Qiang Shu

Treatment of acute respiratory distress syndrome with allogeneic adipose-derived mesenchymal stem cells: a randomized, placebo-controlled pilot study

BackgroundRecent studies have demonstrated that mesenchymal stem cells (MSCs) modulate the immune response and reduce lung injury in animal models. Currently, no clinical studies of the effects of MSCs in acute respiratory distress syndrome (ARDS) exist. The objectives of this study were first to examine the possible adverse events after systemic administration of allogeneic adipose-derived MSCs in ARDS patients and second to determine potential efficacy of MSCs on ARDS.MethodsTwelve adult patients meeting the Berlin definition of acute respiratory distress syndrome with a PaO2/FiO2 ratio ofu2009<u2009200 were randomized to receive allogeneic adipose-derived MSCs or placebo in a 1:1 fashion. Patients received one intravenous dose of 1 × 106 cells/kg of body weight or saline. Possible side effects were monitored after treatment. Acute lung injury biomarkers, including IL-6, IL-8 and surfactant protein D (SP-D), were examined to determine the effects of MSCs on lung injury and inflammation.ResultsThere were no infusion toxicities or serious adverse events related to MSCs administration and there were no significant differences in the overall number of adverse events between the two groups. Length of hospital stay, ventilator-free days and ICU-free days at day 28 after treatment were similar. There were no changes in biomarkers examined in the placebo group. In the MSCs group, serum SP-D levels at day 5 were significantly lower than those at day 0 (pu2009=u20090.027) while the changes in IL-8 levels were not significant. The IL-6 levels at day 5 showed a trend towards lower levels as compared with day 0, but this trend was not statistically significant (pu2009=u20090.06).ConclusionsAdministration of allogeneic adipose-derived MSCs appears to be safe and feasible in the treatment of ARDS. However, the clinical effect with the doses of MSCs used is weak, and further optimization of this strategy will probably be required to reach the goal of reduced alveolar epithelial injury in ARDS.Trial registrationClinical trials.gov, NCT01902082

Differential expression of alpha- and beta-defensins in human peripheral blood.

Backgroundu2002 Human defensin peptides with broad‐spectrum antimicrobial activity have been implicated in the human defence response towards microbial invasion. Two families of defensins designated α‐ and β‐defensins, respectively, have been identified. Little is known about the expression of both defensin families in human peripheral blood. The purpose of this study was to examine the expression of α‐ and β‐defensin genes in human peripheral blood.

Perioperative Risk Factors for Prolonged Mechanical Ventilation Following Cardiac Surgery in Neonates and Young Infants

BACKGROUNDnProlonged mechanical ventilation (PMV) after cardiac surgery in children is associated with a high postoperative morbidity and mortality, as well as increased ICU and hospital resource utilization. Little has been done to identify the predictors of PMV in neonates and young infants. This study was performed to evaluate the perioperative risk factors for PMV in neonates and young infants undergoing cardiac surgery.nnnMETHODSnClinical records of 172 consecutive children aged < or = 3 months were reviewed. PMV was defined as mechanical ventilation (MV) > or = 72 h following operation. After univariate analysis, a stepwise logistic regression analysis was used to evaluate the independent risk factors for PMV following cardiac surgery. The predictive ability of risk factors for PMV was assessed using an area under the receiver operating characteristic (ROC) curve.nnnRESULTSnSixty-one patients required PMV after cardiac surgery. The median duration of MV was 150 h in PMV patients, while it was 28 h in non-PMV patients. The independent risk factors for PMV were risk adjustment for surgery for congenital heart disease (RACHS)-1 (p = 0.041), nosocomial pneumonia (p = 0.001), low cardiac output syndrome (LCOS) [p = 0.001], postoperative cumulative positive fluid balance (p = 0.032), and extubation failure (EF) [p = 0.027]. The value for the ROC curve was 0.940.nnnCONCLUSIONSnThe present results strongly suggest that RACHS-1, nosocomial pneumonia, LCOS, fluid retention postoperatively, and EF are risk factors for PMV in neonates and young infants undergoing reparative surgery for congenital heart disease.

Protection Against pseudomonas Aeruginosa Pneumonia And Sepsis-induced Lung Injury By Overexpression of β-defensin-2 In Rats

ABSTRACT &bgr;-defensin-2 (BD-2), a small cationic antimicrobial peptide, was first described to be an inducible defensin at the epithelial surfaces. In vitro studies have demonstrated that it may play a pivotal role in the anti-inflammatory immune response in addition to its antimicrobial activity. The purpose of this study was to evaluate the effect of overexpression of BD-2 on lung injury to crudely investigate whether the function of BD-2 in the lung attributed to both antimicrobial action and modulation of the immune response. Recombinant adenovirus carrying an expression cassette of rat BD-2 or control adenovirus carrying empty vector was administered intratracheally to Sprague-Dawley rats 48 h before performing acute lung injury, which was induced either by Pseudomonas aeruginosa infection or by cecal ligation and double puncture (2CLP). In vivo antimicrobial activity of BD-2, histological changes of the lungs in both infectious and 2CLP models, pulmonary intracellular adhesion molecule-1 protein level, as well as the 7-day survival rate in the latter model were determined. Amounts of the P. aeruginosa in the lung with BD-2 overexpression were significantly lower compared with that in controls (2.87 ± 0.76 × 104 colony-forming units [CFU]/mL vs. 2.49 ± 0.74 × 106 CFU/mL, P < 0.05). Overexpression of BD-2 reduced alveolar damage, interstitial edema, and infiltration of neutrophils in both models. Furthermore, in the 2CLP model, recombinant BD-2 not only significantly decreased protein levels of intracellular adhesion molecule-1 in lung tissue at 24, 36, and 72 h after 2CLP (P < 0.05), but also significantly improved the survival of rats (P < 0.05). The CFU of abdominal bacteria was comparable to that in the control rats (P > 0.05). Therefore, overexpression of BD-2 protects against P. aeruginosa pneumonia and 2CLP-induced lung injury based on its antimicrobial and anti-inflammatory activities, respectively. Modulating the expression level of BD-2 may serve as an approach to attenuate lung injury.

Triggering Receptor Expressed on Myeloid Cells-2 Protects against Polymicrobial Sepsis by Enhancing Bacterial Clearance

RATIONALEnTriggering receptor expressed on myeloid cells-2 (TREM-2) is a cell surface receptor primarily expressed on macrophages and monocyte-derived cells. TREM-2 not only functions as a regulator of inflammatory response, but also serves as a phagocytic receptor for bacteria. However, the role of TREM-2 in sepsis remains unknown.nnnOBJECTIVESnTo investigate whether TREM-2 plays a role in sepsis.nnnMETHODSnThe manner of expression of TREM-2 was evaluated in patients with sepsis and in polymicrobial septic mouse model induced by the cecum ligation and puncture approach. Recombinant mouse TREM-2 was used to block the effect of TREM-2. Bone marrow-derived myeloid cells (BMMCs) that overexpress TREM-2 were administrated into septic mice at various times after cecum ligation and puncture.nnnMEASUREMENTS AND MAIN RESULTSnThe expression levels of TREM-2 were up-regulated in patients with sepsis and septic mice. The kinetics of TREM-2 expression in polymicrobial sepsis was comparable with that of bacteria burden in peritoneal lavage fluid. Blocking the effect of TREM-2 resulted in markedly increased mortality and bacterial burden in polymicrobial sepsis. Administration of TREM-2-overexpressing BMMCs significantly reduced the mortality, even when it was administered 4 hours after the initiation of sepsis. However, injection of TREM-2-overexpressing BMMCs into LPS-challenged endotoxemia mice did not improve the survival rate. The protective effect of TREM-2 in polymicrobial sepsis was not associated with its antiinflammatory properties, but it enhanced bacterial clearance in vivo. Furthermore, administration of TREM-2-overexpressing BMMCs improved the organ injury.nnnCONCLUSIONSnTREM-2 plays an important role in the host defense response to sepsis by enhancing bacterial clearance.

Plasma sRAGE enables prediction of acute lung injury after cardiac surgery in children

IntroductionAcute lung injury (ALI) after cardiac surgery is associated with a high postoperative morbidity and mortality, but few predictors are known for the occurrence of the complication. This study evaluated whether elevated plasma levels of soluble receptor for advanced glycation end products (sRAGE) and S100A12 reflected impaired lung function in infants and young children after cardiac surgery necessitating cardiopulmonary bypass (CPB).MethodsConsecutive children younger than 3 years after cardiac surgery were prospectively enrolled and assigned to ALI and non-ALI groups, according to the American-European Consensus Criteria. Plasma concentrations of sRAGE and S100A12 were measured at baseline, before, and immediately after CPB, as well as 1 hour, 12 hours, and 24 hours after operation.ResultsFifty-eight patients were enrolled and 16 (27.6%) developed postoperative ALI. Plasma sRAGE and S100A12 levels increased immediately after CPB and remained significantly higher in the ALI group even 24 hour after operation (P < 0.01). In addition, a one-way MANOVA revealed that the overall sRAGE and S100A12 levels were higher in the ALI group than in the non-ALI group immediately after CPB (P < 0.001). The multivariate logistic regression analysis showed that the plasma sRAGE level immediately after CPB was an independent predictor for postoperative ALI (OR, 1.088; 95% CI, 1.011 to 1.171; P = 0.025). Increased sRAGE and S100A12 levels immediately after CPB were significantly correlated with a lower PaO2/FiO2 ratio (P < 0.01) and higher radiographic lung-injury score (P < 0.01), as well as longer mechanical ventilation time (sRAGEN: r = 0.405; P = 0.002; S100A12N: r = 0.322; P = 0.014), longer surgical intensive care unit stay (sRAGEN: r = 0.421; P = 0.001; S100A12N: r = 0.365; P = 0.005) and hospital stay (sRAGEN: r = 0.329; P = 0.012; S100A12N: r = 0.471; P = 0.001).ConclusionsElevated sRAGE and S100A12 levels correlate with impaired lung function, and sRAGE is a useful early biomarker of ALI in infants and young children undergoing cardiac surgery.

Mesenchymal Stromal Cells Affect Disease Outcomes via Macrophage Polarization.

Mesenchymal stromal cells (MSCs) are multipotent and self-renewable cells that reside in almost all postnatal tissues. In recent years, many studies have reported the effect of MSCs on the innate and adaptive immune systems. MSCs regulate the proliferation, activation, and effector function of T lymphocytes, professional antigen presenting cells (dendritic cells, macrophages, and B lymphocytes), and NK cells via direct cell-to-cell contact or production of soluble factors including indoleamine 2,3-dioxygenase, prostaglandin E2, tumor necrosis factor-α stimulated gene/protein 6, nitric oxide, and IL-10. MSCs are also able to reprogram macrophages from a proinflammatory M1 phenotype toward an anti-inflammatory M2 phenotype capable of regulating immune response. Because of their capacity for differentiation and immunomodulation, MSCs have been used in many preclinical and clinical studies as possible new therapeutic agents for the treatment of autoimmune, degenerative, and inflammatory diseases. In this review, we discuss the central role of MSCs in macrophage polarization and outcomes of diseases such as wound healing, brain/spinal cord injuries, and diseases of heart, lung, and kidney in animal models.

Application of Adipose-Derived Stem Cells in Heart Disease

Therapy with mesenchymal stem cells is one of the promising tools to improve outcomes after myocardial infarction. Adipose-derived stem cells (ASCs) are an ideal source of mesenchymal stem cells due to their abundance and ease of preparation. Studies in animal models of myocardial infarction have demonstrated the ability of injected ASCs to engraft and differentiate into cardiomyocytes and vasculature cells. ASCs secrete a wide array of angiogenic and anti-apoptotic paracrine factors such as vascular endothelial growth factor, hepatocyte growth factor, and insulin-like growth factor 1. ASCs are capable of enhancing heart function, reducing myocardial infarction, promoting vascularization, and reversing remodeling in the ischemically injured hearts. Furthermore, several ongoing clinical trials using ASCs are producing promising results for heart diseases. This article reviews the isolation, differentiation, immunoregulatory properties, mechanisms of action, animal models, and ongoing clinical trials of ASCs for cardiac disease.

Percutaneous radiofrequency ablation for treatment of hepatoblastoma recurrence.

Radiofrequency ablation (RFA) has been widely reported as a minimally invasive treatment for liver tumours in adults, but has not been documented as a treatment for hepatoblastoma in a child. We report a 2-year-old boy with local recurrence of hepatoblastoma after partial hepatectomy. Percutaneous RFA was performed under real-time sonographic guidance. There was no imaging evidence of recurrence after a follow-up of 2xa0years. We consider this a promising technique in children.

Mesenchymal stem cells in the treatment of pediatric diseases.

BackgroundIn recent years, the incredible interests in mesenchymal stem cells have boosted the expectations of both patients and physicians. Unlike embryonic stem cells, neither their procurement nor their use is deemed controversial. Moreover, their immunomodulatory capacity coupled with low immunogenicity has opened up their allogenic use, consequently broadening the possibilities for their application. In May 2012, Canadian health regulators approved Prochymal, the first mesenchymal stem cells-based drug, for acute graft-versus-host diseases in children who have failed to respond to steroid treatment. The aim of this article is to review the recent advances in mesenchymal stem cells for pediatric diseases.Data sourcesA literature review was performed on PubMed from 1966 to 2013 using the MeSH terms “mesenchymal stem cells”, “clinical trials” and “children”. Additional articles were identified by a hand search of the references list in the initial search.ResultsThe following categories are described: general properties, mechanisms of action, graft-versus-host diseases, cardiovascular diseases, liver diseases, inflammatory bowel diseases, osteoarticular diseases, autoimmune diseases, type 1 diabetes, and lung diseases.ConclusionsMesenchymal stem cells, owing to their availability, immunomodulatory properties, low immunogenicity, and therapeutic potential, have become one of the most attractive options for the treatment of a wide range of diseases. It is expected to see more and more clinical trials and applications of mesenchymal stem cells for pediatric diseases in the near future.