The protective effects of cyclosporin A on vascular permeability in sepsis rats / 药学学报

The protective effects of cyclosporin A (CsA), an inhibitor of mitochondrial permeability transition pore (MPTP), on vascular permeability in sepsis rats were investigated. Cecal ligation and puncture (CLP)-induced sepsis rats were used for in vivo studies, and the effects of CsA (1 and 5 mg·kg-1) on vascular permeability of lung, kidney, and intestine, mitochondrial respiratory control ratio, and the survival of the sepsis rats were observed. Lipopolysaccharide (LPS) was used for stimulating vascular endothelial cells (VECs) in vitro, and the effects of CsA on leakage of microvascular, immunofluorescence of zonula occludes-1 (ZO-1), and transendothelial electrical resistance (TER) were observed. All the animal welfare and experimental procedures are in accordance with the regulations of the Animal Ethics Committee of the Army Medical University. Compared with sham-operated group, the vascular permeability of lung, kidney, and intestine in sepsis rats increased significantly (P<0.05). Compared with conventional treatment group, CsA could significantly decrease the vascular permeability of lung, kidney, and intestine (P<0.05 or P<0.01), and prolong the survival period. The results of microcirculation also showed that CsA could significantly reduce the permeability of mesenteric venules in sepsis rats. At the cellular level, LPS stimulation significantly increased the permeability of vascular endothelial cells, including the decrease of transmembrane resistance and protein expression of ZO-1 (P<0.05). CsA can significantly reduce the increase of permeability of vascular endothelial cells induced by LPS stimulation (P<0.01). The function of mitochondria in the kidneys and intestines of sepsis rats was obviously impaired, and the respiratory control ratio of mitochondria was decreased. LPS significantly increased MPTP opening of VECs, while CsA significantly inhibited MPTP opening and improved mitochondrial function. CsA may protect mitochondrial function by inhibiting the opening of MPTP and play a protective role in the vascular permeability of sepsis rats. This study will provide an insight for the treatment of sepsis vascular leakage.

Tipos de cirugías arteriales en pacientes diabéticos / Types of arterial surgeries in diabetic patients

Introducción: Las cirugías arteriales en los pacientes diabéticos permiten disminuir las frecuencias de amputaciones que se realizan en estos pacientes. Objetivo: Exponer los principales tipos de cirugías arteriales en los miembros inferiores que se realizan en pacientes diabéticos y sus resultados. Métodos: Estudio de búsqueda y síntesis bibliográfica en el que consultaron y tamizaron 162 documentos (artículos, registros médicos y tesis) publicados en las bases de datos de sistemas referativos MEDLINE, PubMed y SciELO e indexadas en la Web of Sciencies, Scopus, Redalyc y Latindex, con la utilización de descriptores: cirugía revascularizadora, permeabilidad arterial, pie diabético, cirugía endovascular, endarterectomía, angioplastia transluminal percutánea. Esto generó que se seleccionara 43 artículos y tres registros médicos. Resultados: La técnica en la revascularización del sector aortoiliaco incluye la cirugía derivativa anatómica [by-passaorto-femoral (bi o uni)]y la extraanatómica [by-pass (axilo-femoral, fémoro-femoral), la endarterectomía y la cirugía endovascular en el sector iliaco. Las técnicas quirúrgicas a aplicar en el sector femoropoplíteo y distal son el by-pass secuencial, endarterectomía, simpatectomía, tratamiento endovascular. Es importante tener en cuenta las características de los pacientes por separado para la decisión del tipo de cirugía. Conclusiones: Las cirugías arteriales en el paciente diabético son diversas y para su éxito es necesario valorar siempre el riesgo quirúrgico y la anatomía de las lesiones de cada paciente(AU)

Introduction: Arterial surgeries in diabetic patients allow reducing the frequency of amputations that are performed in these patients. Objective: To show the main types of arterial surgery in the lower limbs performed in diabetic patients and their results. Methods: Bibliographic search and synthesis study in which 162 materials (articles, medical records and theses) published in the MEDLINE, PubMed and SciELO reference databases were searched and indexed in the Web of Sciencies, Scopus, Redalyc and Latindex, using as descriptors: revascularization surgery, arterial permeability, diabetic foot, endovascular surgery, endarterectomy, percutaneous transluminal angioplasty. This led to the quoting of 43 articles and three medical records. Results: The technique in the revascularization of the aorto iliac sector includes the anatomical derivative surgery [aorto-femoral by-pass (bi or uni)] and extra-anatomical [by-pass (axillo-femoral, femoro-femoral), endarterectomy and endovascular surgery in the iliac sector. The surgical techniques to be applied in the femoro popliteal and distal sectors are the sequential by-pass, endarterectomy, sympathectomy, and endovascular treatment. It is important to consider the characteristics of patients separately to decide the type of surgery. Conclusions: The arterial surgeries in the diabetic patient are diverse and for the success of them it is necessary to always assess the surgical risk and the anatomy of the lesions of each patient(AU)

Effect of ultrasound combined with SonoVue microbubbles on vascular permeability in hind limbs of rats / 上海交通大学学报（医学版）

Objective • To investigate the effect of 500 kHz pulsed ultrasound combined with SonoVue microbubbles on the vascular permeability of hind limbs in rats and the permeability dynamics for the duration. Methods • Eighty male Sprague Dawley rats were randomly divided into eight groups (n=10), including control group, only microbubble group (MB group), and microbubble combined with ultrasound groups (MB+US group). And MB+US groups classified into time subgroups according to the interval from the endpoint of ultrasound exposure to the injection of Evans blue (EB), included 2.5 min group, 5 min group, 10 min group, 20 min group, 30 min group and 60 min group. The change of vascular permeability was quantitively analyzed by detecting the content of EB after ultrasound irradiation. Meanwhile, four rats in each group were randomly selected. Two of them were performed hematoxylin-eosin (H-E) staining; and the rest of them underlied transmission electron microscope analysis. Results • The results of EB content detected from muscle samples demonstrated that the exposure of ultrasound in conjunction with microbubbles could alter the vascular permeability of hind limbs of rats. The optimal time window for extravasation was within 30 min after ultrasound exposure. And the permeability could return to the normal status 60 min after ultrasound irradiation. There was no apparent damage on arteries and muscles in the slices with H-E staining. From the observation of transmission electron microscope, the tight junctions between endothelial cells on the arterial wall were significantly widened in MB+US groups. Conclusion • The application of ultrasound with the frequency of 500 kHz combined with SonoVue microbubbles can reversibly change the vascular permeability of hind limbs in rats without obvious damage to the tissues.

In Vitro Effects of Plasma Collected From Rats Administered Naftopidil on Whole Urinary Bladder Preparation Isolated From Rats / 대한배뇨장애요실금학회지

PURPOSE: Alpha-1-adrenoceptor blockers (e.g., naftopidil) are prescribed for the treatment of male lower urinary tract symptoms. Although the mechanism of action of naftopidil has been studied in various organs, that in the urinary bladder remains unknown. To clarify the direct effects of naftopidil on this organ, activities were assessed in the isolated rat whole urinary bladder.METHODS: A total of 30 female rats were used. In Experiment 1, bladder activity was measured during a cumulative administration of 2.5–75μM naftopidil (n=7). In Experiment 2, rats were divided into 2 groups: control (n=10) and naftopidil (5 mg/animal/day, oral gavage, once-daily for 2 weeks) (n=13). After the treatment period, plasma was obtained from each rat. The urinary bladders were harvested from the control rats. Isovolumetric rhythmic bladder contractions were induced at above the threshold volume, and intravesical pressure was recorded. Control plasma was added to the organ bath; after subsequent wash-out, plasma collected from rats administered naftopidil was added. In Experiment 3, the plasma levels of monoamines and amino acids were quantified using the individual plasma prepared in the Experiment 2.RESULTS: Cumulative dosing with naftopidil did not change the interval between spontaneous contractions compared to the interval at baseline. After adding control plasma, the interval was shortened compared to the baseline (P=0.008). The plasma collected from rats administered naftopidil suppressed the shortening of the interval compared to the control plasma (P=0.041). Naftopidil resulted in a decrease in the level of noradrenaline (P=0.009) and an increase in that of glycine (P=0.014).CONCLUSIONS: Although naftopidil did not directly act on the interval between spontaneous contractions of the urinary bladder, the plasma collected from rats administered naftopidil, with changing levels of monoamines and amino acids, may suppressed shortening the interval.

Clinical Value of Extravascular Lung Water Monitoring for Rapid Recovery in Pediatric Patients After Complete Repair of Tetralogy of Fallot / 中国循环杂志

Objective: To explore the clinical value of extravascular lung water monitoring for rapid recovery in pediatric patients after complete repair of tetralogy of Fallot (TOF). Methods: A total of 43 pediatric patients received complete repair of TOF were studied. The pulse contour cardiac index (PCCI), global end diastolic volume index (GEDI), stroke volume variation (SVV), systemic vascular resistance index (SVRI), global ejection fraction (GEF), maximum of pressure increase in aorta (dPmax), extravascular lung water index (EVWI) and pulmonary vascular permeability index (PVPI) were recorded by pulse-indicated continuous cardiac output (PICCO) monitoring at immediately enter pediatric ICU (PICU) and 6h, 12h, 18h, 24h post-operation. Meanwhile, the heart rate, blood pressure, central venous pressure (CVP), left atrium pressure (LAP) and balance of liquid were monitored; mechanical ventilation time, PICU stay time, re-intubation,re-occlusion of major aortopulmonary collateral arteries (MAPCAs) and other complications were recorded. Based on post-operative mechanical ventilation time, the patients were divided into 2 groups: Rapid recovery (R) group, patients with mechanical ventilation≤24h, n=29 and Delayed recovery (D) group, patients with mechanical ventilation>24h, n=14. Results: Compared with group D, group R had the shorter mechanical ventilation time (14.2±8.0) h vs (86.3±44.5) h and PICU stay time (2.5±1.7) days vs (5.3±3.6) days, both P<0.05; decreased PVPI at immediately enter PICU and 6h, 12h, 18h, 24h post-operation as (4.9±1.3 vs 6.4±1.5),(5.1±1.8 vs 6.5±1.3),(4.8±2.0 vs 6.5±1.6),(4.4±1.1vs 6.9±1.8), (4.4±2.5 vs 6.5±2.2) respectively, all P<0.05; Lower ELWI at 12h and 18h post-operation as(20.9±6.1) ml/kg vs (26.8±5.7) ml/kg and(19.1±5.5) ml/kg vs (26.7±5.5)ml/kg, both P<0.05. Group R had no patient received re-occlusion of MAPCAs after operation, while Group D had 3. No death, no catheter-related complication occurred in either group. Conclusion: MAPCAs may increase extravascular lung water, pulmonary vascular permeability and cause lung perfusion, therefore affect the early recovery of complete repair of pediatric TOF. PICCO monitoring may conduct bedside quantitative observation of lung perfusion, combining with ELWI and PVPI, clinicians may identify and manage MAPCAs as necessity for rapid recovery in relevant patients.

Correlation between pulmonary vascular permeability index and calcitonin in acute respiratory distress syndrome associated with septic shock / 上海交通大学学报（医学版）

Objective · To analyze the assessment value of pulmonary vascular permeability index (PVPI) and procalcitonin (PCT) levels to the severity and prognosis of acute respiratory distress syndrome (ARDS) associated with septic shock.Methods·Clinic data of 100 ARDS patients admitted to Affiliated Hospital of Nantong University was analyzed retrospectively.The clinical data was collected as follows:gender,age,infection site,acute physiology,chronic health evaluation Ⅱ (APACHE Ⅱ),sequential organ failure (SOFA) score,serum PCT level,and hemodynamic parameters which were monitored by pulse indicator continuous cardiac output (PiCCO).Patients with septic shock associated with ARDS patients were divided into mild,moderate and severe groups.The patients were divided into survival group and death group according to the 28-day prognosis,and the differences in the parameters between two groups were analyzed,to evaluate PVPI and PCT in predicting the severity and prognosis of septic shock associated ARDS.Results · There were significant differences in PVPI and PCT between ARDS group associated with septic shock and not (P=0.000).PVPI and PCT increased with the severity of ARDS,and there was a statistically significant difference between the ARDS groups in different degrees of PVPI (P=0.000).Pearson correlation analysis showed that PVPI was positively correlated with APACHE Ⅱ score and SOFA score (r=0.554,P=0.000;r=0.431,P=0.000),and PCT was positively correlated with APACHE Ⅱ score and SOFA score (r=0.313,P=0.004;r=0.320,P=0.004).Receiver operating characteristic (ROC) curve analysis showed that the area under the ROC curve of the prognosis of ARDS patients with sepsis was significantly higher than those of the two groups.Conclusion · PVPI can assess the severity of ARDS in patients with septic shock,and PVPI and PCT are predictive factors of prognosis.The combination of PVPI and PCT contributes to early stage diagnosis of ARDS associated with septic shock.

Correlation between pulmonary vascular permeability index and calcitonin in acute respiratory distress syndrome associated with septic shock / 上海交通大学学报（医学版）

Objective: To analyze the assessment value of pulmonary vascular permeability index (PVPI) and procalcitonin (PCT) levels to the severity and prognosis of acute respiratory distress syndrome (ARDS) associated with septic shock. Methods: Clinic data of 100 ARDS patients admitted to Affiliated Hospital of Nantong University was analyzed retrospectively. The clinical data was collected as follows: gender, age, infection site, acute physiology, chronic health evaluation Ⅱ (APACHE Ⅱ), sequential organ failure (SOFA) score, serum PCT level, and hemodynamic parameters which were monitored by pulse indicator continuous cardiac output (PiCCO). Patients with septic shock associated with ARDS patients were divided into mild, moderate and severe groups. The patients were divided into survival group and death group according to the 28-day prognosis, and the differences in the parameters between two groups were analyzed, to evaluate PVPI and PCT in predicting the severity and prognosis of septic shock associated ARDS. Results: There were significant differences in PVPI and PCT between ARDS group associated with septic shock and not (P=0.000). PVPI and PCT increased with the severity of ARDS, and there was a statistically significant difference between the ARDS groups in different degrees of PVPI (P=0.000). Pearson correlation analysis showed that PVPI was positively correlated with APACHE Ⅱ score and SOFA score (r=0.554, P=0.000; r=0.431, P=0.000), and PCT was positively correlated with APACHE Ⅱ score and SOFA score (r=0.313, P=0.004; r=0.320, P=0.004). Receiver operating characteristic (ROC) curve analysis showed that the area under the ROC curve of the prognosis of ARDS patients with sepsis was significantly higher than those of the two groups. Conclusion: PVPI can assess the severity of ARDS in patients with septic shock, and PVPI and PCT are predictive factors of prognosis. The combination of PVPI and PCT contributes to early stage diagnosis of ARDS associated with septic shock.

Application value of extravascular lung water index and pulmonary vascular permeability index in patients with acute respiratory distress syndrome / 中国综合临床

Objective To investigate the value of extravascular lung water index (EVLWI) and pulmonary vascular permeability index (PVPI) in the diagnosis and treatment of acute respiratory distress syndrome(ARDS).Methods From February 2015 to October 2016,selected 80 patients with ARDS in Danzhou Municipal People's Hospital,including 19 cases mild patients,28 cases moderate cases and 33 cases severe cases.The patients' EVLWI,PVPI,acute physiology and chronic health score system Ⅱ (APACHE Ⅱ)score,lung injury score (LIS) were detected.Results The score of APACHE Ⅱ in severe group was 22.81(21.91,25.40) points,significantly higher than that in mild group (19.81 (18.12,21.10) points) and moderate group(20.07 (19.01,22.02),P =0.002).The LIS,EVLWI and PVPI in Severe group were 2.01(1.83,2.11) points,17.01 (14.82,23.02) ml/kg and 3.82 (3.01,5.01),significantly higher than that in mild group (1.01 (0.98) points,1.7412.71 (10.89,13.67) ml/kg,2.71 (2.36,2.94)) and moderate group (1.52 (1.36,1.91) points,14.21 (13.10,16.60) ml/kg,3.01 (2.52,3.03),P ＜ 0.05),LIS,EVLWI and PVPI in moderate group were significantly higher than the mild group (P＜0.05).The mortality rate of 28 d in moderate and severe group was 32.14％ (9/28) and 51.52％ (17/33),which was significantly higher than that in mild group 0.00％(0/19) (P＜0.05).EVLWI and PVPI were 19.12(17.22,22.96) ml/kg and 3.71(3.08,5.22) in patients with death,which were significantly higher than those in survival 14.19 (11.20,16.59) ml/kg and 2.97(2.31,3.10) (P=0,021 and 0.016);EVLWI was positively correlated with PVPI,LIS and APACHE Ⅱ score(rs =0.411,0.323 and 0.304,P＜ 0.001).PVPI was positively correlated with LIS and APACHE Ⅱ score (rs =0.346,0.297,P＜0.001).No correlation between LIS and APACHE Ⅱ score (P＞0.05).Conclusion EVLWI and PVPI have certain apphcation value in the diagnosis and treatment of ARDS,and it is related to the patient's condition and prognosis.

Effects of mild hypothermia on pulmonary vascular permeability in patients with acute respiratory distress syndrome / 中华危重病急救医学

Objective To study the influence of mild hypothermia on pulmonary vascular permeability in patients with acute respiratory distress syndrome (ARDS) induced by infection.Methods A prospective randomized controlled trial was conducted.Patients with ARDS induced by infection satisfied criteria including age 18-70 years,endotracheal intubation and mechanical ventilation (MV),and without severe coagulation disorder admitted to intensive care unit (ICU) of the First Affiliated Hospital of Guangxi Medical University from May 2012 to November 2015 were enrolled,excluding tumor,burn,cardiac disease,vascular disease,and endovascular surgery within 3 months.The patients enrolled were randomly divided into non-temperature controlled group and mild hypothermia group.The primary diseases in all patients were treated according to the treating principles,including respiratory support,integrated treatment of organ support and symptomatic treatment.Besides,the patients in the mild hypothermia group were administered with systemic hypothermia,and the patients' core body temperature (nasopharyngeal temperature) was rapidly decreased to 34-35 ℃ within 1 hour.Acute physiology and chronic health evaluation Ⅱ (APACHE Ⅱ) score,oxygenation index (PaO2/FiO2),extravascular lung water index (EVLWI) and pulmonary vascular permeability index (PVPI) in two groups at 1,24,48,and 72 hours after treatment or core temperature up to standards were monitored respectively.Enzyme-linked immunosorbent assay (ELISA) was used to determine the levels of vascular endothelial growth factor (VEGF) in venous blood as well as tumor necrosis factor-α (TNF-α) and surfactant apoprotein A (SP-A) in bronchoalveolar lavage fluid (BALF),and circulating endothelial cell (CEC) was counted.The duration of mechanical ventilation and 7-day survival rate were recorded.Results Fifty-six patients were enrolled,with 32 in non-temperature controlled group and 24 in mild hypothermia group.There was no difference in baseline variables including gender,age,APACHE Ⅱ score,PaO2/FiO2 between two groups.APACHE Ⅱ score,EVLWI,PVPI,VEGF,CEC,and TNF-α in both groups were gradually increased with treatment time prolongation,and PaO2/FiO2 and SP-A were gradually decreased.Compared with non-temperature controlled group,APACHE Ⅱ score (16.34±4.27 vs.19.24 ± 5.95),EVLWI (mL/kg:12.17 ± 2.26 vs.12.39 ± 4.71),PVPI (15.40 ± 10.95 vs.16.08 ± 10.24),VEGF (ng/L:127.92 ± 31.49 vs.159.12 ± 40.67),CEC (cells/μL:4.15 ± 1.79 vs.5.70 ± 2.38),and TNF-α (ng/L:147.18 ± 48.85 vs.257.17 ±40.84) in mild hypothermia group were significantly decreased from 24 hours (all P ＜ 0.05),and PaO2/FiO2 [mmHg (1 mmHg =0.133 kPa):175.03± 12.64 vs.162.53 ± 14.15] and SP-A (μg/L:80.85 ± 16.18 vs.62.06 ± 17.28) were significantly increased (both P ＜ 0.05),the duration of mechanical ventilation was significantly shortened (days:10.38 ± 1.50 vs.15.74 ± 3.06,P ＜ 0.01),and 7-day survival rate was significantly increased (75.0％ vs.46.9％,P ＜ 0.05).Conclusion Mild hypothermia can reduce the pulmonary vascular permeability,and improve pulmonary function in early phase in patients with ARDS,as well as shorten the duration of mechanical ventilation,and decrease short-term mortality.

Effects of autophagy on lipopolysaccharide-induced vascular hyper-permeability / 中华危重病急救医学

Objective To investigate the effects of autophagy on lipopolysaccharide (LPS)-induced vascular hyper-permeability. Methods ① In vitro: Human umbilical vein endothelial cells (HUVECs) were randomly divided into blank group, LPS group (5 mg/L LPS stimulation), autophagy inhibitor 6-amino-3-methyl purine (3-MA) + LPS group (5 mmol/L 3-MA pretreatment for 30 minutes + 5 mg/L LPS stimulation) and autophagy revulsive Rapamycin (RAP) + LPS group (10 nmol/L RAP pretreatment for 30 minutes + 5 mg/L LPS stimulation). After LPS simulation for 60 minutes in four groups, endothelial permeability was detected by trans-endothelial electrical resistance (TER) determination. The protein expressions of autophagy marker protein microtubule-associated protein 1 light chain 3 (LC3 Ⅱ/Ⅰ) and autophagy related gene Beclin-1 were detected by Western Blot. Cell apoptosis was evaluated by using flow cytometry. Caspase-3 activity was detected by fluorometric assay kit. ② In vivo: 24 Sprague-Dawley (SD) rats were randomly assigned to four groups according to random number table, with 6 rats in each group. The rats in control group received no treatment; rats in model group were tail intravenous injected 10 mg/kg of LPS. The rats in 3-MA pretreatment and RAP pretreatment groups were tail intravenous injected 10 mg/kg of 3-MA or 2 mg/kg of RAP pretreatment for 30 minutes before 10 mg/kg LPS injection. The extravasation of FITC-albumin in mesenteric post-capillary venules was observed by fluorescence microscope. Then the change in fluorescence intensity of FITC-albumin between the intravascular and extravascular space (ΔI) were measured to reflect vascular permeability. Results ① In vitro, compared with blank group, the LC3 Ⅱ/Ⅰ protein, Beclin-1 protein, caspase-3 activity and rate of cell apoptosis in LPS group were increased, and the TER was decreased. Compared with LPS group, the LC3 Ⅱ/Ⅰ, Beclin-1, caspase-3 activity and rate of cell apoptosis in 3-MA+LPS group were decreased, and the TER was increased [LC3 Ⅱ/Ⅰ protein: (288.2±33.3)% vs. (420.5±39.4)%, Beclin-1 protein: (185.3±26.4)% vs. (293.3±36.1)%, caspase-3 activity: (196.6±28.5)% vs. (339.5±25.4)%, rate of cell apoptosis: (9.50±0.99)% vs. (15.40±1.55)%, TER: 0.88±0.09 vs. 0.63±0.05, all P < 0.05]. Compared with LPS group, the LC3 Ⅱ/Ⅰ, Beclin-1, caspase-3 activity and rate of cell apoptosis in RAP+LPS group were further increased, and the TER was further decreased [LC3 Ⅱ/Ⅰ protein: (519.6±45.2)% vs. (420.5±39.4)%, Beclin-1 protein: (359.0±38.3)% vs. (293.3±36.1)%, caspase-3 activity: (449.1±31.0)% vs. (339.5±25.4)%, rate of cell apoptosis: (19.30±1.72)% vs. (15.40±1.55)%, TER: 0.54±0.05 vs. 0.63±0.05, all P < 0.05]. ② In vivo, the albumin extravasation and vascular permeability were increased in model group as compared with those of control group (ΔI: 0.54±0.07 vs. 0.13±0.03, P < 0.05). The albumin extravasation and vascular permeability were obviously decreased in 3-MA pretreatment group as compared with those of model group (ΔI: 0.25±0.05 vs. 0.54±0.07, P < 0.05). The albumin extravasation and vascular permeability were obviously increased in RAP pretreatment group as compared with those of model group (ΔI: 0.67±0.07 vs. 0.54±0.07, P < 0.05). Conclusions Inhibition of autophagy can reduce the LPS-induced vascular hyper-permeability, and enhanced autophagy can further increase vascular permeability. The mechanism of autophagy mediate vascular permeability may be related to the endothelial cells apoptosis.

Assessment of fluid volume in critically ill patients with extravascular lung water index / 中华危重病急救医学

Objective To examine the effect of rapid infusion test guided by extravascular lung water index (EVLWI) on hemodynamics in critically ill patients at different states in order to guide volume resuscitation.Methods A prospective observation was conducted.Forty critically ill patients admitted to Department of Critical Care Medicine of Tianjin Third Central Hospital from June 2012 to April 2014 were enrolled.Based on the levels of EVLWI and pulmonary vascular permeability index (PVPI) and the cardiac function,the patients were divided into four groups:septic patients with normal EVLWI and PVPI (n =17),septic patients with increased EVLWI and PVPI (n =3),septic patients with increased EVLWI and normal PVPI (n =4),and coronary heart disease and heart failure patients with normal EVLWI and PVPI (n =16).The rapid infusion test was conducted in all patients using lactated Ringer solution 250 mL,followed by infusion of crystalloid with rate of 150 mL/h.The conditions of mechanical ventilation and vasoactive drugs were not changed during study.The changes in EVLWI,intrathoracic blood volume index (ITBVI),and cardiac index (CI) before capacity load,at immediate capacity load,and 15,45,105 minutes after load were determined by pulse indicator continuous cardiac output (PiCCO).On the base of volume status before and after the liquid infusion,the standard for the changes were:stroke volume (SV) increased by 12％-15％,central venous pressure (CVP) greater ≥ 2 mmHg (1 mmHg =0.133 kPa),CI ＞ 15％,and ITBVI change greater than 10％.Results There were no statistically significant differences in the observed indicators at the each time point before and after rapid infusion test among the four groups (all P ＞ 0.05).In septic patients with normal EVLWI and PVPI group,ITBVI was slightly increased by 5.4％-9.7％ from 15 minutes to 45 minutes after rapid infusion test.In coronary heart disease and heart failure patients with normal EVLWI and PVPI group,the EVLWI was increased by 11.9％,5.9％,and 14.7％ respectirely at 15,45,and 105 minutes,ITBVI was slightly increased by 6.4％ at 45 minutes,CI was increased by 29.5％ immediately after rapid infusion.In septic patients with increased EVLWI and PVPI group,CVP was increased by 8 mmHg immediately,EVLWI was increased significantly by 15.8％ at 45 minutes,ITBVI was slightly decreased by 10.0％ at 45 minutes,CI was increased by 24.7％ immediately,and increased by 17.0％ at 105 minutes,and PVPI was increased by 15.6％-28.1％ at 15-105 minutes after rapid infusion.In septic patients with increased EVLWI and normal PVPI group,CVP was increased by 1.5 mmHg at 15 minutes,EVLWI was increased immediately,which was increased by 17.4％,24.0％,and 31.4％ respectively at 15,45,and 105 minutes,ITBVI was increased by 13.9％ at 15 minutes,CI was increased by 16.1％ at 15 minutes after rapid fluid infusion.Conclusions Rapid fluid replacement in critically ill patients with crystalloid,regardless of whether the EVLWI was normal or increased,the short-term response was affected by the volume and cardiac function of patients.Different status of patients showed different volume effect curve:no significant changes in hemodynamic parameters were found in patients with normal EVLWI and volume parameters.In patients with potential cardiac dysfunction,CI and EVLWI increased significantly; regardless of PVPI increased or normal,EVLWI and CI were increased in patients with elevated EVLWI; two different changes could be found in the two types of pulmonary edema while ITBVI was increased.

Involvement of Protein Kinase C-delta in Vascular Permeability in Acute Lung Injury

Pulmonary edema is a major cause of mortality due to acute lung injury (ALI). The involvement of protein kinase C-delta (PKC-delta) in ALI has been a controversial topic. Here we investigated PKC-delta function in ALI using PKC-delta knockout (KO) mice and PKC inhibitors. Our results indicated that although the ability to produce proinflammatory mediators in response to LPS injury in PKC-delta KO mice was similar to that of control mice, they showed enhanced recruitment of neutrophils to the lung and more severe pulmonary edema. PKC-delta inhibition promoted barrier dysfunction in an endothelial cell layer in vitro, and administration of a PKC-delta-specific inhibitor significantly increased steady state vascular permeability. A neutrophil transmigration assay indicated that the PKC-delta inhibition increased neutrophil transmigration through an endothelial monolayer. This suggests that PKC-delta inhibition induces structural changes in endothelial cells, allowing extravasation of proteins and neutrophils.

Joint effects of hydroxyethyl starch and furosemide on acute lung injury induced by paraquat in swine / 中华急诊医学杂志

Objective To discuss the jointly therapeutic effects of 6％ hydroxyethyl starch 130/0.4 (voluven) and furosemide on acute lung injury induced by paraquat (PQ) in swine.Methods The ALI/ ARDS models were established with 20％ PQ (20 mL) intraperitoneal injection in 18 healthy female piglets and randomly divided into three groups: voluven group (A), furosemide group (B) and voluven + furosemide group (C) (n =6 in each group).The heart rate (HR), mean arterial pressure (MAP), extravascular lung water index (ELWI), pulmonary vascular permeability index (PVPI), partial pressure of carbon dioxide (PaCO2) and oxygenation index (PaO2/FiO2) among the three groups were carefully measured by PICCO (pulse indicator continuous cardiac output) before modeling (baseline), just aftermodeling (t0), and 2 h (t2), 4 h (t4), 6 h (t6) and 8 h (t8) after trearment.Needle biopsies of lung tissue were made before modeling and at t0 and t8 and prepared for microscopy observation after Hematoxylineosin staining method (HE staning).Repeated measurement data were compared among repeated measures by the ANOVA and the difference between groups was compared by one-wey ANOVA.Results (1) The HR and MAP of all animals increased obviously while the oxygenation index declined significantly at modeling just made (t0) compared to those before modeling (all P ＜ 0.05).At the same time, the HR and MAP of A and B groups were significantly lower than those of C group after treatment (all P ＜ 0.05), while the oxygenation index of A and B were significantly higher (all P ＞ 0.05).(2) The ELWI and PVPI of all animals increased obviously at modeling just made (t0) compared to those before modeling (all P ＜ 0.05).The ELWI and PVPI were decreased after treatment.And at the same time, the ELWI and PVPI of A and B groups were significantly lower than those of C group after treatment (all P ＜ 0.05).(3) The alveolar tissue showed obviously injured changes at modeling just made (t0).The injury was relieved 8h after trearment, which was most markedly in group C.Conclusions With the combination of 6％ hydroxyethyl starch 130/0.4 and furosemide administered, the acute lung injury induced by paraquat poisoning can be effectively relieved, promoting gas exchange, and improve oxygenation.

Vascular permeability and Evans blue dye: a physiological and pharmacological approach.

The acute inflammatory response consists of three main vascular effects: vasodilatation and increased blood flow, increased vascular permeability, and leukocytosis into the injured tissues. All three events are induced relatively quickly, and, for all three, the pattern of response is complex but consistent. Evans blue dye is an alkaline stain, so there is an affinity for the alkali in the acidic nucleus. The use of Evans blue dye as an in vivo marker through vascular permeability, facilitates the investigation of the effect of pathological changes in various disorders mainly, immunological disorders, inflammatory disorders, cardiovascular diseases like atherosclerosis, myocardial infarction, cancers and others. Endothelials have pathophysiological roles in pulmonary hypertension, arterial hypertension, atherosclerosis, cerebral vasospasm and inflammatory processes. The present review discussed with role of evans blue in the assessment of vascular permeability for the various pharmacological activities which are helps for the future investigations

Effect of blood purification on extravascular lung water and permeability index in extrapulmonary acute respiratory distress syndrome / 中国医师进修杂志

Objective To observe the effects of continuous blood purification(CBP) on extravascular lung water and permeability index in patients with severe extrapulmonary acute respiratory distress syndrome (ARDSexp).Methods Fifteen patients with severe ARDSexp were treated with CBP.The level of extravascular lung water index (EVLWI) and pulmonary vascular permeability index (PVPI) was measured before and after treatment,and at the same time the changes of inflammatory indicators were recorded.Results Compared with that before treatment,EVLWI and PVPI was decreased obviously after treatment (P ＜ 0.01),the level of C-reactive protein and interleukin 6 (IL-6),calcitonin and systemic inflammatory response syndrome score and the acute physiology and chronic health Ⅱ score was significantly decreased (P ＜ 0.01).Conclusion CBP can improve the level of EVLWI,PVPI and inflammatory indicators and also the prognosis of severe ARDSexp.

Role of post-hemorrhagic shock mesenteric lymph in enhancement of vas-cular permeability / 中国病理生理杂志

AIM: To investigate the role of post-hemorrhagic shock mesenteric lymph (PHSML) in the enhancementof vascular permeability .METHODS: Eighteen Wistar rats were randomized into sham group , shock group,and shock plus mesenteric lymph drainage (shock +drainage) group.The rats in shock group and shock +drainagegroup were routinely subjected to hemorrhagic shock and hypotension [(40 ±2) mmHg] was maintained for 90 min, andthen the fluid resuscitation was performed.Mesenteric lymph was drained in the rats in shock +drainage group from resuscitationfinished to 6 h, for the observation of PHSML drainage on the vascular permeability in multiple tissues of hemorrhagicshock rats.Afterwards, human umbilical vein endothelial cells (HUVECs) were incubated with the PHSML in vitro to observethe effects of PHSML on the morphology and permeability of HUVECs .RESULTS: The degree of blue color and concentrationsof Evens blue in the lung, myocardium, kidney, liver, spleen and small intestine were significantly increased inthe shocked rats than that in sham group, while the ratios of the dry weight to the wet weight were decreased .The mesentericlymph drainage reversed these changes .Meanwhile, 4% and 10% of PHSML at 0 ~3 h and 3 ~6 h after resuscitation,and lipopolysaccharide (10 mg/L) all caused the damage of HUVECs, decreased the viability and trans-endothelial electricalresistance of HUVECs, and increased the permeability of HUVECs to fluorescein isothiocyanate -labeled albumin. CONCLUSION: PHSML is a vital factor in the enhancement of vascular permeability .

Effect of ginkgolide B on junctional proteins in oxidized LDL-stimulated human umbilical vein endothelial cells / 中国药理学通报

Aim To investigate the effect of ginkgolide B on junctional proteins in ox-LDL-stimulated human umbilical vein endothelial cells ( HUVECs) . Methods After incubation with ginkgolide B ( 0 . 2 ,0 . 4 ,0 . 6 g · L-1 ) for 1 h, HUVECs were treated with ox-LDL (0. 1 g·L-1 ) for 4 h. The expressions of JAM-A and Cx43 were analyzed with Western blot and immunofluo-rescence. The effect of ginkgolide B on vascular per-meability was analyzed by Transwell experiments. Re-sults JAM-A and Cx43 expressions increased by 22%and 24% in ox-LDL-treated HUVECs, respectively. Whereas ginkgolide B significantly decreased JAM-A and Cx43 expressions. LY294002, a specific inhibitor of PI3K, suppressed JAM-A and Cx43 expressions in ox-LDL-stimulated cells. Ginkgolide B potently re-duced monocyte migration in ox-LDL-treated cells. Conclusion Ginkgolide B significantly suppresses JAM-A and Cx43 expressions, and reduces monocyte migration in ox-LDL-stimulated cells. This demon-strates that ginkgolide B can improve vascular permea-bility. The mechanism might be associated with the in-hibition of PI3K/Akt signaling pathway.

Amelioration of diabetic nephropathy in rats by resveratrol: involvement of anti-inflammatory effect / 中国药学杂志

OBJECTIVE: To observe the protective effect of resveratrol (Rev) on diabetic nephropathy in rats with inflammation impairment. METHODS: Male rats were divided into two groups and fed with commercially available normal pellet diet (NPD) or in-house prepared high-fat diet (HFD), respectively. After 4 weeks of dietary feed, the rats from HFD group were injected intraperitoneally with low dose of streptozotocin (STZ) (40 mg·kg-1). Half of the rats from both groups were administered with a dose of Rev(50 mg·kg-1·d-1)for 32 weeks. The rats were allowed to continue to be feed on their respective diets until the end of the study. After 32 weeks, the body weight, levels of FPG, TC, TG, BUN, SCr, Cys C, and urine protein and kidney vascular permeability were assayed; the contents of IL-1β, IL-6 and ICAM-1 in serum were detected by ELISA; the vascular permeability of kidney was detected by Evans blue; glomerular morphological analysis was performed in PAS stained pathological section; the levels of ICAM-1 mRNA and the expression of ICAM-1 in kidney were detected by RT-PCR and Immunohistochemistry and Western blot. RESULTS: Rev had remarkably suppressed weight gain and lowered levels of FPG, TC, TG, BUN, SCr, Cys C, IL-1β, IL-6 and ICAM-1 in serum (P<0.05), decreased urine protein (P<0.05), and reduced kidney vascular permeability (P<0.05). Increased indices for glomerular injury were significantly ameliorated by Rev treatment (P<0.05). The expression of ICAM-1 mRNA was markedly up-regulated in the kidneys of diabetic rats, which was effectively suppressed by Rev treatment (P<0.05). Western blot and immunohistoehemistry analysis showed that the expression of ICAM-1 was reduced significantly by Rev treatment. CONCLUSION: Rev can ameliorate diabetic nephropathy damage in rats, and the protection role may be attributed to its effect to lower lipid and glucose levels in serum and inhibit inflammation in kidney.

The study of mitochondrial DNA in the pathopoiesis mechanisms of paraquat poisoning in vitro / 中华急诊医学杂志

Objective To investigate the effects of mitochondrial DNA (mtDNA) on the pathopoiesis mechanisms of paraquat poisoning in vitro.Methods Firstly,the survival rate of A549 cells (human type Ⅱ alveolar epithelial cells) was measured with cell counting kit-8 after exposure to paraquat.Afterwards,the concentration of mtDNA in supernant of culture medium for culturing A549 and the chauge of mitochondrial membrance potential were detected with absolute quantitative PCR and confocal laser microscopy,respectively.Then,The chemotactic activity of mtDNA in peripheral blood mononuclear cells (PBMC) and neutrophils (PMN) were detected by transwell chemotaxis,and the subtype of chemotactic cells was measured with flow cytometry.Meanwhile,the role of mtDNA in vascular permeability was measured by using Xcelligence system and in vitro using vascular permeability kits.Finally,the effects of mtDNA in cell proliferation were to verify.Results The 50％ of lethal concentration (LD50) of paraquat for A549 was 600 μmol/L.Cell viability and concentration of mtDNA following challenge of PQ revealed in a concentration-and time-dependent manner (P ＜ 0.05).The mtDNA had a power in aggregating PBMC nonspecifically,but there was no effect on the vascular permeability was found.Moreover,the proliferation of human fibroblasts was not stimulated directly by mtDNA,but TGF-β1 (transforming growth factor-beta 1),a major pro-fibrotic factor,was increased compared to control group (P ＜ 0.05).Conclusions The mtDNA could play an important role in the inflammatory and proliferation responses to paraquat poisoning.

Diversity of vascular permeability in iris and ciliary body after penetrating keratoplasty / 中华实验眼科杂志

Background Allograft rejection is a main cause of failure of penetrating keratoplasty,especially in the patient with high risk of rejection condition.Previous study on allograft rejection mechanism focused on limbal and corneal neovascularization,but these factors did not explain all the phenomena of allograft rejection.Research found that immune cells appeared in iris and ciliary body when rejection occurred,but the relationship between these immune cells and allograft rejection is unclear Objective This study was to evaluate the relationship between diversity of vascular permeability in the iris and ciliary body and allograft rejection after penetrating keratoplasty.Methods Seventy clean eight-week-old BALB/c mice were divided into allogeneic corneal transplantation group (60 mice) and blank control group (10 mice).Allogeneic corneal transplantation was performed with the same age of C57BL/6 mice as donor and BALB/c mice as the recipients.The grafts were examined under the slit lamp microscope and scored based on the criteria of Hegde.The mice were sacrificed and iris and ciliary tissue were obtained 5,10 days and rejection after surgery.Immunohistochemistry and reverse transcription PCR (RT-PCR) was used respectively to detect the expression diversities of occludin,zonula occludens protein-1 (ZO-1),matrix metalloproteinase-9(MMP-9),major histocompatibility complex-Ⅱ (MHC-Ⅱ),and CCR5,CCR7 and their mRNA in iris and ciliary body.Image-J image analysis software was used to calculate the quantity of positive cells on iris wholemount,and absorbance of target genes (A values).The use and care of the experimental animals complied the ARVO Resolution on the Use of Animals in Research.Results The mean survival time of corneal gratts was (17±3) days after operation.The mean score was 0.6 in 5 days and 0.5 in 10 days,and 3.3 in 18 days after operation.Expression of ZO-1 reduced significantly,and that of MMP-9 increased obviously at the time of rejection.MHC Ⅱ + cells were scattered in iris and ciliary body in normal mice,and the number of the positive cells (cells/field) was increased after operation with a peak value when rejection occurred.A significant difference was seen between normal mice and rejection mice (1559.67±350.29 vs.4021.83±495.18) (P=0.000).The expressions of occludin mRNA and ZO-1 mRNA in the iris and ciliary body decreased obviously in the rejection mice.Compared with normal mice,theA value of ZO-1 and occluding were 36.74±3.13 vs.110.11±11.88 and 57.54±3.41 vs.59.90±3.50respectively,with significant differences between them (all P＜0.05).The expressions of MMP-9 mRNA,CCR5 mRNA and CCR7 mRNA in the iris and ciliary body increased gradually with the time lapse after operation and peaked when the rejection appeared.The A value of MMP-9 mRNA,CCR5 mRNA and CCR7 mRNA were significantly higher than those of normal mice (20.29±1.19 vs.2.77±0.85 for MMP-9 mRNA; 35.43±2.56 vs.9.11±0.29 for CCR5 mRNA,and 60.83±0.87 vs.0.89 ±0.95 for CCR7 mRNA) respectively (all P＜0.05).Conclusions The permeability of vascules in the iris and ciliary body increase during the allograft rejection after penetrating keratoplasty.Increased antigen presenting cells were also detected.