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BACKGROUND@#Vascular endothelial dysfunction is considered a key pathophysiologic process for the development of acute lung injury. In this study, we aimed at investigating the effects of unfractionated heparin (UFH) on the lipopolysaccharide (LPS)-induced changes of vascular endothelial-cadherin (VE-cadherin) and the potential underlying mechanisms.@*METHODS@#Male C57BL/6 J mice were randomized into three groups: vehicle, LPS, and LPS + UFH groups. Intraperitoneal injection of 30 mg/kg LPS was used to induce sepsis. Mice in the LPS + UFH group received subcutaneous injection of 8 U UFH 0.5 h before LPS injection. The lung tissue of the mice was collected for assessing lung injury by measuring the lung wet/dry (W/D) weight ratio and observing histological changes. Human pulmonary microvascular endothelial cells (HPMECs) were cultured and used to analyze the effects of UFH on LPS- or tumor necrosis factor-alpha (TNF-α)-induced vascular hyperpermeability, membrane expression of VE-cadherin, p120-catenin, and phosphorylated myosin light chain (p-MLC), and F-actin remodeling, and on the LPS-induced activation of the phosphatidylinositol-3 kinase (PI3K)/serine/threonine kinase (Akt)/nuclear factor kappa-B (NF-κB) signaling pathway.@*RESULTS@#In vivo, UFH pretreatment significantly attenuated LPS-induced pulmonary histopathological changes (neutrophil infiltration and erythrocyte effusion, alveolus pulmonis collapse, and thicker septum), decreased the lung W/D, and increased protein concentration (LPS vs. LPS + UFH: 0.57 ± 0.04 vs. 0.32 ± 0.04 mg/mL, P = 0.0092), total cell count (LPS vs. LPS + UFH: 9.57 ± 1.23 vs. 3.65 ± 0.78 × 10/mL, P = 0.0155), polymorphonuclear neutrophil percentage (LPS vs. LPS + UFH: 88.05% ± 2.88% vs. 22.20% ± 3.92%, P = 0.0002), and TNF-α (460.33 ± 23.48 vs. 189.33 ± 14.19 pg/mL, P = 0.0006) in the bronchoalveolar lavage fluid. In vitro, UFH pre-treatment prevented the LPS-induced decrease in the membrane expression of VE-cadherin (LPS vs. LPS + UFH: 0.368 ± 0.044 vs. 0.716 ± 0.064, P = 0.0114) and p120-catenin (LPS vs. LPS + UFH: 0.208 ± 0.018 vs. 0.924 ± 0.092, P = 0.0016), and the LPS-induced increase in the expression of p-MLC (LPS vs. LPS + UFH: 0.972 ± 0.092 vs. 0.293 ± 0.025, P = 0.0021). Furthermore, UFH attenuated LPS- and TNF-α-induced hyperpermeability of HPMECs (LPS vs. LPS + UFH: 8.90 ± 0.66 vs. 15.84 ± 1.09 Ω·cm, P = 0.0056; TNF-α vs. TNF-α + UFH: 11.28 ± 0.64 vs. 18.15 ± 0.98 Ω·cm, P = 0.0042) and F-actin remodeling (LPS vs. LPS + UFH: 56.25 ± 1.51 vs. 39.70 ± 1.98, P = 0.0027; TNF-α vs. TNF-α + UFH: 55.42 ± 1.42 vs. 36.51 ± 1.20, P = 0.0005) in vitro. Additionally, UFH decreased the phosphorylation of Akt (LPS vs. LPS + UFH: 0.977 ± 0.081 vs. 0.466 ± 0.035, P = 0.0045) and I kappa B Kinase (IKK) (LPS vs. LPS + UFH: 1.023 ± 0.070 vs. 0.578 ± 0.044, P = 0.0060), and the nuclear translocation of NF-κB (LPS vs. LPS + UFH: 1.003 ± 0.077 vs. 0.503 ± 0.065, P = 0.0078) in HPMECs, which was similar to the effect of the PI3K inhibitor, wortmannin.@*CONCLUSIONS@#The protective effect of UFH against LPS-induced pulmonary endothelial barrier dysfunction involves VE-cadherin stabilization and PI3K/Akt/NF-κB signaling.
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BACKGROUND@#Atrial natriuretic peptide (ANP) and its natriuretic peptide receptors A (NPR-A) and C (NPR-C) are involved in the regulation of physiological and pathophysiological process of blood pressure. The present study aimed to determine the role of NPR-C in the development of salt-sensitive hypertension.@*METHODS@#The Dahl salt-sensitive (DS) and salt-resistant (DR) rats were used in this study. Animals were matched according to their age and weight, and then placed on either a high-salt (HS, 8%) or a normal-salt (NS, 0.4%) diet for 6 weeks randomly using random number table. The systolic blood pressure (SBP), plasmatic sodium concentration (PLNa), urinary sodium excretion (UVNa), and serum creatinine concentration (Scr) were measured. The concentration of ANP in blood and tissues (heart and kidney) was detected by enzyme-linked immunosorbent assay. The expression of ANP, NPR-A, and NPR-C in kidney was evaluated with western blot analysis. Regarding renal redox state, the concentration changes in malondialdehyde (MDA), lipofuscin, nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (Nox), and nitric oxide synthase (NOS) in kidney were detected by a spectrophotometric method. The kidney damage was evaluated using pathological techniques and the succinodehydrogenase (SDHase) examination. Furthermore, after an intra-peritoneal injection of C-atrial natriuretic peptide (ANP)4-23 (C-ANP4-23), an NPR-C receptor agonist, the SBP, biochemical values in blood and urine, and renal redox state were evaluated. The paired Student's t test and analysis of variance followed by the Bonferroni test were performed for statistical analyses of the comparisons between two groups and multiple groups, respectively.@*RESULTS@#The baseline SBP in all groups was within the normal range. At the end of the 6-week experiment, HS diet significantly increased the SBP in DS rats from 116.63 ± 2.90 mmHg to 162.25 ± 2.15 mmHg (t = -10.213, P 0.05). The significant increase of PLNa, UVNa, and Scr related to an HS diet was found in both DS and DR rats (all P < 0.05). However, significant changes in the concentration (t = -21.915, P < 0.001) and expression of renal ANP (t = -3.566, P = 0.016) and the expression of renal NPR-C (t = 5.864, P = 0.002) were only observed in DS hypertensive rats. The significantly higher desmin immunochemical staining score (t = -5.715, P = 0.005) and mitochondrial injury score (t = -6.325, P = 0.003) accompanied by the lower SDHase concentration (t = 3.972, P = 0.017) revealed mitochondrial pathologic abnormalities in podocytes in DS rats with an HS diet. The distinct increases of MDA (t = -4.685, P = 0.009), lipofuscin (t = -8.195, P = 0.001), and Nox (t = -12.733, P < 0.001) but not NOS (t = -0.328, P = 0.764) in kidneys were also found in DS hypertensive rats. C-ANP4-23 treatment significantly decreased the SBP induced by HS in DS rats (P < 0.05), which was still higher than NS groups with the vehicle or C-ANP4-23 treatment (P < 0.05). Moreover, the HS-induced increase of MDA, lipofuscin, Nox concentrations, and Nox4 expression in DS rats was significantly attenuated by C-ANP4-23 treatment as compared with those with HS diet and vehicle injection (all P < 0.05).@*CONCLUSIONS@#The results indicated that the renal NPR-C might be involved in the salt-sensitive hypertension through the damage of mitochondria in podocytes and the reduction of the anti-oxidative function. Hence, C-ANP4-23 might serve as a therapeutic agent in treating salt-sensitive hypertension.
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OBJECTIVE: To analyze the incidence, clinical characteristics and prognosis of sepsis-related liver injury(SELI). METHODS: The data of septic patients in the department of Critical Care Medicine of the First Affiliated Hospital of China Medical University from January 2013 to December 2014 were collected and the basic information, infection site, emergency operation and residence were recorded. Also, the duration of ICU, the first 24 h APACHE II and SOFA score, mechanical ventilation, MODS, nutritional support, serum total bilirubin and aminotransferase, the duration of liver dysfunction and the duration of liver dysfunction during ICU stay were recorded. Rank sum test was used to compare age, APACHE II score, SOFA score, length of stay in ICU, duration of mechanical ventilation; Chi square test was used to compare the patient's source, type of operation, whether MODS, and nutritional support; The logistic regression analysis was used to analyze the related factors of death. RESULTS: A total of 341 septic patients with sepsis were included in the study, including 96 patients with septis-related liver dysfunction. The main manifestations were elevated transaminase in 17 cases(17.71%), elevated bilirubin in 31 cases(32.29%), elevated bilirubin and transaminase in 48 cases(50%) and liver injury in 66 cases(68.75%) of sepsic patients occurred within 1-3 days of ICU 3.22 days(1-40 days). The morbidity and mortality of MODS in sepsis-related liver injury patients were 70.83% and 33.33%. Statistically differences in APACHE II scores, SOFA scores, mechanical ventilation duration, and MODS in patients with different prognosis were revealed. Further logistic regression analysis showed that sepsis with MODS was an independent risk factor for death. There were statistical difference in duration of symptoms, duration of ICU stay and prognosis. CONCLUSION: The morbidity of SELI is high, mostly in the early stage of sepsis, men are more prone to the disease. The abdominal cavity is the most common site of infection. High APACHEII score, prolonged mechanical ventilation and MODS are independent risk factors for SELI.
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In 2017, the American Society of Critical Care Medicine (SCCM) and European Society Intensive Care Medicine (ESICM) issued the latest guidelines for sepsis in 2016. The guide updated the guidelines of 2012 and proposed more precise, accurate and effective diagnosis and treatment program. This article elaborated the new enlightenment and thinking of the guide in order to improve the understanding and clinical practice of the sepsis guidelines for the intensive medical doctors.
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<p><b>BACKGROUND</b>Urine output (UO) is an essential criterion of the Kidney Disease Improving Global Outcomes (KDIGO) definition and classification system for acute kidney injury (AKI), of which the diagnostic value has not been extensively studied. We aimed to determine whether AKI based on KDIGO UO criteria (KDIGOUO) could improve the diagnostic and prognostic accuracy, compared with KDIGO serum creatinine criteria (KDIGOSCr).</p><p><b>METHODS</b>We conducted a secondary analysis of the database of a previous study conducted by China Critical Care Clinical Trial Group (CCCCTG), which was a 2-month prospective cohort study (July 1, 2009 to August 31, 2009) involving 3063 patients in 22 tertiary Intensive Care Units in Mainland of China. AKI was diagnosed and classified separately based on KDIGOUOand KDIGOSCr. Hospital mortality of patients with more severe AKI classification based on KDIGOUOwas compared with other patients by univariate and multivariate regression analyses.</p><p><b>RESULTS</b>The prevalence of AKI increased from 52.4% based on KDIGOSCrto 55.4% based on KDIGOSCrcombined with KDIGOUO. KDIGOUOalso resulted in an upgrade of AKI classification in 7.3% of patients, representing those with more severe AKI classification based on KDIGOUO. Compared with non-AKI patients or those with maximum AKI classification by KDIGOSCr, those with maximum AKI classification by KDIGOUOhad a significantly higher hospital mortality of 58.4% (odds ratio [OR]: 7.580, 95% confidence interval [CI]: 4.141-13.873, P< 0.001). In a multivariate logistic regression analysis, AKI based on KDIGOUO (OR: 2.891, 95% CI: 1.964-4.254, P< 0.001), but not based on KDIGOSCr (OR: 1.322, 95% CI: 0.902-1.939, P = 0.152), was an independent risk factor for hospital mortality.</p><p><b>CONCLUSION</b>UO was a criterion with additional value beyond creatinine criterion for AKI diagnosis and classification, which can help identify a group of patients with high risk of death.</p>
Subject(s)
Aged , Female , Humans , Male , Middle Aged , Acute Disease , Mortality , Creatinine , Blood , Critical Illness , Mortality , Hospital Mortality , Kaplan-Meier Estimate , Kidney Diseases , Blood , Mortality , Pathology , Urine , Logistic Models , Prognosis , Prospective Studies , Risk FactorsABSTRACT
<p><b>BACKGROUND</b>Sepsis is the leading cause of death among critically ill patients. Herein, we conducted a national survey to provide data on epidemiology and treatment of sepsis in the clinical practice in China, which has no detailed epidemiological data available on sepsis.</p><p><b>METHODS</b>This was a prospective cross-sectional survey from December 1, 2015 to January 31, 2016 in all provinces/municipalities of the mainland of China. The primary outcome of this study was the incidence of sepsis, and the secondary outcome was its etiology in China. Patients with sepsis admitted to the Intensive Care Units were included in this study. The demographic, physiological, bacteriological, and therapeutic data of these patients were recorded. The incidence of sepsis was estimated using the data from the sixth census in China, reported by the Chinese National Health and Family Planning Commission and the National Bureau of Statistics as the standard population. The independent risk factors for increased mortality from sepsis were calculated.</p><p><b>CONCLUSIONS</b>This study indicated the incidence and outcome of sepsis in China. It also showed the most common etiology of different sites and types of infection, which could guide empiric antibiotic therapy. Moreover, it provided information on the independent risk factors for increased mortality due to sepsis. The findings provide evidence to guide clinical management and may help improve the outcome in septic patients.</p><p><b>TRIAL REGISTRATION</b>ClinicalTrials.gov, NCT02448472; https://clinicaltrials.gov/show/NCT02448472.</p>
Subject(s)
Female , Humans , Male , China , Epidemiology , Cross-Sectional Studies , Epidemiologic Studies , Incidence , Intensive Care Units , Prospective Studies , Sepsis , EpidemiologyABSTRACT
<p><b>BACKGROUND</b>Acute kidney injury (AKI) has been recognized as a major healthcare problem affecting millions of patients worldwide. However, epidemiologic data concerning AKI in China are still lacking. The objectives of this study were to characterize AKI defined by RIFLE criteria, assess the association with hospital mortality, and evaluate the impact of AKI in the context of other risk factors.</p><p><b>METHODS</b>This prospective multicenter observational study enrolled 3,063 consecutive patients from 1 July 2009 to 31 August 2009 in 22 ICUs across mainland China. We excluded patients who were admitted for less than 24 hours (n = 1623), younger than 18 years (n = 127), receiving chronic hemodialysis (n = 29), receiving renal transplantation (n = 1) and unknown reasons (n = 28). There were 1255 patients in the final analysis. AKI was diagnosed and classified according to RIFLE criteria.</p><p><b>RESULTS</b>There were 396 patients (31.6%) who had AKI, with RIFLE maximum class R, I, and F in 126 (10.0%), 91 (7.3%), and 179 (14.3%) patients, respectively. Renal function deteriorated in 206 patients (16.4%). In comparison with non AKI patients, patients in the risk class on ICU admission were more likely to progress to the injury class (odds ratio (OR) 3.564, 95% confidence interval (CI) 1.706 - 7.443, P = 0.001], while patients in the risk class (OR 5.215, 95% CI 2.798-9.719, P < 0.001) and injury class (OR 13.316, 95% CI 7.507-23.622, P < 0.001) had a significantly higher probability of deteriorating into failure class. The adjusted hazard ratios for 90-day mortality were 1.884 for the risk group, 3.401 for the injury group, and 5.306 for the failure group.</p><p><b>CONCLUSIONS</b>The prevalence of AKI was high among critically ill patients in Chinese ICUs. In comparison with non-AKI patients, patients with RIFLE class R or class I on ICU admission were more susceptibility to progression to class I or class F. The RIFLE criteria were robust and correlated well with clinical deterioration and mortality.</p>
Subject(s)
Adult , Aged , Female , Humans , Male , Middle Aged , Acute Kidney Injury , Epidemiology , Pathology , China , Epidemiology , Intensive Care Units , Prospective Studies , Risk FactorsABSTRACT
The objective of this study was to investigate the function of vimentin in PRRSV infection. Vimentin gene from Marc-145 cells was amplified by RT-PCR, cloned into pET-28a vector and expressed in Escherichia coli BL21(DE3). The expressed vimentin was confirmed by Western blot and purified which was used to immunize BALB/c mice for the production of antibodies. Vimentin and antibodies were tested for blocking PRRSV infection of Marc-145 cells. The binding of vimentin to PRRSV N and GP5 proteins were tested by the ELISA. The results showed that vimentin gene was amplified successfully and expressed as identified by SDS-PAGE and Western blot. Mouse anti-vimentin antibodies were produced with the titer of 10(5). PRRSV infection of Marc-145 cells was blocked partially by vimentin while blocked completely by the antibobies. In addition, vimentin was bound N protein, but not GP5. These results provide additional information on PRRSV entry into Marc-145 cells.
Subject(s)
Animals , Female , Mice , Antibodies , Allergy and Immunology , Metabolism , Cell Line , Escherichia coli , Genetics , Metabolism , Genetic Vectors , Genetics , Mice, Inbred BALB C , Porcine Reproductive and Respiratory Syndrome , Genetics , Metabolism , Virology , Porcine respiratory and reproductive syndrome virus , Physiology , Protein Binding , Physiology , Recombinant Proteins , Genetics , Allergy and Immunology , Metabolism , Swine , Vimentin , Genetics , Allergy and Immunology , Metabolism , Viral Proteins , MetabolismABSTRACT
<p><b>OBJECTIVE</b>To investigate the profile and significance of changes in thyroid function and cortisol in critically ill patients.</p><p><b>METHODS</b>Chemiluminescent microparticle immunoassay (CMIA) was used to measure the serum thyroid hormone, thyroid stimulating hormone and cortisol levels in 51 patients at the first day and in the 45 patients still alive at the third day after hospitalized in ICU. In the 45 patients, 17 cases were complicated with multiple organ dysfunction syndrome (MODS) and 28 cases were not. The age, blood glucose levels and APACHE II scores were also recorded at the first day.</p><p><b>RESULTS</b>In the 45 patients, serum FT(3) decreased in 41 patients (91%), cortisol increased in 33 patients (73%), especially in the first 24 hours. Compared with non-MODS group, serum FT(3), FT(4) and cortisol levels changed significantly in MODS group. Serum FT(4) reduced apparently in 6 dead patients. Serum FT(3) level was negatively correlated with APACHE II, and cortisol level was positively correlated with APACHE II.</p><p><b>CONCLUSIONS</b>Thyroid hormone and cortisol were apparently abnormal and correlated with APACHE II score, especially in patients with MODS. Serum FT(4) might serve as an index to judge the prognosis of the patients.</p>
Subject(s)
Adult , Aged , Aged, 80 and over , Female , Humans , Male , Middle Aged , APACHE , Critical Illness , Hydrocortisone , Blood , Prognosis , Retrospective Studies , Thyroid Hormones , Blood , Time FactorsABSTRACT
<p><b>OBJECTIVE</b>To study the therapeutic effects of early administration of low-dose heparin in patients with severe sepsis.</p><p><b>METHODS</b>Twenty-two patients were randomly divided into experimental group and control group. In addition to the routine treatment, the patients in experimental group were given low-dose heparin, while those in control group were not. Prothrombin time (PT), activated partial thromboplastin time (APTT), platelet count, APACHE II score, ICU days, hospital days, cure rate, and 28-day survival rate were investigated in the two groups.</p><p><b>RESULTS</b>After the treatment, PT and APTT recovered normal in the experimental group, but remained abnormal in the control group. There was no significant difference in platelet count between the two groups. ICU days in experimental group was shorter than that in control group (P < 0.01). Cure rate in experimental group was 81.8%, which was significantly higher than that in control group (54.5%). There was no significant difference in hospital days and 28-day survival rate between the two groups.</p><p><b>CONCLUSIONS</b>Early administration of low-dose heparin therapy can improve coagulative function in patients with severe sepsis, however, the survival rate was not improved.</p>