谷氨酰胺诱导热休克蛋白的表达及对肺损伤的保护作用的研究

目的 通过利用谷氨酰胺(Gln)诱导大鼠热休克蛋白70(HSP70)表达以探讨HSP70对急性肺损伤的保护作用.方法 雄性SD大鼠42只随机分成三组:O组为油酸损伤组(经尾静脉按25mL/kg量注入生理盐水后注入油酸);G组为干预组(经尾静脉按25mL/kg量注入3%Gln溶液后注入油酸);C组为正常对照组(经尾静脉注...     

Low basal levels of circulating adiponectin in patients undergoing coronary stenting predict in-stent restenosis, independently of basal levels of inflammatory markers: lipoprotein associated phospholipase A2, and myeloperoxidase

Objective

The aim of this study was to find a pre-interventional marker with the capacity to predict in-stent restenosis (ISR). Considering the anti-atherosclerotic role of adiponectin (APO), an adipocytokine with anti-inflammatory, anti-proliferative, anti-oxidative and anti-thrombotic properties, low plasma levels of APO might be correlated with the risk of ISR. We investigated the correlations between the plasma levels of APO and two markers of inflammation: lipoprotein associated phospholipase A2 (Lp-PLA2) and myeloperoxidase (MPO).

Design and methods

80 patients with angiographically significant stenosis underwent percutaneous coronary intervention (PCI) with bare metal stent. Plasma APO concentration and plasma Lp-PLA2 and MPO activities were evaluated immediately before and after PCI, then followed-up at 24, 48, 72 h, and at 1, 3, 6 months, respectively. ISR was evaluated at 6 months after stenting by follow-up coronary angiograms, and it was defined as > 50% stenosis of the target lesion.

Results

ISR was present in 33.75% of patients. Baseline APO plasma concentration, measured before PCI, was lower in ISR patients than those without ISR [3.97 (± 1.05) vs 6.65 (± 2.95) μg/mL respectively, p < 0.001]. The patients with APO values less than 4.9 μg/mL at discharge were more susceptible to develop ISR (odd ratio, 4.27; 95% CI, 1.56–11.72, p < 0.001). ISR rate was independent of inflammation markers Lp-PLA2 and MPO baseline values, measured before PCI.

Conclusions

The persistence of a low APO plasma level at discharge and 6 months afterwards may be used as a clinically useful marker for ISR prediction in patients undergoing PCI.     

Rationale and design of ENDEAVOR: A sequential phase 2b–3 randomized clinical trial to evaluate the effect of myeloperoxidase inhibition on symptoms and exercise capacity in heart failure with preserved or mildly reduced ejection fraction

Aims

Mitiperstat (formerly AZD4831) is a novel selective myeloperoxidase inhibitor. Currently, no effective therapies target comorbidity-induced systemic inflammation, which may be a key mechanism underlying heart failure with preserved or mildly reduced ejection fraction (HFpEF/HFmrEF). Circulating neutrophils secrete myeloperoxidase, causing oxidative stress, microvascular endothelial dysfunction, interstitial fibrosis, cardiomyocyte remodelling and diastolic dysfunction. Mitiperstat may therefore improve function of the heart and other organs, and ameliorate heart failure symptoms and exercise intolerance. ENDEAVOR is a combined, seamless phase 2b–3 study of the efficacy and safety of mitiperstat in patients with HFpEF/HFmrEF.

Methods

In phase 2b, approximately 660 patients with heart failure and ejection fraction >40% are being randomized 1:1:1 to mitiperstat 2.5 mg, 5 mg or placebo for 48 weeks. Eligible patients have baseline 6-min walk distance (6MWD) of 30–400 m with a <50 m difference between screening and randomization and Kansas City Cardiomyopathy Questionnaire total symptom score (KCCQ-TSS) ≤90 points at screening and randomization. The dual primary endpoints are change from baseline to week 16 in 6MWD and KCCQ-TSS. The sample size provides 85% power to detect placebo-adjusted improvements of 21 m in 6MWD and 6.0 points in KCCQ-TSS at overall two-sided alpha of 0.05. Safety is monitored throughout treatment, with a focus on maculopapular rash. In phase 3 of ENDEAVOR, approximately 820 patients will be randomized 1:1 to mitiperstat or placebo.

Conclusion

ENDEAVOR is the first phase 2b–3 study to evaluate whether myeloperoxidase inhibition can improve symptoms and exercise capacity in patients with HFpEF/HFmrEF.     

髓过氧化物酶和过氧化氢酶基因多态性及其酶活力与燃煤污染型地方性砷中毒关系的探讨

目的 了解燃煤污染型地方性砷中毒患者体内髓过氧化物酶(MPO)基因和过氧化氢酶(CAT)基因的多态性及其酶活力,分析其与砷中毒发生的关系.方法 以贵州省兴仁县交乐村燃煤污染型地方性砷中毒病区的130例砷中毒患者为病例(砷中毒)组,以居住在距病区约13 km非砷污染大果垛村的140例健康居民为对照组.采集两组人群静脉血,采用PCR-限制性片段长度多态性(PCR-RFLP)方法检测MPO基因-463 G/A位点和CAT基因-262C/T位点的多态性;采用紫外分光光度法检测MPO活力;采用比色法检测CAT活力.结果 砷中毒组MPO-463G/A位点GG、GA和AA基因型分布频率为47.24%(60/127)、44.09%(56/127)和8.67%(11/127),对照组为42.34%(58/137)、48.17%(66/137)和9.49%(13/137),两组比较差异无统计学意义(χ2=0.642,P>0.05).砷中毒组CAT-262C/T位点CC、CT和TT基因型分布频率为65.60%(82/125)、28.80%(36/125)和5.60%(7/125),对照组为76.51%(101/132)、18.94%(25/132)和4.55%(6/132),两组比较差异无统计学意义(χ2=3.845,P>0.05).未发现MPO-463G/A位点和CAT-262C/T位点多态性与砷中毒发病风险(比值比,OR)的关联度有统计学意义(MPO:Oradj=1.36,95%CI:0.74～2.50;CAT:Oradj=1.35,95%CI:0.69～2.63).砷中毒组MPO和CAT活力分别为(25.30±8.70)U/L和(2.80±1.09)×103U/L,对照组分别为(22.76±7.59)U/L和(3.90±1.01)×103U/L,两组比较差异有统计学意义(F值分别为0.760、0.855,P均<0.05).MPO-463G/A和CAT-262C/T不同基因型个体MPO和CAT酶活力比较,差异无统计学意义(F值分别为1.312、2.822,0.151、0.036,P均>0.05).结论 未发现MPO基因-463G/A位点和CAT基因-262C/T位点多态性与燃煤污染型地方性砷中毒的发病风险有关;砷可致MPO和CAT酶活力改变,此改变可能不受MPO-463G/A和CAT-262C/T多态性的影响.     

Anti-inflammatory effect of kaurenoic acid, a diterpene from Copaifera langsdorffii on acetic acid-induced colitis in rats

Kaurenoic acid, a diterpene from Copaifera langsdorffii (Leguminaceae), was evaluated on rat colitis induced by acetic acid. Rats were pretreated orally (15 and 2 h before) or rectally 2 h before induction of colitis with kaurenoic acid (50 and 100 mg/kg) or vehicle (1 ml, 3% DMSO). Colitis was induced by intracolonic instillation of a 2 ml of 4% (v/v) acetic acid solution and, 24 h later, the colonic mucosal damage was analysed macroscopically for the severity of mucosal damage, the myeloperoxidase (MPO) activity and the malondialdehyde (MDA) levels in the colon segments. A marked reduction in gross damage score (52% and 42%) and wet weight of damaged colon tissue (39% and 32%) were observed in rats that received 100 mg/kg kaurenoic acid, respectively, by rectal and oral routes. This effect was confirmed biochemically by a two- to three-fold reduction of colitis associated increase in MPO activity, the marker of neutrophilic infiltration and by a marked decrease in MDA level, an indicator of lipoperoxidation in colon tissue. Furthermore, light microscopy revealed the marked diminution of inflammatory cell infiltration and submucosal edema formation in the colon segments of rats treated with the test compound. These findings indicate the anti-inflammatory potential of kaurenoic acid in acetic acid-induced colitis.     

大鼠心肌缺血再灌注模型中中性粒细胞与心肌损伤程度的相关性研究

目的；观察大鼠心肌缺血再灌注模型中中性粒细胞与心肌损伤程度的相关性，为进一步探讨机理和寻求新药提供依据。方法：采用冠脉结扎建立大鼠心肌缺血再灌注模型，分别在不同时程测定血清中肌酸激酶（CPK）、心肌组织中脂质过氧化物（MDA）含量，采用测定髓过氧化物酶（MPO）活性来定量分析中性粒细胞。结果；随着缺血30min后再灌注时间的增加 ，CPK、MDA和MPO都呈现出时间相关性，而且在再灌注2h时都达到峰值。结论：在大鼠心肌缺血再灌注损伤中心肌组织的损伤程度与心肌组织中浸润的中性粒细胞有密切相关性。     

Prospective evaluation of thracic-duct drainage in the treatment of respiratory failure complicating severe acute pancreatitis

Thoracic duct drainage (TDD) may be of value for removing toxic substances released by the inflamed pancreas and which are responsible for lung damage. We have prospectively assessed the efficacy of TDD in improving pulmonary gas exchange in 12 patients with severe acute pancreatitis (SAP) complicated by persistent respiratory failure despite standard conservative treatment including peritoneal dialysis in 8 patients. In group A were 6 patients (mean Ranson score=7.3) with adult respiratory distress syndrome (ARDS) and in group B were 6 hypoxemic patients (mean Ranson score=6.6) judged to be at risk of developing ARDS. The duration of TDD ranged from 3 to 10 days and the total amount of drained lymph (L) varied from 770 to 15 600 ml. Immunoreactive trypsin levels were significantly higher in L when compared to blood in both groups. Leukocyte myeloperoxidases in L (normal value < than 332±82 ng/ml in plasma) were increased in 5 of 5 group A patients (830±317 ng/ml) and in 3 of 6 patients in group B (671±467 ng/ml). After TDD pulmonary gas exchange as measured by median PaO₂/FiO₂ (mmHg) improved from 148±60 to 285±42 in group A and from 192±37 to 330±42 in group B (p<0.05). All patients were weaned after ventilation for a mean of 8 days in group A and 4 days in group B. All patients survived apart from 1 group B patient who died of sepsis on day 34. These data suggest that TDD, by allowing removal of potential mediators of lung injury is of major therapeutic value in ARDS complicating SAP. This approach may also prevent further respiratory impairment in susceptible patients.     

A low-morbidity murine model of peritonitis

PURPOSE: Peritonitis continues to be a major source of mortality and morbidity in patients undergoing abdominal surgery. The aim of this study was to develop a nonfatal model of bacterial peritonitis in mice so that we could study aspects of the pathobiology and treatment of peritonitis in an in vivo model. METHODS: Mice were inoculated via a midline laparotomy with 0.5 mg of zymosan in 0.1 ml of saline into the subomental space. At 24, 48, and 96 hours after treatment, animals were killed, and analysis was performed to determine the degree of peritoneal inflammation. End points included intraperitoneal cellular influx, tumor necrosis factor-alpha concentrations, and myeloperoxidase activity. In addition, peritoneal lavage fluid was plated onto blood agar for analysis of bacterial colony-forming units. There were 40 mice in each group. RESULTS: There were no deaths in either group. Facultative Gram-negative bacteria were cultured from the peritoneal cavities of zymosan-treated animals at 24 and 48 hours after insult (colony-forming unit counts of 92 ± 11 vs. 0 in control animals). In the zymosan-treated animals, there were significantly increased numbers of inflammatory cells (especially neutrophils) in the peritoneal cavity at 24 and 48 hours after treatment; these numbers returned to control levels by 96 hours. Myeloperoxidase activity was also elevated both in the peritoneal fluid (2.4 × 10–4 units/ml compared with 1.6 × 10–4 units/ml, P < 0.05) and in remote organs (i.e., lung, P < 0.05; liver, P < 0.001; and kidney, P < 0.05) at 24 hours after treatment. There was no significant difference in tumor necrosis factor-alpha levels between zymosan-treated and control mice in either serum or peritoneal fluid at any time point investigated. There was no mortality in either the zymosan-treated or control animals. CONCLUSION: In this model of bacterial peritonitis in mice, we have demonstrated how the peritoneal cavity can resolve a relatively localized inflammatory insult within 96 hours of induction. This response is characterized by a cellular influx of predominantly neutrophils and macrophages and by pronounced oxidative activity. We will use this in vivo model to characterize aspects of the pathobiology and treatment of peritonitis.     

Multilineage Involvement of Light Microscopic Myeloperoxidase-Negative Acute Leukemia

We report an instructive case of diffuse large B-cell lymphoma presenting as acute heart failure. A 69-year-old human immunodeficiency virus-negative man was admitted to our hospital for general fatigue. A computed tomographic scan of the chest and abdomen showed pericardial effusion, but there was no evidence of tumor masses, lymph node enlargement, or hepatosplenomegaly. During the chemotherapy, increased lactate dehydrogenase and pleural effusion appeared. The tumor cells in the effusion showed positivity for CD5, CD19, CD20, kappa chain, and Bcl-2 and negativity for CD10 and CD23. The chromosomes showed t(8;14)(q24;q32) with c-myc/immunoglobulin (Ig)H rearrangement, and the MIB-1 index was not high (60%). Neither human herpes virus 8 nor Epstein-Barr virus DNA was detected in the cells by polymerase chain reaction. The response to chemotherapy was very poor, and the patient died 4 months after the diagnosis. A spectrum of the symptoms of CD5+ lymphoma encompasses pericardial effusion and also can accompany c-myc/IgH rearrangement.     

冠心病合并焦虑抑郁患者血清MPO和LXA水平的变化研究

目的观察冠心病合并焦虑抑郁患者体内血清髓过氧化物酶(MPO)以及脂氧素A4(LXA4)的变化及其临床意义。方法选择冠心病患者共156例,根据医院焦虑抑郁情绪评定表(HADS)得分将冠心病患者分为抑郁焦虑组(81例)和非抑郁焦虑组(75例),另匹配80例体检者为对照,检测MPO、LXA4及两者比值。结果冠心病患者血清MPO、LXA4及两者比值(M/L)显著高于对照组。抑郁焦虑组血清MPO水平、M/L显著高于非抑郁焦虑组,但LXA4在两组中无统计学差异(P0.05)。冠心病患者血清MPO、LXA4及两者比值与HADS亚量表得分均具有较好的相关性(r=0.439~0.581,P均0.05)。结论冠心病患者存在血清MPO、LXA4水平及其比值上升,对于合并焦虑抑郁之冠心病病人而言,炎症及其消退间的平衡失调更加明显。