to four group: PBS group, LPS group, sFlt group, or LPS + sFlt group. The levels of vascular endothelial growth factor and total protein in bronchoalveolar lavage fluid were compared, together with lung injury score and the histopathology of alveolar epithelial barrier. The expressions of vascular endothelial growth factor and tight junction proteins mRNA in lung tissue were also studied. Results Lipopolysaccharide (LPS) inhaling was accompanied with increasing lung vascular endothelial growth factor (VEGF) expression. Anti-VEGF with soluble fms-like tyrosine kinase-1 (sFlt-1) attenuated the lung injury effectively. Conclusions Our data indicate that anti-vascular endothelial growth factor with soluble fms-like tyrosine kinase-1 could maintain the normal structure and function of respiratory membrane in acute respiratory distress syndrome mice model and might be a suitable therapeutic tool for the treatment of acute respiratory distress syndrome.

It is believed that inhaled anesthetics occupy hydrophobic pockets within target proteins, but how inhaled anesthetics with diverse shapes and sizes fit into highly structurally selective pockets is unknown. For hydroxide ions are hydrophobic, we determined whether hydroxide ions could bridge inhaled anesthetics and protein pockets. We found that small additional load of cerebral hydroxide ions decreases anesthetic potency. Multiple-water entanglement network, derived from Ising model, has a great ability to amplify ultralow changes in the cerebral hydroxide ion concentration, and consequently, amplified hydroxide ions account for neural excitability. Molecular dynamics simulations showed that inhaled anesthetics produce anesthesia by attenuating the formation of multiple-water entanglement network. This work suggests amplified hydroxide ions underlying a unified mechanism for the anesthetic action of inhaled anesthetics.

In this study, we have investigated feasibility of remifentanil and sufentanil anesthesia in children with congenital heart disease surgery and its effects on cardiac function and serological parameters. For this purpose, a retrospective study was conducted on 120 children with congenital heart disease who underwent repair of ventricular septum or atrial septum in our hospital, specifically from January 2016 to January 2018, and 60 patients in each group were randomly divided into the control and treatment groups, respectively. The control group was anesthetized with sufentanil, and the treatment group was anesthetized with remifentanil. The heart function, serological indexes, and adverse reactions were observed and compared. We have observed that there was no significant difference in HR levels between these groups ( P > 0.05 ), but SDP and DBP values of the two groups were decreased after anesthetic induction ( P < 0.05 ). ACH, cortisol, and lactic acid in the treatment group were significantly lower than those in the control group, and the difference was statistically significant ( P < 0.05 ). The incidence of bradycardia, nausea and vomiting, hypotension, muscle rigidity, and respiratory depression in the treatment group was 16.67% lower than that in the control group ( P < 0.05 ). Remifentanil has less influence on hemodynamics and a better analgesic effect than fentanyl in inhibiting stress response in congenital heart surgery, which provides reference and basis for children congenital heart surgery.

What We Already Know about This Topic What This Article Tells Us That Is New Background Xenon is an elemental anesthetic with nine stable isotopes. Nuclear spin is a quantum property which may differ among isotopes. Xenon 131 (131Xe) has nuclear spin of 3/2, xenon 129 (129Xe) a nuclear spin of 1/2, and the other seven isotopes have no nuclear spin. This study was aimed to explore the effect of nuclear spin on xenon anesthetic potency. Methods Eighty C57BL/6 male mice (7 weeks old) were randomly divided into four groups, xenon 132 (132Xe), xenon 134 (134Xe), 131Xe, and 129Xe groups. Due to xenon’s low potency, loss of righting reflex ED50 for mice to xenon was determined with 0.50% isoflurane. Loss of righting reflex ED50 of isoflurane was also measured, and the loss of righting reflex ED50 values of the four xenon isotopes were then calculated. The exact polarizabilities of the isotopes were calculated. Results Combined with 0.50% isoflurane, the loss of righting reflex ED50 values were 15 ± 4%, 16 ± 5%, 22 ± 5%, and 23 ± 7% for 132Xe, 134Xe, 131Xe, and 129Xe, respectively. For xenon alone, the loss of righting reflex ED50 values of 132Xe, 134Xe, 131Xe, and 129Xe were 70 ± 4%, 72 ± 5%, 99 ± 5%, and 105 ± 7%, respectively. Four isotopes had a same exact polarizability of 3.60 Å3. Conclusions Xenon isotopes with nuclear spin are less potent than those without, and polarizability cannot account for the difference. The lower anesthetic potency of 129Xe may be the result of it participating in conscious processing and therefore partially antagonizing its own anesthetic potency. Nuclear spin is a quantum property, and our results are consistent with theories that implicate quantum mechanisms in consciousness.

WHAT THIS ARTICLE TELLS US THAT IS NEW: BACKGROUND:: Xenon is an elemental anesthetic with nine stable isotopes. Nuclear spin is a quantum property which may differ among isotopes. Xenon 131 (Xe) has nuclear spin of 3/2, xenon 129 (Xe) a nuclear spin of 1/2, and the other seven isotopes have no nuclear spin. This study was aimed to explore the effect of nuclear spin on xenon anesthetic potency.Eighty C57BL/6 male mice (7 weeks old) were randomly divided into four groups, xenon 132 (Xe), xenon 134 (Xe), Xe, and Xe groups. Due to xenon's low potency, loss of righting reflex ED50 for mice to xenon was determined with 0.50% isoflurane. Loss of righting reflex ED50 of isoflurane was also measured, and the loss of righting reflex ED50 values of the four xenon isotopes were then calculated. The exact polarizabilities of the isotopes were calculated.Combined with 0.50% isoflurane, the loss of righting reflex ED50 values were 15 ± 4%, 16 ± 5%, 22 ± 5%, and 23 ± 7% for Xe, Xe, Xe, and Xe, respectively. For xenon alone, the loss of righting reflex ED50 values of Xe, Xe, Xe, and Xe were 70 ± 4%, 72 ± 5%, 99 ± 5%, and 105 ± 7%, respectively. Four isotopes had a same exact polarizability of 3.60 Å.Xenon isotopes with nuclear spin are less potent than those without, and polarizability cannot account for the difference. The lower anesthetic potency of Xe may be the result of it participating in conscious processing and therefore partially antagonizing its own anesthetic potency. Nuclear spin is a quantum property, and our results are consistent with theories that implicate quantum mechanisms in consciousness.

Epidermal growth factor receptor (EGFR) has been reported to initiate the inflammatory response, but its activation in lipopolysaccharide (LPS)-induced murine model of acute lung injury (ALI) remains unclear. In this study, we investigated the role of EGFR in the LPS-induced murine model of ALI and explored whether its inhibitor erlotinib could affect the progression of lung injury. We first detected the phosphorylated EGFR (p-EGFR)/EGFR ratio at different time points after LPS stimulation, and then different concentrations of erlotinib were used to treat mice at 1 h before LPS stimulation and collected samples at the time point of the highest p-EGFR/EGFR ratio. Lung injury indicators were detected and compared among groups. EGFR and toll-like receptor 4 (TLR4)/nuclear factor kappa B (NF-κB) signal transduction factors, including p-EGFR, p-AKT, p-ERK1/2, p-p65, tumor necrosis factor-α (TNF-α), and interleukin-1β (IL-1β), were measured with western blot. We found that the mice challenged with LPS suffered from the most serious lung injury at 24 h after LPS stimulation when the p-EGFR/EGFR ratio was relatively the highest. Erlotinib significantly diminished LPS-induced exudation of total cells, neutrophils, and proteins in BALF. Both the ELISA and western blot results showed that erlotinib attenuated the expression of TNF-α and IL-1β in LPS-induced ALI in mice. Inhibition of EGFR by erlotinib downregulated the expression of p-p65 protein level as well as blocked the activation of AKT and ERK1/2 signaling pathway. Taken together, erlotinib alleviated the LPS-induced ALI in a dose-dependent manner by suppressing EGFR activation and downregulating the NF-κB-mediated secretion of proinflammatory cytokines.

Ketamine (KTM), a N-methyl-D-aspartate (NMDA) receptor antagonist, was found to has an anti-inflammatory effect, but some patients suffered from exacerbated pro-inflammatory reactions after anesthesia with KTM. The present study was aimed to examine the underlying mechanism of pro-inflammatory effects of KTM. In this study, RAW264.7 cells were exposed to KTM and NMDA alone or combined for 30 min before lipopolysaccharide (LPS) stimulation. The expression levels of IL-6 and TNF-α were detected by RT-PCR and ELISA, and those of NMDA receptors by RT-PCR in RAW264.7 cells. Additionally, the TLR4 expression was determined by RT-PCR and flow cytometry, respectively. The results showed that in RAW264.7 cells, KTM alone promoted the TLR4 expression, but did not increase the expression of IL-6 or TNF-α. In the presence of LPS, KTM caused a significantly higher expression of IL-6 and TNF-α than LPS alone. NMDA could neither alter the IL-6 and TNF-α mRNA expression, nor reverse the enhanced expression of IL-6 and TNF-α mRNA by KTM in LPS-challenged cells. After TLR4-siRNA transfection, RAW264.7 cells pretreated with KTM no longer promoted the IL-6 and TNF-α expression in the presence of LPS. In conclusion, KTM accelerated LPS-induced inflammation in RAW264.7 cells by promoting TLR4 expression, independent of NMDA receptor.

Background Alveolar macrophages (AMs) activated into M1 phenotype are involved in the development of lipopolysaccharide-induced acute lung injury (ALI). However, whether AMs express amphiregulin and what roles amphiregulin plays in lipopolysaccharide-induced ALI remain poorly understood. Methods Acute lung injury was induced by intratracheal instillation of lipopolysaccharide in male C57BL/6 mice. Lung injury scores, level of protein, and level of neutrophils in bronchial alveolar lavage fluid of lipopolysaccharide-induced ALI mice were compared with those in mice challenged with recombinant exogenous amphiregulin and antiamphiregulin antibody. Amphiregulin expression in macrophages and neutrophils in bronchial alveolar lavage fluid of lipopolysaccharide-induced ALI mice was determined by using immunofluorescence technique and further detected in M0, M1, and M2 phenotypes of both peritoneal macrophages and AMs. The effect of amphiregulin on apoptosis of MLE12 cells and activation of epithelial growth factor receptor-AKT pathway were, respectively, examined by using flow cytometry and western blotting. Results Alveolar macrophages were found to highly express amphiregulin in ALI mice. Amphiregulin neutralization aggravated, whereas recombinant exogenous amphiregulin attenuated lipopolysaccharide-induced ALI in mice (n = 6). In cultured AMs and peritoneal macrophages, amphiregulin was mainly generated by M1, rather than M0 or M2 phenotype (n = 5). Apoptosis ratio of lipopolysaccharide-challenged MLE12 cells was significantly reduced by recombinant exogenous amphiregulin from 16.60 ± 1.82 to 9.47 ± 1.67% (n = 5) but significantly increased from 17.45 ± 1.13 to 21.67 ± 1.10% (n = 5) after stimulation with supernatant of M1-polarized AM media conditioned with amphiregulin-neutrolizing antibody. Western blotting revealed that amphiregulin activated epithelial growth factor receptor and AKT in the lung tissues and MLE12 cells (n = 5). Conclusions Different from the common notion that classically activated AMs have just a detrimental effect on the lung tissues, the results of this study showed that classically activated AMs also exerted a protective effect on the lung tissues by producing high-level amphiregulin in lipopolysaccharide-induced ALI.

The immune system plays a key role in protecting the organism from infection. Timely resolution of the inflammatory response to infection plays a vital role in returning homeostasis and maintaining normal organ function. Angiopoietin1 prevents endothelial activation, part of the inflammatory response to a pathogen, and has an anti-inflammatory effect in acute lung injury. We designed this study to investigate whether increasing serum production of angiopoietin1 by IV administration of adenoviral-delivered angiopoietin1 could accelerate the resolution of inflammation in endotoxin-induced acute lung injury in mice.Lipopolysaccharide was intratracheally instilled to induce acute lung injury in animals pretreated for 24 hours with adenoviral-GFP vector or adenoviral-GFP-angiopoietin1, respectively. An additional 6 mice in each pretreatment group were killed before lipopolysaccharide instillation to serve as controls. Indices of resolution of inflammation were analyzed. Apoptotic polymorphonuclear leukocytes and their phagocytosis by macrophages were determined by fluorescent activated cell sorter. The expression of angiopoietin1 in tissues and granulocyte macrophage colony-stimulating factor in the bronchoalveolar lavage fluid were measured.Lipopolysaccharide induced leukocyte infiltration into air spaces, with maximal infiltration 48 hours after lipopolysaccharide instillation. Pretreatment with adenovirus-GFP-angiopoietin1 markedly increased angiopoietin1 expression, reduced leukocyte, and neutrophil infiltration and shortened the duration of inflammation. Adenovirus-GFP-angiopoietin1 pretreatment augmented the magnitude without altering the time course of granulocyte macrophage colony-stimulating factor.Our results suggest that angiopoietin1 pretreatment promotes resolution of inflammation in endotoxin-induced acute lung injury in mice by accelerating the apoptosis of neutrophils and their phagocytosis by macrophages.

Although empirically well understood in their clinical administration, volatile anesthetics are not yet well comprehended in their mechanism studies. A major conundrum emerging from these studies is that there is no validated model to assess the presumed candidate sites of the anesthetics. We undertook this study to test the hypothesis that the single-celled Paramecium could be anesthetized and served as a model organism in the study of anesthetics. We assessed the motion of Paramecium cells with Expert Vision system and the chemoresponse of Paramecium cells with T-maze assays in the presence of four different volatile anesthetics, including isoflurane, sevoflurane, enflurane and ether. Each of those volatiles was dissolved in buffers to give drug concentrations equal to 0.8, 1.0, and 1.2 EC50, respectively, in clinical practice. We could see that after application of volatile anesthetics, the swimming of the Paramecium cells was accelerated and then suppressed, or even stopped eventually, and the index of the chemoresponse of the Paramecium cells (denoted as I ( che )) was decreased. All of the above impacts were found in a concentration-dependent fashion. The biphasic effects of the clinical concentrations of volatile anesthetics on Paramecium simulated the situation of high species in anesthesia, and the inhibition of the chemoresponse also indicated anesthetized. In conclusion, the findings in our studies suggested that the single-celled Paramecium could be anesthetized with clinical concentrations of volatile anesthetics and therefore be utilized as a model organism to study the mechanisms of volatile anesthetics.

Cognitive decline is a common complication after cardiac surgery with cardiopulmonary bypass (CPB), but as such no pharmacological therapy has been shown to be efficacious in preventing the decline. However, gastrodin has been shown to have multi-pharmacological effects on neurological functions. We undertook this study to test the hypothesis that gastrodin would potentially prevent CPB-associated neurocognitive decline. We randomly assigned 200 patients undergoing mitral valve replacement surgery to receive either gastrodin (40 mg/kg) or saline after the induction of anesthesia and subsequently evaluated cognitive function before surgery, at discharge, and at 3rd month after surgery by using a battery of five neurocognitive tests, or adverse effects of gastrodin postoperatively. Neurocognitive decline in postoperative function was defined as a drop of 1 SD or more in the scores on tests of any one of the four domains of cognitive function. Cognitive decline occurred in 9% of the patients in the gastrodin group in contrast to 42% in the control group (P