Current status and prospects of basic research and clinical application of mesenchymal stem cells in acute respiratory distress syndrome

Acute respiratory distress syndrome (ARDS) is a common and clinically devastating disease that causes respiratory failure. Morbidity and mortality of patients in intensive care units are stubbornly high, and various complications severely affect the quality of life of survivors. The pathophysiology of ARDS includes increased alveolar–capillary membrane permeability, an influx of protein-rich pulmonary edema fluid, and surfactant dysfunction leading to severe hypoxemia. At present, the main treatment for ARDS is mechanical treatment combined with diuretics to reduce pulmonary edema, which primarily improves symptoms, but the prognosis of patients with ARDS is still very poor. Mesenchymal stem cells (MSCs) are stromal cells that possess the capacity to self-renew and also exhibit multilineage differentiation. MSCs can be isolated from a variety of tissues, such as the umbilical cord, endometrial polyps, menstrual blood, bone marrow, and adipose tissues. Studies have confirmed the critical healing and immunomodulatory properties of MSCs in the treatment of a variety of diseases. Recently, the potential of stem cells in treating ARDS has been explored via basic research and clinical trials. The efficacy of MSCs has been shown in a variety of in vivo models of ARDS, reducing bacterial pneumonia and ischemia-reperfusion injury while promoting the repair of ventilator-induced lung injury. This article reviews the current basic research findings and clinical applications of MSCs in the treatment of ARDS in order to emphasize the clinical prospects of MSCs.     

尿铜蓝蛋白、肾损伤因子1与糖尿病肾病患者肾功能的关系及对预后不良的预测价值研究

摘要 目的：探讨尿铜蓝蛋白（CP）、肾损伤因子1（KIM-1）与糖尿病肾病（DKD）患者肾功能的关系及对预后不良的预测价值。方法：回顾性分析2017年1月～2019年1月陆军第八十二集团军医院肾内科收治的160例DKD患者（DKD组）的临床资料,随访3年,根据是否发展为终末期肾脏疾病（ESRD）分为预后不良组42例和预后良好组118例,另选取同期56例单纯2型糖尿病（T2DM）患者作为T2DM组和47例体检健康者作为对照组。采用微量法和酶联免疫吸附试验法检测尿CP、KIM-1水平,并计算尿白蛋白/肌酐比值（UACR）和估算肾小球滤过率（eGFR）。通过Spearman相关性分析DKD患者尿CP、KIM-1与UACR、eGFR的相关性,单因素和多因素Logistic回归分析DKD患者预后不良的影响因素,受试者工作特征（ROC）曲线分析尿CP、KIM-1对DKD患者预后不良的预测价值。结果：随访3年,160例DKD患者有42例发展为ESRD,预后不良发生率为26.25％（42/160）。DKD组尿CP、KIM-1、UACR高于T2DM组、对照组,eGFR低于T2DM组、对照组（P＜0.05）;T2DM组尿CP、KIM-1、UACR高于对照组,eGFR低于对照组（P＜0.05）。Spearman相关性分析显示,DKD患者尿CP、KIM-1与UACR呈正相关（P均＜0.001）,与eGFR呈负相关（P均＜0.001）。多因素Logistic回归分析显示,高血压、DKD分期4期和糖化血红蛋白（HbA1c）（较高）、低密度脂蛋白胆固醇（LDL-C）（较高）、UACR（较高）、尿CP（较高）、尿KIM-1（较高）为DKD患者预后不良的独立危险因素（P＜0.05）,eGFR（较高）为独立保护因素（P＜0.05）。ROC曲线分析显示,尿CP、KIM-1联合预测DKD患者预后不良的曲线下面积大于各指标单独预测。结论：DKD患者尿CP、KIM-1升高与肾功能降低和预后不良密切相关,尿CP、KIM-1联合预测DKD患者预后不良的价值较高。     

A comparative study of the effects of iloprost and PGE1 on pulmonary arterial pressure and edema formation in the isolated perfused rat lung model

Isolated lungs from male Wistar rats (250–350 g) were perfused at a constant flow rate (10 ml/min, non -recirculating) with Krebs-Ringerbicarbonate buffer containing 4.5 % bovine serum albumin, and were ventilated at a positive pressure (60 breaths/min). Pulmonary arterial pressure and lung weight (as a measure of edema formation) were recorded continuously. After an equilibration period of 20 minutes the various test compounds were added to the perfusion fluid and experimental recording was continued for another 60 minutes.The effects of the stable PGI₂-mimetic, iloprost, of PGE₁, and of the biologically active PGE₁-metabolite, 13,14-dihydro-PGE,, were evaluated in this model (n=6). Iloprost showed slight, but not significant vasodilation; however, lung weight remained unchanged. PGE₁ and 13,14-dihydro-PGE₁ also caused slight vasodilation, but in contrast to iloprost these compounds induced distinct pulmonary edema. The lung weight gain was discernible at concentrations of 2.8 × 10^-6 mol/1 (significant at 2.8 × 10^-5 mol/l; p 0.05) and was accompanied by increases in the wet-weight to dry-weight ratios. These findings were duplicated in a second set of experiments (n = 6) from which the same results were obtained.The results indicate that at high concentrations PGE, (and 13,14-dihydro-PGE₁), but not iloprost, can induce pulmonary edema in rats probably by increasing the permeability of the pulmonary vasculature.     

Phosphorylation of Myristoylated Alanine-Rich C Kinase Substrate (MARCKS) by Proline-Directed Protein Kinases and Its Dephosphorylation

Abstract: Excitatory amino acid (EAA) neurotransmitters may play a role in the pathophysiology of traumatic injury to the CNS. Although NMDA receptor antagonists have been reported to have therapeutic efficacy in animal models of brain injury, these compounds may have unacceptable toxicity for clinical use. One alternative approach is to inhibit the release of EAAs following traumatic injury. The present study examined the effects of administration of a novel sodium channel blocker and EAA release inhibitor, BW1003C87, or the NMDA receptor-associated ion channel blocker magnesium chloride on cerebral edema formation following experimental brain injury in the rat. Animals (n = 33) were subjected to fluid percussion brain injury of moderate severity (2.3 atm) over the left parietal cortex. Fifteen minutes after injury, the animals received a constant infusion of BW1003C87 (10 mg/kg, i.v.), magnesium chloride (300 µmol/kg, i.v.), or saline over 15 min (2.75 ml/kg/15 min). In all animals, regional tissue water content in brain was assessed at 48 h after injury, using the wet weight/dry weight technique. In saline-treated control animals, fluid percussion brain injury produced significant regional brain edema in injured left parietal cortex ( p < 0.001), the cortical area adjacent to the site of maximal injury ( p < 0.001), left hippocampus ( p < 0.001), and left thalamus ( p = 0.02) at 48 h after brain injury. Administration of BW1003C87 15 min postinjury significantly reduced focal brain edema in the cortical area adjacent to the site of maximal injury ( p < 0.02) and left hippocampus ( p < 0.01), whereas magnesium chloride attenuated edema in left hippocampus ( p = 0.02). These results suggest that excitatory neurotransmission may play an important role in the pathogenesis of posttraumatic brain edema and that pre- or post-synaptic blockade of glutamate receptor systems may attenuate part of the deleterious sequelae of traumatic brain injury.     

Impairment of Protein Synthesis in the Retinal Tissue in Diabetic Rabbits: Secondary Reduction of Fast Axonal Transport

Protein biosynthesis in the retina and fast axonal transport along the optic pathway were studied in rabbits in which diabetes had been experimentally induced. Retinal protein biosynthesis and axonal transport were significantly reduced in the diabetic rabbits, and the reduction was correlated to the severity of the diabetes. The "somal delay time' was only slightly elongated and the O/R ratio was fairly constant in the various levels of blood glucose; thus intrasomal protein movement seems to be less affected in diabetic rabbits. Velocity and the distribution pattern of axonally transported protein remained unaffected in the diabetic rabbits. These findings suggest that a disturbance in the metabolism in the cell body is the most important factor related to quantitative reduction of fast axonal transport in diabetic rabbits.     

Alterations of Inositol Lipid Metabolism of Rat Sciatic Nerve in Streptozotocin-Induced Diabetes

Abstract: The composition and metabolism of rat sciatic nerve phospholipids were studied 20 weeks after induction of chronic diabetes by intraperitoneal injection of streptozotocin (50 mg/kg). On a wet weight basis the nerves from the diabetic animals showed a 7% decrease in total phospholipid from that of controls and a relative decrease in phosphatidylinositol. Incubations of isolated sciatic nerves of diabetic rats in a medium containing [³³P]orthophosphate gave decreased labeling of phosphatidylinositol and substantial changes in the labeling pattern of phosphatidylinositol phosphate and 4,5-bisphosphate from that of controls. The ratio of label in these polyphosphoinositides decreased from 2.5 for normal nerve to about 1.0 for diabetic nerve within a 2-h incubation period. These metabolic alterations were not observed in acutely diabetic animals 5 days after streptozotocin (100 mg/kg) administration. Because polyphosphoinositides may be involved in the control of membrane permeability during axonal conduction, alterations in their relative amounts or turnover rates could be related to the physiological changes of early diabetic neuropathy.     

The effect of streptococcus on the persistence of Brugia malayi and on the production of elephantiasis in cats

Cats were exposed to 200 Brugia malayi larvae on one hind foot over a 3 week period. Six weeks after the initial exposure to B. malayi, 10 of the cats were challenged on both hind legs with a Group G streptococcus. The remaining 10 cats were not exposed to the streptococcus. Following bacterial challenge, the B. malayi-infected leg of 9 of 10 cats displayed sequelae including erysipelas and abscesses. In addition, 5 of the affected legs had an elephantoid appearance, both by gross observation and as seen at necropsy 10 weeks after the initial B. malayi infection. The contralateral, uninfected leg of each cat remained normal in appearance. Histologic processing and examination of the elephantoid tissue showed it to be collagen; eosinophils and mast cells were plentiful in the collagen matrix. In the controls, only 1 animal displayed erysipelas and no abscesses were seen. Lymphedema seen in the B. malayi-infected leg of 5 control cats was less extensive than in uninfected cats challenged with streptococci and at necropsy no significant collagen matrix was evident. The location and number of worms in the lymphatics were noted. This study demonstrated that secondary microbial infections can contribute to the causation of elephantiasis under certain circumstances and that developing B. malayi were in some way adversely affected by the streptococcal involvement of the filaria-infected lymphatics.     

不同剂量熊果酸干预糖尿病小鼠视网膜病变的作用及机制研究

目的:探究不同剂量熊果酸(UA)干预糖尿病小鼠视网膜病变的作用及机制。方法:选取雄性健康C57BL/6小鼠60只,其中50只按50 mg/kg的剂量一次性往小鼠尾静脉注射新鲜配置的四氯嘧啶生理盐水溶液构建小鼠糖尿病视网膜病变模型,随机分为5组,每组10只,分别为模型组、阳性对照组(小鼠玻璃体注射3μL 40 mg/m L的曲安奈德),低剂量UA干扰组(小鼠玻璃体注射3μL剂量为0.5μg/μL的UA)、中剂量UA干扰组(小鼠玻璃体注射3μL剂量为1.0μg/μL的UA),高剂量UA干扰组(小鼠玻璃体注射3μL剂量为2.0μg/μL的UA),余下10只小鼠作为正常对照组。观察各组小鼠对胰岛素敏感性、视网膜内糖代谢情况、小鼠视网膜神经节细胞(RGCs)凋亡情况,比较各组小鼠视网膜组织中血管内皮生长因子(VEGF)、环氧化酶-2(COX-2)、基质金属蛋白酶2(MMP-2)蛋白及其mRNA的表达情况。结果:建模后,正常对照组胰岛素抵抗指数(HOMA-IR)、视网膜含糖量、葡萄糖转运体-1(GLUT-1)与葡萄糖转运体-3(GLUT-3)含量、RGCs凋亡率、视网膜组织中VEGF、COX-2、MMP-2蛋白及其mRNA的表达量低于模型组(P0.05);经干扰后,阳性对照组、不同剂量UA干扰组HOMA-IR、视网膜含糖量、GLUT-1、GLUT-3的含量、RGCs凋亡率、视网膜组织中VEGF、COX-2、MMP-2蛋白及其mRNA的表达量低于模型组(P0.05),且随UA干扰剂量的升高而降低(P0.05)。结论:UA能够降低HOMA-IR和视网膜糖代谢能力,抑制RGCs的凋亡,对VEGF、COX-2、MMP-2蛋白及其mRNA的表达具有一定的抑制作用,高剂量UA对糖尿病小鼠视网膜病预防治疗效果较好。     

社区2型糖尿病患者血糖自我管理水平调查及并发糖尿病周围神经病变的影响因素分析

摘要 目的：调查社区2型糖尿病（T2DM）患者血糖自我管理水平及分析T2DM并发糖尿病周围神经病变（DPN）的影响因素。方法：于2016年6月~2017年6月期间采用整群随机抽样法随机抽取苏州市6个社区符合纳排标准的539例T2DM患者进行问卷调查,了解社区T2DM患者血糖自我管理水平情况,对患者进行体格检查并检测血生化指标,统计社区T2DM患者的DPN发生情况,采用多因素logistic回归分析T2DM患者并发DPN的影响因素。结果：本次研究共发放调查问卷539份,实际回收531份,其中T2DM并发DPN者86例,根据是否并发DPN将所有入选患者分为DPN组（n=86）和无DPN组（n=445）。社区T2DM患者的糖尿病自我管理行为量表（SDSCA）平均得分率为（49.38±5.23）%,DPN组和无DPN组在病程、体质量指数（BMI）、腰围、糖化血红蛋白（HbAlc）、空腹胰岛素（FINS）、低 密 度 脂 蛋 白（LDL-C）、血 尿 素 氮（BUN）、血肌酐（Cr）、合并外周动脉疾病（PAD）、合并糖尿病视网膜病变（DR）中比较差异有统计学意义（P<0.05）。多因素logistic回归分析结果显示：病程≥7年、HbAlc≥8 mmol/L、合并PAD、合并DR、BMI≥25 kg/m²是社区 T2DM患者并发DPN的危险因素（P<0.05）。结论：苏州市6个社区的T2DM患者血糖自我管理水平较低,且T2DM并发DPN的概率较高,病程≥7年、HbAlc≥8 mmol/L、合并PAD、合并DR、BMI≥25 kg/m²均是社区 T2DM患者并发DPN的危险因素,临床可对上述危险因素采取积极有效的措施,以有效降低T2DM并发DPN的发生率。     

大鼠脑缺血/再灌注过程中血流量和脑组织含水量的变化趋势*

目的:研究大鼠脑缺血/再灌注过程中血流量及与脑组织水含量变化的趋势。方法:选取5只成年SD雄性大鼠(n=5),参照改良Zea-Longa线栓法制备大鼠大脑中动脉缺血/再灌注模型,2 h后拔出线栓。利用PeriCam PSI血流灌注成像系统实时监测大鼠在缺血前及缺血5 min、30 min、1 h、2 h、再灌注5 min、30 min、1 h、2 h、4 h、6 h及24 h的血流灌注量,记录在ROI(感兴趣区)测量的数值。再选取15只成年SD雄性大鼠,分为Control组、缺血2 h、再灌注30 min、4 h及24 h组(n=3)。正常组不做任何处理,实验组按上述线栓法制备MCAO模型。取新鲜脑组织用干湿重法测定其左、右半球的水含量。结果:栓塞时缺血侧血流量逐渐下降,缺血2 h下降最低(P＜0.05);再灌注早期血流量恢复较大(P＜0.05),30 min时显著下降(P＜0.05),4 h明显上升(P＜0.05),24 h再次上升(P＜0.05)但低于缺血前血流量(P＞0.05)。脑组织水含量测量,缺血2 h组和再灌注30 min组与正常组无明显差异(P＞0.05);再灌4 h组和再灌24 h组明显增高(P＜0.05),且再灌24 h组明显高于再灌4 h组(P＜0.05)。结论:大鼠脑缺血/再灌注过程中血流量和脑组织中水含量的变化存在一定的规律,且脑组织中水含量与再灌注过程中血流量的变化有一定关系。