Intrathecally administered pizotifen alleviates neuropathic and inflammatory pain in mice by enhancing GABAergic inhibition.

Chronic pain, such as chronic neuropathic pain and chronic inflammatory pain, is often difficult to manage and bring great trouble to patients. 5-HT plays a key role in the process of pain transmission both in centrally and peripherally. Tricyclic antidepressants (TCA) such as amitriptyline are classical 5-HT reuptake inhibitors, are recommended as the first-line treatment for chronic pain. Pizotifen, a 5-HT2 receptor antagonist, is currently used in the prevention of vascular headaches. However, the antinociceptive effect of pizotifen on non-headache pain especially chronic pain in the spinal level is still unknown. Here we find that intrathecal pizotifen attenuates neuropathic and inflammatory pain mainly due to elevated GABAergic synaptic inhibition. Neuropathic pain is induced by segmental spinal nerve ligation (SNL), and inflammatory pain is induced by intraplantar injection of complete Freund's adjuvant (CFA). Both in SNL and CFA mice, spinally administered pizotifen reduced mechanical and thermal hyperalgesia dose-dependently. Since the levels of GAD65/67 were increased, and the frequency of mIPSCs in the spinal dorsal horn was increased, together with the antinociceptive effect being reversed by both GABAAR and GAD blockade, this antinociceptive effect might be generated from strengthened GABAergic inhibition. Furthermore, high dose of pizotifen (5 µg) weakly affected motor performance and did not influence the locomotor activity in normal animals. In summary, our findings suggest that pizotifen strengthens the inhibitory synaptic transmission and exerts antinociceptive effect on both neuropathic pain and inflammatory pain in the spinal cord, and may serve as a promising remedy for chronic pain.

Chinese Association for the Study of Pain: Expert consensus on chronic postsurgical pain.

Chronic postsurgical pain is a common surgical complication that severely reduces a patient's quality of life. Many perioperative interventions and management strategies have been developed for reducing and managing chronic postsurgical pain. Under the leadership of the Chinese Association for the Study of Pain, an editorial committee was formed for chronic postsurgical pain diagnosis and treatment by experts in relevant fields. The editorial committee composed the main content and framework of this consensus and established a working group. The working group conducted literature review (1989-2020) using key words such as "surgery", "post-surgical", "post-operative", "pain", "chronic", and "persistent" in different databases including MEDLINE, EMBASE, PubMed, Cochrane Central Register of Controlled Trials and Cochrane Database of Systematic Reviews. Only publications in the English language were included. The types of literature included systematic reviews, randomized controlled studies, cohort studies and case reports. This consensus was written based on clinical practice combined with literature evidence. The first draft of the consensus was rigorously reviewed and edited by all the editorial committee experts before being finalized. The level of evidence was assessed by methodological experts based on the Oxford Centre for Evidence-Based Medicine Levels of Evidence. The strength of recommendation was evaluated by all editorial committee experts, and the opinions of most experts were adopted as the final decision. The recommendation level "strong" generally refers to recommendations based on high-level evidence and consistency between clinical behavior and expected results. The recommendation level "weak" generally refers to the uncertainty between clinical behavior and expected results based on low-level evidence.

Finite element analysis of wedge and biconcave deformity in four different height restoration after augmentation of osteoporotic vertebral compression fractures.

PURPOSE: Biomechanical comparison of wedge and biconcave deformity of different height restoration after augmentation of osteoporotic vertebral compression fractures was analyzed by three-dimensional finite element analysis (FEA). METHODS: Three-dimensional finite element model (FEM) of T11-L2 segment was constructed from CT scan of elderly osteoporosis patient. The von Mises stresses of vertebrae, intervertebral disc, facet joints, displacement, and range of motion (ROM) of wedge and biconcave deformity were compared at four different heights (Genant 0-3 grade) after T12 vertebral augmentation. RESULTS: In wedge deformity, the stress of T12 decreased as the vertebral height in neutral position, flexion, extension, and left axial rotation, whereas increased sharply in bending at Genant 0; L1 and L2 decreased in all positions excluding flexion of L2, and T11 increased in neutral position, flexion, extension, and right axial rotation at Genant 0. No significant changes in biconcave deformity. The stress of T11-T12, T12-L1, and L1-L2 intervertebral disc gradually increased or decreased under other positions in wedge fracture, whereas L1-L2 no significant change in biconcave fracture. The utmost overall facet joint stress is at Genant 3, whereas there is no significant change under the same position in biconcave fracture. The displacement and ROM of the wedge fracture had ups and downs, while a decline in all positions excluding extension in biconcave fracture. CONCLUSIONS: The vertebral restoration height after augmentation to Genant 0 affects the von Mises stress, displacement, and ROM in wedge deformity, which may increase the risk of fracture, whereas restored or not in biconcave deformity.

Thermographic follow-up of postherpetic neuralgia (PHN) subsequent to Ramsay Hunt syndrome with multicranial nerve (V, VII, VIII and IX) involvement: a case report.

BACKGROUND: Ramsay Hunt syndrome (RHS) is caused by a reactivation of varicella-zoster virus (VZV) infection, and it is characterized by the symptoms of facial paralysis, otalgia, auricular rash, and/or an oral lesion. Elderly patients or immunocompromised patients, deep pain at the initial visit and no prompt treatment are significant predictors of postherpetic neuralgia (PHN). When PHN occurs, especially involved cranial polyneuropathy, multiple modalities should be administered for patients with the intractable PHN. The use of thermography in the follow-up of PHN secondary to RHS with multicranial nerve involvement has not yet been described yet in the literature. CASE PRESENTATION: The patient was a 78-year-old man with the chief complaint of a 3-month history of PHN secondary to RHS with polycranial nerve (V, VII, VIII, and IX) involvement. Multimodality therapy with oral gabapentin, pulsed radiofrequency (PRF) application to the Gasserian ganglion for pain in the trigeminal nerve region, linear-polarized near-infrared light irradiation for pain in the facial nerve region, and 2% lidocaine spray for pain in the glossopharyngeal nerve region was used to the treat patient, and follow-up evaluations included thermography. This comprehensive treatment obviously improved the quality of life, resulting in considerable pain relief, as indicated by a decrease in the numerical rating scale (NRS) score from 9 to 3 and a decrease in thermal imaging temperature from higher to average temperature on the ipsilateral side compared with the contralateral side. Lidocaine spray on the tonsillar branches of the glossopharyngeal nerve resulted in an improvement in odynophagia, and the NRS score decreased from 9 to 0 for glossopharyngeal neuralgia after three applications. CONCLUSION: Although the use of thermography in the follow-up of RHS with multiple cranial nerve (V, VII, VIII, and IX) involvement is very rare, in this patient, thermal imaging showed the efficacy of combination therapy (oral gabapentin, 2% lidocaine sprayed, PRF application and linear-polarized near-infrared light irradiation) and that is a good option for treatment.

Remimazolam tosilate in upper gastrointestinal endoscopy: A multicenter, randomized, non-inferiority, phase III trial.

BACKGROUND AND AIM: Remimazolam tosilate (RT) is a new short-acting GABA(A) receptor agonist, having potential to be an effective option for procedural sedation. Here, we aimed to compare the efficacy and safety of RT with propofol in patients undergoing upper gastrointestinal endoscopy. METHODS: This positive-controlled, non-inferiority, phase III trial recruited patients at 17 centers, between September 2017 and November 2017. A total of 384 patients scheduled to undergo upper gastrointestinal endoscopy were randomly assigned to receive RT or propofol. Primary endpoint was the success rate of sedation. Adverse events (AEs) were recorded to evaluate safety. RESULTS: The success rate of sedation in the RT group was non-inferior to that in the propofol group (97.34% vs 100.00%; difference in rate -2.66%, 95% CI -4.96 to -0.36, meeting criteria for non-inferiority). Patients in the RT group had longer time to adequate sedation (P < 0.0001) but shorter time to fully alert (P < 0.0001) than that in the propofol group. The incidences of hypotension (13.04% vs 42.86%, P < 0.0001), treatment-related hypotension (0.54% vs 5.82%, P < 0.0001), and respiratory depression (1.09% vs 6.88%, P = 0.0064) were significantly lower in the RT group. AEs were reported in 74 (39.15%) patients in the RT group and 114 (60.32%) patients in the propofol group, with significant difference (P < 0.0001). CONCLUSION: This trial established non-inferior sedation success rate of RT compared with propofol. RT allows faster recovery from sedation compared with propofol. The safety profile is favorable and appears to be superior to propofol, indicating that it was feasible and well tolerated for patients.

Intrathecal delivery of hydromorphone vs morphine for refractory cancer pain: a multicenter, randomized, single-blind, controlled noninferiority trial.

Hydromorphone is an alternative to morphine for intrathecal drug delivery system to treat refractory cancer pain; however, there is not enough clinical evidence to prove it. In our study, 233 patients from 12 different pain management centers across China were enrolled, 121 and 112 in the intrathecal hydromorphone (ITHM) and intrathecal morphine (ITMO) groups, respectively. The primary outcome was the clinical success rate, which was defined as ratio of patients achieving ≥50% pain relief. The noninferiority margin was defined as -0.15. Other outcomes included daily visual analogue scale score, breakthrough pain (BTP) incidence, intrathecal dose change, and patient-controlled analgesia bolus count change, GAD-7/PHQ-9. Clinical success was achieved in 85 and 79 of the 121 ITHM patients (70.2%) and 112 ITMO patients (70.5%), respectively. Compared to the corresponding baseline findings, significantly decreased visual analogue scale scores and BTP incidence were noted in both groups. The dose change rate decreased and increased with time in the ITHM and ITMO groups, respectively (ITHM -3.33% vs ITMO 35.4%, P < 0.01, t test) from the third week. The patient-controlled analgesia bolus change rate was lower in the ITHM group than in the ITMO group (ITHM -19.88% vs ITMO 7.79%, P < 0.01, t test) from first week. Our result shows that ITHM is noninferior to ITMO on pain relief to treat refractory cancer pain, however, at different doses and that the doses of morphine tended to increase, whereas those of hydromorphone decreased over time. Hydromorphone offers advantage over morphine in controlling BTP.

α-lipoic acid attenuates spatial learning and memory impairment induced by hepatectomy.

The aim of the present study was to compare the effects of α-lipoic acid (ALA) on postoperative cognitive dysfunction (POCD) between wild type (WT) and leptin receptor-deficient (db/db) mice and to elucidate the underlying mechanism of treatment with ALA. The present study compared the effects of ALA on spatial learning and memory of WT and db/db mice using a Morris water maze following hepatectomy. The expression levels of proteins, including cyclin-dependent kinase 5 (Cdk5), tau, phosphorylated tau and amyloid ß (Aß) were measured in the hippocampus. Surgery impaired postoperative cognitive function in both WT and db/db mice. Furthermore, the expression levels of Cdk5 and Aß, and the phosphorylation of tau in the hippocampus increased after the surgery in both WT and db/db mice. The ultrastructure of hippocampal neurons and synapses was analyzed by transmission electron microscopy and the results revealed that surgery damaged the structure of neurons and synapses in both WT and db/db mice. Treatment with ALA protected the postoperative cognitive function and the structure of hippocampal neurons and synapses, and prevented the increase in protein expression levels of Cdk5 and Aß, and the phosphorylation of tau in the hippocampus of WT but not db/db mice. The results of the present study suggest that ALA may be used for the treatment of POCD. The molecular mechanisms underlying the activity of ALA require further investigation.

Risk factors for early postoperative cognitive dysfunction after colorectal surgery.

BACKGROUND: It has been reported that postoperative cognitive dysfunction (POCD) is correlated with the degeneration of the central nervous system, oxidative stress, inflammation, and endocrine and immune dysfunction. Increased age, predisposed comorbidity, long surgery time, and prolonged stay in the intensive care unit have been reported to be risk factors for developing POCD for cardiac surgery. In the present study, the risk factors of early POCD after colorectal surgery were investigated. METHODS: Eighty patients, who provided informed consents for their participation in this study, were enrolled and received colorectal surgery under general anesthesia. Neuropsychological tests were performed preoperatively and on postoperative day seven. The risk factors for POCD were analyzed using a multivariate logistic regression model. RESULTS: Nineteen patients were diagnosed with POCD (24.7%). Diabetes history (OR = 8.391 [2.208-31.882], P = 0.012), fasting over 3 days after surgery (OR = 5.236 [1.998-13.721], P = 0.001) and an SIRS score of > 3 on the second day after surgery (OR = 6.995 [1.948-25.111], P = 0.003) were risk factors for early POCD in colorectal cancer patients. CONCLUSION: The risk factors for early POCD after colorectal surgery included diabetes history, fasting over 3 days, and an SIRS score of > 3 on the second day.

LncRNA X inactive specific transcript contributes to neuropathic pain development by sponging miR-154-5p via inducing toll-like receptor 5 in CCI rat models.

Noncoding RNAs, including long non-coding RNAs (lncRNAs) and microRNAs, are involved in the development of neuropathic pain. Currently, we investigated that lncRNA X inactive-specific transcript (XIST) and toll-like receptor 5 (TLR5) were greatly upregulated in chronic constriction injury rat models, whereas miR-154-5p (microRNA-154-5p) was significantly downregulated. Bioinformatics analysis was used to predict miR-154-5p as a target gene of XIST, and dual-luciferase reporter tests proved the correlation between them. We observed that miR-154-5p was negatively modulated by XIST in vitro. XIST overexpression markedly induced neuropathic pain development in rats with chronic constriction injury, whereas the upregulation of miR-154-5p could reverse this phenomenon. Furthermore, TLR5 was demonstrated to be a target gene of miR-154-5p by using bioinformatics predictions. miR-154-5p negatively regulated TLR5 expression in vitro, and TLR5 was able to promote neuropathic pain development. In addition, overexpressing miR-154-5p can reverse the role of TLR5 neuropathic pain in vivo. Taken these together, we indicated that XIST could increase TLR5 expression by acting as a sponge of miR-154-5p in neuropathic pain development. This study revealed that XIST can contribute to neuropathic pain progression in rats through decreasing miR-154-5p and increasing TLR5. The XIST/miR-154-5p/ TLR5 axis can be provided as a novel therapeutic target in treating neuropathic pain.

Network meta-analysis of percutaneous vertebroplasty, percutaneous kyphoplasty, nerve block, and conservative treatment for nonsurgery options of acute/subacute and chronic osteoporotic vertebral compression fractures (OVCFs) in short-term and long-term effects.

BACKGROUND: Osteoporotic vertebral compression fractures (OVCFs) commonly afflicts most aged people resulting back pain, substantial vertebral deformity, functional disability, decreased quality of life, and increased adjacent spinal fractures and mortality. Percutaneous vertebral augmentation (PVA) included percutaneous vertebroplasty (PVP) and percutaneous kyphoplasty (PKP), nerve block (NB), and conservative treatment (CT) are used for the nonsurgery treatment strategy of OVCFs, however, current evaluation of their efficacy remains controversial. METHODS AND ANALYSIS: A systematic literature search was carried out in PubMed, EMBASE, Web of Knowledge, and the Cochrane Central Register of Controlled Trials up to October 31, 2017. Randomized controlled trials (RCTs) were compared PVP, PKP, NB, or CT for treating OVCFs. The risk of bias for each trial was rated according to the Cochrane Handbook. Mean differences (MDs) with 95% confidence intervals (CIs) were utilized to express VAS (visual analog scale) outcomes. The network meta-analysis (NMA) of the comparative efficacy measured by change of VAS on acute/subacute and chronic OVCFs was conducted for a short-term (<4 weeks) and long-term (≥6-12months) follow-up with the ADDIS software. RESULTS: A total of 18 trials among 1994 patients were included in the NMA. The PVA (PVP and PKP) had better efficacy than CT. PKP was first option in alleviating pain in the case of the acute/subacute OVCFs for long term, and chronic OVCFs for short term and long term, while PVP had the most superiority in the case of the acute/subacute OVCFs for short term. NB ranks higher probability than PKP and PVP on acute/subacute OVCFs in short and long-term, respectively. CONCLUSIONS: The present results suggest that PVA (PVP/PKP) had better performance than CT in alleviating acute/subacute and chronic OVCFs pain for short and long-term. NB may be used as an alternative or before PVA, as far as pain relief is concerned. Various nonsurgery treatments including CT, PVA (PVP/PKP), NB, or a combination of these treatments are performed with the goal of reducing pain, stabilizing the vertebrae, and restoring mobility.

The Diagnosis and Therapy of Degenerative Knee Joint Disease: Expert Consensus from the Chinese Pain Medicine Panel.

At present, there are many constantly updated guidelines and consensuses on the diagnosis and treatment of osteoarthritis both at home and abroad. The recommendations established using methods of evidence-based medicine has experienced strict research on controlling bias and promoting reproduction rate. As a result, the previous evidence was reevaluated, and a lot of changes were provoked in the diagnosis and treatment concept of osteoarthritis. However, several methods not recommended by foreign guidelines are still in use in the current clinical practice in China. On the one hand, Chinese experts have not reached extensive consensus on whether it is necessary to make changes according to foreign guidelines. On the other hand, almost all the current relevant guidelines are on osteoarthritis, but the lesions around knee joints which, as a whole, bear the largest weight in human body, cannot be ignored. For this purpose, Chinese Association for the Study of Pain (CASP) organized some leading experts to formulate this Chinese Pain Specialist Consensus on the diagnosis and treatment of degenerative knee osteoarthritis (DKOA) in combination with the guidelines in foreign countries and the expert experience of clinical practice in China. The consensus, which includes the definition, pathophysiology, epidemiology, clinical manifestation, diagnostic criteria, and treatments of DKOA, is intended to be used by first-line doctors, including pain physicians to manage patients with DKOA.

[Effects of dexmedetomidine on microcirculatory perfusion in rabbits with renal ischemia/reperfusion injury: quantitative evaluation with contrast-enhanced ultrasound].

OBJECTIVE: To investigate the effects of dexmedetomidine on renal microcirculatory perfusion in rabbits with renal ischemia/reperfusion (I/R) injury rabbit by quantitative analysis of contrast-enhanced ultrasound (CEUS). METHODS: Twenty- four New Zealand rabbits were randomly divided into 3 groups (8 in each), including a control group, renal I/R injury group and dexmedetomidine group. In the latter two groups, the right kidney of the rabbits was resected and I/R injury was induced in the left kidney. In dexmedetomidine group, the rabbits received an intraperitoneal dose of 10 µg/kg dexmedetomidine 30 min before renal ischemia, and 24 h after reperfusion, the renal size and renal artery resistance (RI) were measured, and renal cortex perfusion was observed by CEUS. The time-to-peak intensity (TTP), peak signal intensity (PSI), gradient between start frame to peak frame (Grad) and area under the curve (AUC) were quantitatively analyzed using the time-intensity curves. Pathological changes of the kidney were also observed. RESULTS: Compared with the control group, the rabbits in I/R and dexmedetomidine groups showed distinct changes of the renal size with obvious renal pathologies. RI, PPT and AUC all increased, and PSI and Grad decreased significantly in I/R and dexmedetomidine groups (P<0.05). Compared with I/R group, obvious improvement of the renal size and renal pathologies were observed in dexmedetomidine group, which showed significantly decreased RI, PPT and AUC and increased PSI and Grad (P<0.05). CONCLUSION: CEUS combined with the time-intensity curve parameters allows quantitative and dynamic analysis of the protective effects of dexmedetomidine on microcirculatory perfusion in rabbits with renal I/R injury.

The relationship between apolipoprotein E gene ε2/ε3/ε4 polymorphism and breast cancer risk: a systematic review and meta-analysis.

OBJECTIVE: We conducted a systematic review and meta-analysis aiming to assess the relationship between apolipoprotein E (APOE) gene ε2/ε3/ε4 polymorphism and breast cancer risk. METHODS: Yun-Long Liu and Hao-Min Zhang independently completed literature retrieval and data collection, and statistical analyses were performed by Stata. Individual odds ratio (OR) and 95% confidence interval (CI) were pooled in a random-effects model using the DerSimonian-Laird method. Heterogeneity was evaluated by I (2) statistic at a significance level of 50%. Publication bias was assessed by Egger's test. RESULTS: Eleven articles including 2,074 breast cancer patients and 2,372 controls were summarized. Using the most common allele ε3 as a reference, the ε2 (OR =0.87, 95% CI =0.72-1.05, P=0.154, I (2)=0.0%) and ε4 (OR =1.07, 95% CI =0.80-1.42, P=0.654, I (2)=71.8%) alleles were not found to be significantly associated with breast cancer risk in the overall analyses. Subgroup analyses revealed that the comparison of allele ε4 with ε3 was significant in Asians (OR =1.58, 95% CI =1.17-6.32, P=0.003, I (2)=12.1%) and in studies that used the restriction fragment length polymorphism (RFLP) genotyping method (OR =1.27; 95% CI =1.01-1.61, P=0.045, I (2)=34.3%), and was marginally significant in hospital-based studies (OR =1.33; 95% CI =0.98-1.79, P=0.065, I (2)=30.2%), without heterogeneity. Moreover, the presence of the ε2 allele was significantly associated with breast cancer in small studies (total sample size <500) (OR =0.73, 95% CI =0.54-1.00, P=0.052, I (2)=0.0%) without heterogeneity. The Egger's test indicated low probabilities of publication bias. CONCLUSION: We observed a significant association between APOE gene ε4 allele and breast cancer risk in Asian populations. Moreover, the findings of our subgroup analyses suggest that source of controls, genotyping platform, and sample size might be the potential causes of heterogeneity.

[Effects of ulinastatin on cognitive function in patients with coronary artery bypass grafting].

OBJECTIVE: To investigate the effects of ulinastatin(UTI) on postoperative cognitive function in patients undergoing coronary artery bypass grafting. METHODS: One hundred and twenty-seven patients undergoing elective coronary artery bypass surgery were randomly divided into three groups:high-dose UTI group(16000 U/kg i.v.), low-dose UTI group(8000 U/kg i.v.) and control group(normal saline). The levels of plasma cortisol were measured before and one day after surgery. The level of IL-6, IL-10, TNF-α and S100ß were measured before operation(T0), at open chest(T1), end of operation(T2), 6 h(T3)and 24 h(T4) after operation. A neuropsychological test scale was to evaluate the cognitive function 1 day before operation, 1 week and 3 months after operation. RESULTS: Ninety-three patients completed the study. There was no significant difference in general information of patients among three groups(P>0.05). The level of plasma cortisol one day after operation was significantly higher than that before operation in control group(P<0.01). The levels of plasma cortisol in high-dose UTI group and low-dose UTI group were lower than that of control group(P<0.01). In all groups, the level of plasma IL-6, IL-10, TNF-α and S100B increased remarkably at T2, T3, T4 compared to those at T0(all P<0.05). The level of plasma IL-6, TNF-α(at T2, T3, T4)and S100ß(at T3)in high-dose UTI group and low-dose UTI group were all lower than those of control group(P<0.05),while there were no significant differences between high-dose UTI group and low-dose UTI group(P>0.05). The incidence of postoperative cognitive dysfunction in POCD 1 week after operation in high-dose UTI and low-dose UTI groups(25.8% and 23.3%)was lower than that in control group(50.0%), while there were no significant difference 1 month after operation between high-dose UTI group(12.9%) or low-dose UTI group(16.7%)and control group(28.1%). The level of plasma S100ß at T2 of POCD patients(n=31)was higher than that of non-POCD group(n=62)(P<0.05). CONCLUSION: Ulinastatin can reduce the incidence of postoperative cognitive dusfunction 1 week after coronary artery bypass surgery, which might be associated with inhibition of inflammation and S100ß expression.

Celecoxib inhibits insulin-like growth factor 1 induced growth and invasion in non-small cell lung cancer.

Despite a large number of studies indicating that celecoxib plays an important role in the prevention and treatment of tumors, the detailed molecular mechanisms are not well understood. The aim of the present study was to investigate the effect of celecoxib on insulin-like growth factor 1 (IGF-1)-induced growth and invasion in non-small cell lung cancer (NSCLC). For these experiments, IGF-1-induced cell growth and invasion were analyzed in A549 cells in the presence and absence of celecoxib. The effects of celecoxib on the expression of phosphorylated type-1 IGF receptor (IGF-1R) and phosphorylated AKT (p-AKT) were examined using western blot analysis. The influence of celecoxib on IGF-binding protein-3 (IGFBP-3) expression was analyzed using ELISA. Celecoxib inhibited IGF-1-stimulated growth and invasion in a dose-dependent manner. Celecoxib also reduced the expression of IGF-1R, IGFBP-3 and phosphorylation of AKT. The results suggest that modulating the IGF axis may be a new mechanism for the anticancer effect of celecoxib on NSCLC.

Effects of adiponectin on acute lung injury in cecal ligation and puncture-induced sepsis rats.

BACKGROUND: The purpose of this study was to elucidate the possible beneficial effects of adiponectin (APN) on acute lung injury in a rat model of sepsis. METHODS: We subjected male Sprague-Dawley rats to cecal ligation and puncture (CLP) to establish sepsis models. We randomly animals divided into four groups: control (C), model (CLP), preemptive APN administration (APN plus CLP), and delayed APN administration (CLP plus APN). We killed the animals 24 h after CLP and collected blood samples to determine PaO2 and PaCO2. Lung samples were taken for histologic assessment and measurement of myeloperoxidase activity. We measured neutrophil and macrophage count and cytokine production (tumor necrosis factor-α and macrophage inflammatory protein-2) in bronchoalveolar lavage fluid. RESULTS: Histology findings and lung injury score analysis revealed acute lung injury in rats in the CLP group, whereas those in the APN-treated group had mild lung injury. The effects of sepsis on the increasing cell number in bronchoalveolar lavage fluid as well as the wet/dry weight ratio, neutrophil infiltration, and myeloperoxidase activity of lung tissue were significantly attenuated by APN administration. Adiponectin also significantly alleviated hypoxemia and hypercapnia resulting from the development of lung injury. In addition, in APN-treated rats, the levels of pulmonary inflammatory molecule (macrophage inflammatory protein-2) and cytokine (tumor necrosis factor-α) were down-regulated compared with the CLP group. CONCLUSIONS: Adiponectin administration ameliorates acute lung injury in a rat model of sepsis induced by CLP, no matter whether it is administrated before or after the onset of sepsis.

Effects of adiponectin on mortality and its mechanism in a sepsis mouse model.

The mortality of sepsis is increasing and conventional therapies for it have no better therapeutic effects. We investigated the effects of adiponectin (APN) on mortality and high mobility group box 1 (HMGB1) in polymicrobial sepsis mouse models. Sepsis models were established by cecal ligation and puncture (CLP) in BALB/c mice. Animals were randomly divided into four groups including control group (C group), model group (CLP group), early APN treatment group (APN + CLP group), and late APN treatment group (CLP + APN group). Mice in each group were killed at 6, 12, 24, and 48 hr after CLP, respectively, to collect samples for determining the levels of serum interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), high mobility group protein-1 (HMGB1), and the expression of lung tissue HMGB1 mRNA. The survival curves in the four groups were drawn. The mortality rates were significantly lower in APN + CLP (30%) and CLP + APN (40%) groups than in CLP group (80%) seven days after CLP. Serum levels of cytokines (IL-6 and TNF-α) and HMGB1 were significantly reduced (p < .05) in APN + CLP and CLP + APN groups compared with those of CLP group. There was a significant correlation between serum HMGB1 and lung HMGB1 mRNA (r = 0.891). The levels of HMGB1 and HMGB1 mRNA were higher in CLP, APN + CLP, and CLP + APN groups than in C group (p < .01), but were lower in APN + CLP and CLP + APN groups than in CLP group (p < .01). APN can reduce the mortality rate and plays an anti-inflammatory role in polymicrobial sepsis mouse models through inhibiting HMGB1.

Effects of propofol on the outcomes of rats with sepsis.

OBJECTIVE: To explore the effects of propofol on the outcomes of rats with sepsis. METHODS: Cecal ligation and puncture (CLP) was performed in 48 male Wistar rats. The 48 rats were divided into four groups (each group with 12 rats) including control group (C group), model group (CLP group), early propofol treatment group (PPF+CLP group) and late propofol treatment group (CLP+PPF group). Rats in each group were killed 24 h and 48 h after CLP, respectively, to collect blood and lung tissue samples for determining the level of serum high mobility group box-1 (HMGB1), the expression of lung tissue HMGB1 mRNA and the functional parameters of organs. The survival curves were drawn. RESULTS: There was a significant correlation between the serum HMGB1 and the lung HMGB1 mRNA (r = 0.93). The levels of HMGB1 and HMGB1 mRNA were higher in CLP, PPF+CLP, and CLP+PPF groups than in C group (P < 0.05), but were lower in PPF+CLP and CLP+PPF groups than in CLP group (P < 0.01). Compared with CLP group, the levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), blood urea nitrogen (BUN), creatinine (Cr), and creatine kinase (CK) were significantly decreased in PPF+CLP and CLP+PPF groups (P < 0.01). The survival rates of rats were higher in PPF+CLP and CLP+PPF groups than in CLP group (P < 0.01). CONCLUSIONS: Propofol can significantly improve the survival rate, inhibit HMGB1 expression and protect important organs such as the liver, kidney, and heart in rats with sepsis.