Chun Pan

Activation of Wnt/β-catenin signalling promotes mesenchymal stem cells to repair injured alveolar epithelium induced by lipopolysaccharide in mice

IntroductionMesenchymal stem cells (MSCs) have potential for re-epithelization and recovery in acute respiratory distress syndrome (ARDS). In a previous in vitro study, the results showed that the canonical Wnt/β-catenin pathway promoted the differentiation of MSCs into type II alveolar epithelial cells, conferred resistance to oxidative stress, and promoted their migration, suggesting that the Wnt/β-catenin pathway might be one of the key mechanisms underling the therapeutic effect of mouse MSCs in ARDS.MethodsMouse MSCs stable transfected with β-catenin or green fluorescent protein control were transplanted intratracheally into the ARDS mice induced by lipopolysaccharide. Lung tissue injury and repair assessment were examined using haematoxylin and eosin staining, lung injury scoring, Masson’s trichrome staining and fibrosis scoring. Homing and differentiation of mouse MSCs were assayed by labelling and tracing MSCs using NIR815 dye, immunofluorescent staining, and Western immunoblot analysis. The inflammation and permeability were evaluated by detecting the cytokine and protein measurements in bronchoalveolar lavage fluid using enzyme-linked immunosorbent assay.ResultsIn this study, β-catenin-overexpressing MSC engraftment led to more significant effects than the GFP controls, including the retention of the MSCs in the lung, differentiation into type II alveolar epithelial cells, improvement in alveolar epithelial permeability, and the pathologic impairment of the lung tissue.ConclusionThese results suggest that the activation of canonical Wnt/β-catenin pathway by mouse MSCs by overexpressing β-catenin could further improve the protection of mouse MSCs against epithelial impair and the therapeutic effects of mouse MSCs in ARDS mice.

Comparison of the effects of albumin and crystalloid on mortality in adult patients with severe sepsis and septic shock: a meta-analysis of randomized clinical trials

IntroductionThe aim of this study was to examine whether albumin reduced mortality when employed for the resuscitation of adult patients with severe sepsis and septic shock compared with crystalloid by meta-analysis.MethodsWe searched for and gathered data from MEDLINE, Elsevier, Cochrane Central Register of Controlled Trials and Web of Science databases. Studies were eligible if they compared the effects of albumin versus crystalloid therapy on mortality in adult patients with severe sepsis and septic shock. Two reviewers extracted data independently. Disagreements were resolved by discussion with other two reviewers until a consensus was achieved. Data including mortality, sample size of the patients with severe sepsis, sample size of the patients with septic shock and resuscitation endpoints were extracted. Data were analyzed by the methods recommended by the Cochrane Collaboration Review Manager 4.2 software.ResultsA total of 5,534 records were identified through the initial search. Five studies compared albumin with crystalloid. In total, 3,658 severe sepsis and 2,180 septic shock patients were included in the meta-analysis. The heterogeneity was determined to be non-significant (P = 0.86, I2 = 0%). Compared with crystalloid, a trend toward reduced 90-day mortality was observed in severe sepsis patients resuscitated with albumin (odds ratio (OR) 0.88; 95% CI, 0.76 to 1.01; P = 0.08). However, the use of albumin for resuscitation significantly decreased 90-day mortality in septic shock patients (OR 0.81; 95% CI, 0.67 to 0.97; P = 0.03). Compared with saline, the use of albumin for resuscitation slightly improved outcome in severe sepsis patients (OR 0.81; 95% CI, 0.64 to 1.08; P = 0.09).ConclusionsIn this meta-analysis, a trend toward reduced 90-day mortality was observed in severe sepsis patients resuscitated with albumin compared with crystalloid and saline. Moreover, the 90-day mortality of patients with septic shock decreased significantly.

Low tidal volume protects pulmonary vasomotor function from “second-hit” injury in acute lung injury rats

BackgroundSepsis could induce indirect acute lung injury(ALI), and pulmonary vasomotor dysfunction. While low tidal volume is advocated for treatment of ALI patients. However, there is no evidence for low tidal volume that it could mitigate pulmonary vasomotor dysfunction in indirect ALI. Our study is to evaluate whether low tidal volume ventilation could protect the pulmonary vascular function in indirect lipopolysaccharide (LPS) induced acute lung injury rats.MethodsAn indirect ALI rat model was induced by intravenous infusion of LPS. Thirty rats (n = 6 in each group) were randomly divided into (1)Control group; (2) ALI group; (3) LV group (tidal volume of 6mL/kg); (4) MV group (tidal volume of 12mL/kg); (5)VLV group (tidal volume of 3mL/kg). Mean arterial pressure and blood gas analysis were monitored every 2 hours throughout the experiment. Lung tissues and pulmonary artery rings were immediately harvested after the rats were bled to be killed to detect the contents of endothelin-1 (ET-1), endothelial nitric oxide synthase (eNOS) and TNF-α. Acetylcholine (Ache)-induced endothelium-dependent and sodium nitroprusside (SNP)-induced endothelium-independent relaxation of isolated pulmonary artery rings were measured by tensiometry.ResultsThere was no difference within groups concerning blood pressure, PaCO2 and SNP-induced endothelium-independent relaxation of pulmonary artery rings. Compared with MV group, LV group significantly reduced LPS-induced expression of ET-1 level (113.79 ± 7.33pg/mL vs. 152.52 ± 12.75pg/mL, P < 0.05) and TNF-α (3305.09 ± 334.29pg/mL vs.4144.07 ± 608.21pg/mL, P < 0.05), increased the expression of eNOS (IOD: 15032.05 ± 5925.07 vs. 11454.32 ± 6035.47, P < 0.05). While Ache (10-7mol/L-10-4mol/L)-induced vasodilatation was ameliorated 30% more in LV group than in MV group.ConclusionsLow tidal volume could protect the pulmonary vasodilative function during indirect ALI by decreasing vasoconstrictor factors, increasing expressions of vasodilator factors in pulmonary endothelial cells, and inhibiting inflammation injuries.

Pulmonary acute respiratory distress syndrome: positive end-expiratory pressure titration needs stress index

BACKGROUND The heterogeneity of lung injury in pulmonary acute respiratory distress syndrome (ARDS) may have contributed to the greater response of hyperinflated area with positive end-expiratory pressure (PEEP). PEEP titrated by stress index can reduce the risk of alveolar hyperinflation in patients with pulmonary ARDS. The authors sought to investigate the effects of PEEP titrated by stress index on lung recruitment and protection after recruitment maneuver (RM) in pulmonary ARDS patients. MATERIALS AND METHODS Thirty patients with pulmonary ARDS were enrolled. After RM, PEEP was randomly set according to stress index, oxygenation, static pulmonary compliance (Cst), or lower inflection point (LIP) + 2 cmH2O strategies. Recruitment volume, gas exchange, respiratory mechanics, and hemodynamic parameters were collected. RESULTS PEEP titrated by stress index (15.1 ± 1.8 cmH2O) was similar to the levels titrated by oxygenation (14.5 ± 2.9 cmH2O), higher than that titrated by Cst (11.3 ± 2.5 cmH2O) and LIP (12.9 ± 1.6 cmH2O) (P < 0.05). Compared with baseline, PaO2/FiO2 and recruitment volume were significantly improved after PEEP titration with the four strategies (P < 0.05). PaO2/FiO2 and recruitment volume were similar when using PEEP titrated by stress index and oxygenation but higher than that titrated by Cst and LIP. Compared with baseline, lung compliance increased significantly when PEEP determined by Cst, but there was no difference of Cst in these four strategies. There was no influence of PEEP titration with the four strategies on hemodynamic parameters. CONCLUSIONS PEEP titration by stress index might be more beneficial for pulmonary ARDS patients after RM.

The Effect of Early Goal-Directed Therapy on Outcome in Adult Severe Sepsis and Septic Shock Patients: A Meta-Analysis of Randomized Clinical Trials.

BACKGROUND:Whether early goal-directed therapy (EGDT) improves outcome in severe sepsis and septic shock remains unclear. We performed a meta-analysis of existing clinical trials to examine whether EGDT improved outcome in the resuscitation of adult sepsis patients compared with control care. METHODS:We searched for eligible studies using MEDLINE, Elsevier, Cochrane Central Register of Controlled Trials, and Web of Science databases. Studies were eligible if they compared the effects of EGDT versus control care on mortality in adult patients with severe sepsis and septic shock. Two reviewers extracted data independently. Data including mortality, sample size of the patients with severe sepsis and septic shock, and resuscitation end points were extracted. Data were analyzed using methods recommended by the Cochrane Collaboration Review Manager 4.2 software. Random errors were evaluated by trial sequential analysis (TSA). RESULTS:Nine studies compared EGDT with control care, and 5202 severe sepsis and septic shock patients were included. A nonsignificant trend toward reduction in the longest all-cause mortality was observed in the EGDT group compared with control care (relative risk, 0.89; 99% confidence interval, 0.74–1.07; P = 0.10). However, EGDT significantly reduced intensive care unit mortality in severe sepsis and septic shock patients (relative risk, 0.72; 99% confidence interval, 0.57–0.90; P = 0.0002). TSA indicated lack of firm evidence for a beneficial effect. CONCLUSIONS:In this meta-analysis, a nonsignificant trend toward reduction in the longest all-cause mortality in patients resuscitated with EGDT was noted. However, EGDT significantly reduced intensive care unit mortality in severe sepsis and septic shock patients. TSA indicated a lack of firm evidence for the results. More powered, randomized controlled trials are needed to determine the effects.

The Orphan Receptor Tyrosine Kinase ROR2 Facilitates MSCs to Repair Lung Injury in ARDS Animal Model

There are some limitations to the therapeutic effects of mesenchymal stem cells (MSCs) on acute respiratory distress syndrome (ARDS) due to their low engraftment and differentiation rates in lungs. We found previously that noncanonical Wnt5a signaling promoted the differentiation of mouse MSCs (mMSCs) into type II alveolar epithelial cells (AT II cells), conferred resistance to oxidative stress, and promoted migration of MSCs in vitro. As receptor tyrosine kinase-like orphan receptor 2 (ROR2) is an essential receptor for Wnt5a, it was reasonable to deduce that ROR2 might be one of the key molecules for the therapeutic effect of MSCs in ARDS. The mMSCs that stably overexpressed ROR2 or the green fluorescent protein (GFP) control were transplanted intratracheally into the ARDS mice [induced by intratracheal injection of lipopolysaccharide (LPS)]. The results showed that ROR2-overexpressing mMSCs led to more significant effects than the GFP controls, including the retention of the mMSCs in the lung, differentiation into AT II cells, improvement of alveolar epithelial permeability, improvement of acute LPS-induced pulmonary inflammation, and, finally, reduction of the pathological impairment of the lung tissue. In conclusion, MSCs that overexpress ROR2 could further improve MSC-mediated protection against epithelial impairment in ARDS.

Stress index for positive end-expiratory pressure titration in prone position: a piglet study

Prone position ventilation is an important treatment for acute respiratory distress syndrome (ARDS), but chest wall elastance increases in prone position ventilation, and stress index may not reflect the changes in lung mechanics. We therefore investigated the effects of stress index guided PEEP titration on pulmonary mechanics and hemodynamics in the prone position in a piglet acute lung injury model.

The effects of low tidal ventilation on lung strain correlate with pulmonary compliance

Methods Nineteen patients were divided into high (Chigh group) and low pulmonary compliance (Clow group) groups based on their pulmonary compliance values (0.6 ml/[cmH2O·kg]). End-expiratory lung volumes (EELV) with different tidal volumes (VT at baseline and at 6, 8, 10 and 12 ml/kg predicted body weight [PBW]) were measured by nitrogen wash-in/washout. Lung strain was calculated as the ratio between tidal volume and EELV.

Predictive utilities of neutrophil gelatinase-associated lipocalin (NGAL) in severe sepsis

BACKGROUND We aim to investigate the predictive value of plasma neutrophil gelatinase-associated lipocalin (pNGAL) in patients with severe sepsis. METHODS A total of 124 patients were enrolled in this observational study. Blood samples were obtained at admission, on day 2 and day 7. Receiver operating characteristic (ROC) curves were generated to assess the utility of pNGAL in prediction of 28-day mortality and need for CRRT. Cox regression curves were built with and without pNGAL for 28-day mortality prediction to determine NGALs contributive predictive value. RESULTS Plasma NGAL was significantly increased in non-survivors group on day 2 and 7 and predicted 28-day mortality with AuROC values of 0.675 (95% CI 0.570-0.780) and 0.752 (95% CI 0.619-0.885). Addition of day 2 NGAL to the clinical model resulted in a net reclassification index (NRI) increment of 0.40 (95% CI 0.06-0.75, P = 0.028) for prediction of 28-day mortality. The AuROC of NGAL at admission and day 2 was greater than creatinine in prediction of the need for CRRT. CONCLUSION Plasma NGAL discriminated 28-day survivors from non-survivors on day 2 and 7 and was a relatively robust predictor of 28-day mortality prediction. Plasma NGAL possibly outperformed creatinine in the prediction of need for CRRT.

Acute Respiratory Distress Syndrome: Challenge for Diagnosis and Therapy

Objective: Acute respiratory distress syndrome (ARDS) is a devastating clinical syndrome whose diagnosis and therapy are still in question. The aim of this review was to discuss the current challenge for the diagnosis and treatment of ARDS. Data Sources: Data sources were the published articles in English through December 2017 in PubMed using the following key words: “acute respiratory distress syndrome,” “definition”, “diagnosis,” “therapy,” “lung protective strategy,” “right ventricular dysfunction,” and “molecular mechanism.” Study Selection: The selection of studies focused on both preclinical studies and clinical studies of therapy of ARDS. Results: The incidence of ARDS is still high, and ARDS causes high intensive care units admissions and high mortality. The Berlin Definition proposed in 2012 is still controversial owing to lack of sensitivity and specificity. ARDS is still under recognition and it is associated with high mortality. Lung protective strategies with low tidal volume (VT) and lung recruitment should consider the physiology of ARDS because ARDS presents lung inhomogeneity; the same low VT might increase local stress and strain in some patients with low compliance, and lung recruitment could injure lungs in ARDS patients with low recruitability and hemodynamic instability. Acute cor pulmonale is common in severe ARDS. ARDS itself and some treatments could worsen acute cor pulmonale. Molecular understanding of the pathogenic contributors to ARDS has improved, but the molecular-associated treatments are still under development. Conclusions: ARDS is a devastating clinical syndrome whose incidence and mortality has remained high over the past 50 years. Its definition and treatments are still confronted with challenges, and early recognition and intervention are crucial for improving the outcomes of ARDS. More clinical studies are needed to improve early diagnosis and appropriate therapy.