Rho-kinase Inhibitor Ameliorates Lipopolysaccharide-induced Kidney Injury by Inhibiting Toll-like Receptor 4 and Nuclear Factor-κB Signaling Pathway / 中国医科大学学报

Objective To explore whether Rho kinase inhibitor protects endotoxemia mice from kidney injury,and to investigate the mechanism underlying this effect. Methods Adult male C57BL/6 mice were randomly divided into three groups (n = 8 for each group): control,lipopolysaccharide (LPS),and LPS+ Y-27632 (Rho kinase inhibitor). For induction of acute kidney injury,mice were administered 30 mg/kg LPS intraperitoneally. Y-27632 (10 mg/kg body weight) was injected intraperitoneally 18 h and 1 h before injection of LPS,and an equal volume of sterile saline was administered at the corresponding time point in each group. The mice were killed 8 h after LPS administration. Blood samples and kidney tissues were taken and preserved for subsequent analysis. Results Pretreatment with Y-27632 significantly attenuated LPS-induced kidney injury;pretreatment with Y-27632 markedly reduced renal expression of inflammatory cytokines (TNF-α and IL-1β) in endotoxemia mouse,and also significantly inhibited LPS-induced caspase-3 expression in the kidney; and Y-27632 pretreatment dramatically reduced TLR4 protein expression and NF-κBp65 phosphorylation in kidney tissues of endotoxemia mouse. Conclusion Rho kinase inhibitor may inhibit TLR4 and NF-κB signaling pathway to reduce the inflammatory response in the kidneys of endotoxemia mice and alleviate acute renal injury induced by LPS.

Comparision of risk factors and pathogens in patients with early-and late-onset ventilator-associated pneumonia in intensive care unit / 中华内科杂志

Objective To compare risk factors and bacterial etiology in patients with early-onset versus late-onset ventilator-associated pneumonia (VAP) in intensive care unit (ICU).Methods This prospective cohort study enrolled mechanically ventilated patients hospitalized for more than 48 hours in the first affiliated hospital,China Medical University from Jan 2012 to Jun 2016.Subjects were classified by ventilator status:early-onset VAP (＜ 5 d ventilation,E-VAP) or late-onset VAP (≥ 5 d ventilation,L-VAP).Potential risk factors and pathogen were evaluated.Results A total of 4 179 patients in adult ICU were screened,3 989 (95.5％) of whom were mechanically ventilated,962 patients with mechanical ventilation time ≥ 48 h.VAP developed in 142 patients.E-VAP and L-VAP had different potential risk factors based on statistical analysis.Independent risk factors for E-VAP included male (OR =1.825,95％ CI 1.006-3.310),chronic obstructive pulmonary disease (COPD;OR =3.746,95％ CI 1.795-7.818),emergency intubation (OR =1.932,95％ CI 1.139-3.276),aspiration (OR =3.324,95％ CI 1.359-8.130).Whereas independent risk factors for L-VAP were coma (OR =2.335,95％ CI 1.300-4.194),renal dysfunction (OR =0.524,95％ CI O.290-O.947),emergency intubation (OR =2.184,95％ CI 1.334-3.574).Mortality in E-VAP and L-VAP group were both higher than the non-VAP group[30.2％(19/63)vs 19.8％ (162/820),P=0.044;29.1％ (23/79) vs 19.8％(162/820),P=0.046].The pathogens isolated from early-onset versus late-onset VAP were not significantly different between groups,which the most common ones were acinetobacter baumannii,pseudomonas aeruginosa and klebsiella pneumoniae.Conclusion E-VAP and L-VAP have different risk factors,however related pathogens are similar.Different specific preventive strategies are suggested based on different onset of VAP.

Comparision of risk factors and pathogens in patients with early-and late-onset ventilator-associated pneumonia in intensive care unit / 中华内科杂志

Objective To compare risk factors and bacterial etiology in patients with early-onset versus late-onset ventilator-associated pneumonia (VAP) in intensive care unit (ICU).Methods This prospective cohort study enrolled mechanically ventilated patients hospitalized for more than 48 hours in the first affiliated hospital,China Medical University from Jan 2012 to Jun 2016.Subjects were classified by ventilator status:early-onset VAP (＜ 5 d ventilation,E-VAP) or late-onset VAP (≥ 5 d ventilation,L-VAP).Potential risk factors and pathogen were evaluated.Results A total of 4 179 patients in adult ICU were screened,3 989 (95.5％) of whom were mechanically ventilated,962 patients with mechanical ventilation time ≥ 48 h.VAP developed in 142 patients.E-VAP and L-VAP had different potential risk factors based on statistical analysis.Independent risk factors for E-VAP included male (OR =1.825,95％ CI 1.006-3.310),chronic obstructive pulmonary disease (COPD;OR =3.746,95％ CI 1.795-7.818),emergency intubation (OR =1.932,95％ CI 1.139-3.276),aspiration (OR =3.324,95％ CI 1.359-8.130).Whereas independent risk factors for L-VAP were coma (OR =2.335,95％ CI 1.300-4.194),renal dysfunction (OR =0.524,95％ CI O.290-O.947),emergency intubation (OR =2.184,95％ CI 1.334-3.574).Mortality in E-VAP and L-VAP group were both higher than the non-VAP group[30.2％(19/63)vs 19.8％ (162/820),P=0.044;29.1％ (23/79) vs 19.8％(162/820),P=0.046].The pathogens isolated from early-onset versus late-onset VAP were not significantly different between groups,which the most common ones were acinetobacter baumannii,pseudomonas aeruginosa and klebsiella pneumoniae.Conclusion E-VAP and L-VAP have different risk factors,however related pathogens are similar.Different specific preventive strategies are suggested based on different onset of VAP.

Persistent inflammation immunosuppression catabolism syndrome: a special type of chronic critical illness / 中华胃肠外科杂志

After the concept of "chronic critical illness (CCI)" was proposed, the new concept persistent inflammation immunosuppression catabolism syndrome (PICS) is present recently. Patients with PICS are manifested by fast decreasing body weight, poor nutritional status, long-term immunosuppression and repeated nosocomial infections. These patients are faced with great challenges of persistent inflammation, acquired immunosuppression and high catabolism, which finally results in repeated nosocomial infections, prolonged hospital stay and increased mortality. At present, main problems of PICS diagnosis standard include varying length of ICU stay, difference in normal C reactive protein value, poor value of nutrition indexes, absence of clinical verification. Though associated pathophysiology mechanism is not clear, PICS is preventable and magageable with certain therapy, including early comprehensive prevention and treatment focused on infection control for CCI patients to stop the progression of PICS, application of immune modulator to improve immune function and prognosis of patients, and reasonable nutritional support and treatment. Besides, through the analysis of the association between PICS and CCI, authors draw a conclusion that PICS is a new phenotype of CCI, and immune paralysis is its main feature.

Heparin attenuates lipopolysaccharide-induced acute lung injury by inhibiting nitric oxide synthase and transforming growth factor-β/Smad signaling pathway / 中华危重病急救医学

Objective To investigate whether heparin has a beneficial effect on lipopolysaccharide(LPS)-induced acute lung injury(ALI)in rats,and to explore the possible underlying mechanisms. Methods Thirty-two adult Sprague-Dawley(SD)rats were randomly assigned into the control,heparin control,model,and heparin treatment groups,with 8 in each group. ALI rat model was reproduced by intratracheal instillation of LPS at a dose of 1 mg/kg. The rats in the control and heparin control groups received an equal volume of normal saline at the same times. The rats in the heparin control and heparin treatment groups were intravenously received 50 U/kg heparin every 1 hour after the induction of ALI. Animals were sacrificed 24 hours after LPS challenge. Bronchoalveolar lavage fluid(BALF) and lung tissue samples were collected. Histopathological evaluation,lung wet/dry(W/D)ratio,malondialdehyde (MDA),nitric oxide(NO)and myeloperoxidase(MPO)were analyzed. Enzyme-linked immunosorbent assay(ELISA) was used to measure the concentration of inflammatory factor in BALF. Expression of inducible nitric oxide synthase (iNOS)mRNA in the lung of rats was measured by reverse transcription-polymerase chain reaction(RT-PCR). Western Blot was used to determine the expression of transforming growth factor-β1(TGF-β1)and phosphorylation of Smad in the lung tissues. The expression of iNOS in lung was determined by immunohistochemistry. Results In the control and heparin control groups,lung tissue showed a normal structure and clear pulmonary alveoli under a light microscope. In the model group,ALI characters such as extensive thickening of the alveolar wall,significant infiltration of inflammatory cells,demolished structure of pulmonary alveoli,and hemorrhage were found. In the heparin treatment group,heparin treatment markedly alleviated LPS-induced these pathological changes in lung. Compared with control and heparin control groups,lung W/D ratio,lung MDA,NO and MPO levels,and tumor necrosis factor-α(TNF-α) and interleukin-6(IL-6)in BALF in the model group were increased significantly. Compared with the model group, lung W/D ratio,lung MDA,NO and MPO levels,and TNF-αand IL-6 in BALF in the heparin treatment group were significantly decreased〔W/D ratio:7.54±0.17 vs. 10.69±0.15,MDA(mmol/mg):2.01±0.30 vs. 2.51±0.25,NO (μmol/L):3.07±0.21 vs. 3.89±0.14,MPO(U/g):1.94±0.09 vs. 2.74±0.20,TNF-α(μg/L):201.80±0.27 vs. 297.53±0.34,IL-6(μg/L):38.41±0.25 vs. 46.31±0.31,all P<0.05〕. RT-PCR showed that the expression of iNOS mRNA in the heparin treatment group was significantly lower than that in the model group(2-ΔΔCt:3.04±0.18 vs. 4.37±0.15,P<0.05). Western Blot showed that compared with control group,the protein expressions of iNOS and TGF-β1,and phosphorylation of Smad2 and Smad3 were significantly increased,and the heparin could inhibit the protein expressions compared with model group. Immunohistochemistry showed that positive expressions of iNOS in alveolar epithelial cell and capillary endothelial cell in the heparin treatment group were significantly lower than those in the model group. Conclusion Heparin significantly ameliorated the lung injury induced by LPS in rats via the inhibition of nitric oxide synthase expression and the TGF-β/Smad pathway.

Correlation of intestinal fatty acid binding protein and intestinal injury in severe sepsis / 中华危重病急救医学

Objective To investigate the content of intestinal fatty acid binding protein (IFABP) and its clinical significance in patients with severe sepsis.Methods A prospective observational study was conducted.Fifty patients with severe sepsis admitted to intensive care unit (ICU) of the First Affiliated Hospital of China Medical University from July to December 2012 were enrolled,and 20 healthy patients served as control group.The concentrations of serum IFABP,interleukin-6 (IL-6),and tumor necrosis factor-α (TNF-α) were determined with enzyme-linked immunosorbent assay (ELISA) on days 0,1 and 3 after ICU admission.Acute physiology and chronic health evaluation Ⅱ (APACHE Ⅱ) and sequential organ failure assessment (SOFA) score,28-day prognosis,acute gastrointestinal injury (AGI) grade were recorded at the same time.Furthermore,the contents of IFABP were compared between control group and the severe sepsis group,abdominal infection group and non-abdominal infection group,the survival group and the death group,as well as among different AGI-grade groups.Correlation analysis of IFABP and inflammatory factors,IFABP and two scores,and IFABP and time of stay in ICU and mechanical ventilation were studied.Multivariate logistic regression and analysis of 28-day outcome of the patients were also studied.Results IFABP levels were increased in severe sepsis patients on days 0,1 and 3 compared with those of healthy control group (mg/L:731.90 ±53.91,592.07 ±41.94,511.85 ±47.97 vs.439.88 ±23.68,all P =0.000).There was no statistical significance of IFABP levels between abdominal infection group and non-abdominal infection group,the survival group and the death group,or among different AGI-grade groups.The correlation analysis showed that IFABP was statistically related with IL-6 (r=0.794,P=0.000),TNF-α (r=0.878,P=0.010),APACHE Ⅱ score (r=0.428,P=0.000) in patients with severe sepsis.Significant correlations were also found between IFABP and IL-6 (r=0.812,P=0.000),TNF-α (r=0.885,P=0.000) in abdominal infection group,as well as in non-abdominal infection group (IL-6:r=0.739,P=0.000; TNF-α:r=0.828,P=0.000).As shown by multivariate logistic regression analysis,SOFA scores on days 0,1,3 were the independent risk factors for death [odds ratio (OR) was 1.624 (P=0.004),1.411 (P=0.027),1.740 (P=0.012),respectively],but IFABP level,AGI grade,and APACHE Ⅱ score had no influence on death rate.Conclusion IFABP concentrations in patients with severe sepsis were significantly increased,and it is correlated well to IL-6,TNF-α and APACHE Ⅱ score,but did not related obviously with AGI grade and the prognosis of the patients.