Mian Peng

Dexmedetomidine attenuates lipopolysaccharide-induced proinflammatory response in primary microglia

BACKGROUND Neuroinflammation mediated by microglia has been implicated in delirium. Suppression of microglial activation may therefore contribute to alleviate delirium. It has been reported that dexmedetomidine (DEX) has a potent anti-inflammatory property. In the present study, we investigated the effects of DEX on the production of proinflammatory mediators in lipopolysaccharide-stimulated microglia. MATERIALS AND METHODS The concentrations of DEX were chosen to correspond to 1, 10, and 100 times of clinically relevant concentration (i.e., 1, 10, and 100ng/mL). The levels of proinflammatory mediators, such as inducible nitric oxide synthase or nitric oxide, prostaglandin E(2), interleukin 1β, and tumor necrosis factor α, were measured. RESULTS DEX at 1ng/mL did not affect the production of proinflammatory mediators. DEX at 10 and 100ng/mL significantly inhibited the release of nitric oxide, prostaglandin E(2), interleukin 1β, and tumor necrosis factor α and the expression of inducible nitric oxide synthase messenger RNA. CONCLUSIONS These results suggest that DEX is a potent suppressor of lipopolysaccharide-induced inflammation in activated microglia and may be a potential therapeutic agent for the treatment of intensive care unit delirium.

Toll-like receptor 4 regulates heme oxygenase-1 expression after hemorrhagic shock induced acute lung injury in mice: requirement of p38 mitogen-activated protein kinase activation.

Acute lung injury (ALI) leading to respiratory distress is a common sequela of shock or trauma. The toll-like receptors (TLRs) stand at the interface of innate immune activation in the settings of both infection and sterile injury by responding to a variety of microbial and endogenous ligands alike. This work explored the effects of TLR-4 on hemorrhage-induced ALI and characterizes the signaling pathways and the mechanisms involved in noninfectious ALI. Mice underwent hemorrhagic shock and resuscitation (HSR). Arterial blood gases; expressions of TLR-4, heme oxygenase 1 (HO-1), and p38 mitogen-activated protein kinase (p38MAPK); myeloperoxidase activity; lung wet/dry ratios; and IL-10 levels in lung tissues were obtained at 6, 24, and 48 h after HSR. Hemorrhagic shock and resuscitation induced significant expressions of TLR-4, HO-1, and p38MAPK in C3H/HeN mice. IL-10 and myeloperoxidase were markedly increased at 24 h after HSR, and C3H/HeN mice had ALI with PaO2/fraction of inspired oxygen less than 300 mmHg. The induced amount of each cytokine level and the expressions of TLR-4, HO-1, and p38MAPK of C3H/HeN mice were significantly higher compared with C3H/HeJ mice. This study demonstrated that lung p38MAPK is activated after HSR, and p38MAPK inhibitor FR167653 suppresses HO-1 induction after ALI. We concluded that TLR-4 might induce HO-1 messenger RNA expression, which is probably involved in p38MAPK activation in the development of the lung dysfunction after HSR.

The cyclooxygenase-2 inhibitor parecoxib inhibits surgery-induced proinflammatory cytokine expression in the hippocampus in aged rats.

BACKGROUND Neuroinflammatory response triggered by surgery has been increasingly reported to be associated with postoperative cognitive dysfunction. Proinflammatory cytokines, such as interleukin 1β (IL-1β) and tumor necrosis factor α (TNF-α), play a pivotal role in mediating surgery-induced neuroinflammation. The role of cyclooxygenase-2 (COX-2), a critical regulator in inflammatory response, in surgery-induced neuroinflammation is still unknown. The aim of the study was to investigate the changes of COX-2 expression and prostaglandin E2 (PGE2) production in the hippocampus in aged rats following partial hepatectomy. The effects of selective COX-2 inhibitor (parecoxib) on hippocampal proinflammatory cytokine expression were also evaluated. METHODS Aged rats were randomly divided into three groups: control (n = 10), surgery (n = 30), and parecoxib (n = 30). Control animals received sterile saline to control for the effects of injection stress. Rats in the surgery group received partial hepatectomy under isoflurane anesthesia and sterile saline injection. Rats in the parecoxib group received surgery and anesthesia similar to surgery group rats, and parecoxib treatment. On postanesthetic days 1, 3, and 7, animals were euthanized to assess levels of hippocampal COX-2 expression, PGE2 production, and cytokines IL-1β and TNF-α expression. The effects of parecoxib on proinflammatory cytokine expression were also assessed. RESULTS Partial hepatectomy significantly increased COX-2 expression, PGE2 production, and proinflammatory cytokine expression in the hippocampus in aged rats on postoperative days 1 and 3. Parecoxib inhibited hippocampal IL-1β and TNF-α expression through downregulation of the COX-2/PGE2 pathway. CONCLUSION COX-2 may play a critical role in surgery-induced neuroinflammation. The COX-2 inhibitor may be a promising candidate for treatment of neuroinflammation caused by surgical trauma.

TLR4 signaling-induced heme oxygenase upregulation in the acute lung injury: role in hemorrhagic shock and two-hit induced lung inflammation

Resuscitated hemorrhagic shock is believed to promote the development of acute lung injury (ALI) by priming the immune system for an exaggerated inflammatory response to a second trivial stimulus. This work explored effects of TLR4 on hemorrhage-induced ALI and “second-hit” responses, and further explore the mechanisms involved in “second-hit” responses. Expression of HO-1, IL-10, lung W/D and MPO markedly increased at nearly all time-points examined in HSR/LPS group as compared with sham/LPS group in WT mice. In HSR/LPS mice, the induced amount of IL-10 and the expressions of HO-1 of WT mice were significantly higher compared with TLR-4d/d. This study provides in vivo evidence that pulmonary infections after LPS instillation contribute to local tissue release of pro-inflammatory mediators after HSR systemic. Activation of TLR4 might induce HO-1 expression and HO-1 modulates proinflammatory responses that are triggered via TLR4 signaling.

Dexmedetomidine regulates inflammatory molecules contributing to ventilator-induced lung injury in dogs

BACKGROUND Dexmedetomidine reduced mortality and inhibited the inflammatory response during endotoxemia in rats. The aim of this study was to clarify the effect of dexmedetomidine-regulating inflammation on a noninfectious, ventilator-induced lung injury (VILI) in dogs. METHODS Thirty healthy Beagles weighing between 8 and 12 kg were randomly divided into five groups: control group (group C, n = 6), mechanical ventilation (group MV, n = 6), and three different doses of dexmedetomidine group (group DEX1-3, n = 6). VILI was induced by high-tidal volume ventilation (tidal volume 20 mL/kg; respiratory rate 15 breaths/min; FiO2 0.5). Group DEX received intravenous Dex 20 min before endotracheal intubation (0.5, 1.0, and 2.0 μg/kg Dex was infused within 20 min and then a maintenance dose of 0.5, 1.0, and 2.0 μg/kg/h Dex was infused intravenously). Arterial blood samples were obtained from femoral artery at base state, MV1h, MV2h, and MV4h for blood gas analysis. After being mechanically ventilated for 4 h, dogs were killed and the levels of pulmonary inflammatory response and polymorphonuclear neutrophils (PMNs) count in bronchoalveolar lavage fluid were evaluated. RESULTS Histologic findings of the MV, DEX1, DEX2, and DEX3 groups revealed severe, moderate, mild, and normal to minimal inflammation, respectively. Myeloperoxidase level, PMNs/alveoli ratio, nuclear factor-κB messenger RNA (mRNA), tumor necrosis factor-alpha mRNA, and inducible nitric oxide synthase mRNA expression in lung tissues of the DEX2 and DEX3 were significantly lower than those of the MV group. Partial pressures of oxygen was decreased significantly at MV4h as compared with the baseline. There was no statistical significance in partial pressures of oxygen between MV and DEX2 group as well as between group MV and group DEX3. CONCLUSIONS Dexmedetomidine could mitigate pulmonary inflammatory response induced by VILI in dogs.

Altered hippocampal microRNA expression profiles in neonatal rats caused by sevoflurane anesthesia: MicroRNA profiling and bioinformatics target analysis.

Although accumulating evidence has suggested that microRNAs (miRNAs) have a serious impact on cognitive function and are associated with the etiology of several neuropsychiatric disorders, their expression in sevoflurane-induced neurotoxicity in the developing brain has not been characterized. In the present study, the miRNAs expression pattern in neonatal hippocampus samples (24 h after sevoflurane exposure) was investigated and 9 miRNAs were selected, which were associated with brain development and cognition in order to perform a bioinformatic analysis. Previous microfluidic chip assay had detected 29 upregulated and 24 downregulated miRNAs in the neonatal rat hippocampus, of which 7 selected deregulated miRNAs were identified by the quantitative polymerase chain reaction. A total of 85 targets of selected deregulated miRNAs were analyzed using bioinformatics and the main enriched metabolic pathways, mitogen-activated protein kinase and Wnt pathways may have been involved in molecular mechanisms with regard to neuronal cell body, dendrite and synapse. The observations of the present study provided a novel understanding regarding the regulatory mechanism of miRNAs underlying sevoflurane-induced neurotoxicity, therefore benefitting the improvement of the prevention and treatment strategies of volatile anesthetics related neurotoxicity.

Toll-like receptor 4 knockout ameliorates neuroinflammation due to lung-brain interaction in mechanically ventilated mice

Toll-like receptor 4 (TLR4) is a crucial receptor in the innate immune system, and increasing evidence supports its role in inflammation, stress, and tissue injury, including injury to the lung and brain. We aimed to investigate the effects of TLR4 on neuroinflammation due to the lung-brain interaction in mechanically ventilated mice. Male wild-type (WT) C57BL/6 and TLR4 knockout (TLR4 KO) mice were divided into three groups: (1) control group (C): spontaneous breathing; (2) anesthesia group (A): spontaneous breathing under anesthesia; and (3) mechanical ventilation group (MV): 6h of MV under anesthesia. The behavioral responses of mice were tested with fear conditioning tests. The histological changes in the lung and brain were assessed using hematoxylin-eosin (HE) staining. The level of TLR4 mRNA in tissue was measured using reverse transcription-polymerase chain reaction (RT-PCR). The levels of inflammatory cytokines were measured with an enzyme-linked immunosorbent assay (ELISA). Microgliosis, astrocytosis, and the TLR4 immunoreactivity in the hippocampus were measured by double immunofluorescence. MV mice exhibited impaired cognition, and this impairment was less severe in TLR4 KO mice than in WT mice. In WT mice, MV increased TLR4 mRNA expression in the lung and brain. MV induced mild lung injury, which was prevented in TLR4 KO mice. MV mice exhibited increased levels of inflammatory cytokines, increased microglia and astrocyte activation. Microgliosis was alleviated in TLR4 KO mice. MV mice exhibited increased TLR4 immunoreactivity, which was expressed in microglia and astrocytes. These results demonstrate that TLR4 is involved in neuroinflammation due to the lung-brain interaction and that TLR4 KO ameliorates neuroinflammation due to lung-brain interaction after prolonged MV. In addition, Administration of a TLR4 antagonist (100μg/mice) to WT mice also significantly attenuated neuroinflammation of lung-brain interaction due to prolonged MV. TLR4 antagonism may be a new and novel approach for the treatment and management of neuroinflammation in long-term mechanically ventilated patients.

SIRT3 activator honokiol ameliorates surgery/anesthesia-induced cognitive decline in mice through anti-oxidative stress and anti-inflammatory in hippocampus

Increasing evidence indicates that neuroinflammatory and oxidative stress play two pivotal roles in cognitive impairment after surgery. Honokiol (HNK), as an activator of Sirtuin3 (SIRT3), has potential multiple biological functions. The aim of these experiments is to evaluate the effects of HNK on surgery/anesthesia‐induced cognitive decline in mice.

Short-Term Postoperative Cognitive Dysfunction and Inflammatory Response in Patients Undergoing Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy: A Pilot Study

Objectives To assess the association between short-term postoperative cognitive dysfuction (POCD) and inflammtory response in patients undergoing cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). Design A prospective cohort study. Setting University medical centre. Participants Fifty-one adult patients who had undergone CRS-HIPEC and twenty control participants. Measurements The inflammatory marker levels in plasma and cognitive function were measured. Results Twenty (39.2%, 20/51) patients developed POCD at 1 w after CRS-HIPEC. The patients with POCD had higher serum interleukin 1β (IL-1β), serum amyloid A (SAA), S100 calcium-binding protein β (S-100β), and high mobility group box-1 protein (HMGB-1) levels at 1 and 24 h postoperatively than patients without POCD. There was an association between POCD and the maximum IL-1β and S-100β concentrations in serum, which remained following adjustment for age and FBS. Conclusion In this pilot study, perioperative inflammatory marker levels increase significantly after CRS-HIPEC in adult patients, and such elevations are associated with the development of short-term cognitive dysfunction after this complex surgery. These results suggested the need for a larger RCT to replicate and confirm these findings.

NeurimmiRs and Postoperative Delirium in Elderly Patients Undergoing Total Hip/Knee Replacement: A Pilot Study

Objective: Postoperative delirium (POD) is a frequent complication after surgery and its occurrence is associated with poor outcomes. The pathophysiology of this complication is not clear, but identification of risk factors is important for positive postoperative outcomes. The purpose of this study was to investigate the associations between the preoperative expression levels of microRNA (miR)-146a, miR-125b, and miR-181c in cerebrospinal fluid (CSF) and serum and the development and severity of POD. Methods: Forty elderly patients aged 65 years old and older admitted for elective total hip/knee replacement under spinal anesthesia. Preoperatively, baseline cognitive function was assessed using the Mini-Mental State Examination. Each patient was interviewed daily on the first and second postoperative days. Delirium was diagnosed using the Confusion Assessment Method, and delirium severity was measured using the Memorial Delirium Assessment Scale (MDAS). Preoperative serum and CSF miR levels were determined by quantitative real-time PCR (qRT-PCR). Results: POD was detected in 27.5% (11/40) of patients. Up-regulation of miR-146a and miR-181c in CSF and down-regulation of miR-146a in serum were observed preoperatively in patients who developed POD, while patients with and without POD did not differ in serum or CSF levels of miR-125b. Delirious patients had higher CSF/serum ratios of miR-146a and miR-181c levels than non-delirious patients. The lower CSF miR-146a and CSF/serum miR-146a ratios were significantly associated with milder POD severity, represented by a lower MDAS score. Conclusion: The dysregulation of preoperative miR-146a and miR-181c in CSF and serum was associated with the development and severity of POD. These NeurimmiRs might participate in the neuropathogenesis of POD, pending further investigations. Clinical trial registration: this study was registered at ClinicalTrials.gov (NCT02817386).