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NLRP3 activation in macrophages promotes acute intestinal injury in neonatal necrotizing enterocolitis

World Journal of Pediatrics 2024年第2期20卷 153-164页

作者： Bo Shi Cheng-Jie Lyu Zhen-Kai Le Hao-Sen Ji Yi Xiao Yuan-Yuan Zhang Shou-Jiang Huang Lin-Jun Yu Qiang Shu Jin-Fa Tou Deng-Ming Lai Department of Neonatal Surgery Children’s HospitalZhejiang University School of MedicineNational Clinical Research Center for Child HealthHangzhou 310052China Department of Pulmonology Children’s HospitalZhejiang University School of MedicineNational Clinical Research Center for Child HealthHangzhou 310052China Department of Thoracic and Cardiovascular Surgery Children’s HospitalZhejiang University School of MedicineNational Clinical Research Center for Child HealthHangzhou 310052China

Background Macrophages are involved in various immune inflammatory disease *** study aimed to investigate the role and mechanism of macrophages in regulating acute intestinal injury in neonatal necrotizing enterocolitis(NEC).Methods CD68,nucleotide-binding oligomerization domain,leucine-rich repeat,and pyrin domain-containing 3(NLRP3),cysteine aspartate-specific protease-1(caspase-1),and interleukin-1β(IL-1β)in paraffin sections of intestinal tissues from NEC and control patients were detected with immunohistochemistry,immunofluorescence,and western *** pet milk,hypoxia and cold stimulation were used to establish a mouse(wild type and Nlrp3^(-/-))model of *** mouse macrophage(RAW 264.7)and rat intestinal epithelial cell-6 lines were also cultured followed by various ***,intestinal epithelial cell injuries,and IL-1β release were *** Compared to the gut“healthy”patients,the intestinal lamina propria of NEC patients had high macrophage infiltration and high NLRP3,caspase-1,and IL-1β ***,in vivo,the survival rate of Nlrp3^(-/-)NEC mice was dramatically improved,the proportion of intestinal macrophages was reduced,and intestinal injury was decreased compared to those of wild-type NEC ***3,caspase-1,and IL-1β derived from macrophages or supernatant from cocultures of macrophages and intestinal epithelial cells also caused intestinal epithelial cell *** Macrophage activation may be essential for NEC ***3/caspase-1/IL-1β cellular signals derived from macrophages may be the underlying mechanism of NEC development,and all these may be therapeutic targets for developing treatments for NEC.

关键词： Caspase-1 Interleukin-1β Macrophage necrotizing enterocolitis NLRP3

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Umbilical cord mesenchymal stem cell exosomes alleviate necrotizing enterocolitis in neonatal mice by regulating intestinal epithelial cells autophagy

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World Journal of Stem Cells 2024年第6期16卷 728-738页

作者： Lin Zhu Lu He Wu Duan Bo Yang Ning Li Department of Pediatrics Tongji HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhan 430077Hubei ProvinceChina Division of Endocrinology Department of Internal MedicineQilu Hospital of Shandong UniversityJinan 250012Shandong ProvinceChina Shenzhen Research Institute of Shandong University Shenzhen 518000Guangdong ProvinceChina Institute of Organ Transplantation Tongji HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhan 430077Hubei ProvinceChina Department of Physical Education Heze UniversityHeze 274015Shandong ProvinceChina

BACKGROUND necrotizing enterocolitis(NEC)is a severe gastrointestinal disease that affects premature *** mounting evidence supports the therapeutic effect of exosomes on NEC,the underlying mechanisms remain *** To investigate the mechanisms underlying the regulation of inflammatory response and intestinal barrier function by umbilical cord mesenchymal stem cell(UCMSCs)exosomes,as well as their potential in alleviating NEC in neonatal *** NEC was induced in 5-d-old C57BL/6 pups through hypoxia and gavage feeding of formula containing lipopolysaccharide(LPS),after which the mice received human UCMSC exosomes(hUCMSC-exos).The control mice were allowed to breastfeed with their *** tissues were collected from the mice and analyzed by histopathology and *** tissues were collected from NEC neonates and analyzed by *** biology and cell culture approaches were employed to study the related mechanisms in intestinal epithelial *** We found that autophagy is overactivated in intestinal epithelial cells during NEC,resulting in reduced expression of tight junction proteins and an increased inflammatory *** ability of hUCMSC-exos to ameliorate NEC in a mouse model was dependent on decreased intestinal *** also showed that hUCMSC-exos alleviate the inflammatory response and increase migration ability in intestinal epithelial cells induced by *** These results contribute to a better understanding of the protective mechanisms of hUCMSC-exos against NEC and provide a new theoretical and experimental foundation for NEC *** findings also enhance our understanding of the role of the autophagy mechanism in NEC,offering potential avenues for identifying new therapeutic targets.

关键词： necrotizing enterocolitis Autophagy Umbilical cord mesenchymal stem cell Exosomes Intestinal epithelial cell Intestinal barrier function

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Bifidobacterium and Lactobacillus for preventing necrotizing enterocolitis in very-low-birth-weight preterm infants:a systematic review and meta-analysis

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World Journal of Pediatrics 2020年第2期16卷 135-142页

作者： Xue Jiao Meng-Di Fu Ya-Yun Wang Jiang Xue Yuan Zhang School of Medicine Shandong UniversityJinanChina Department of Neonatology Second Hospital of Shandong University247#Beiyuan RoadJinanChina Center of Evidence-Based Medicine Institute of Medical SciencesSecond Hospital of Shandong University247#Beiyuan RoadJinanChina School of Public Health Shandong UniversityJinanChina

Background The therapeutic effect of Bifidobacterium and Lactobacillus on necrotizing enterocolitis(NEC)in very-low-birth-weight preterm infants was controversial,and we aimed to explore the exact impact of the two *** The PubMed,EMBASE,Web of Science and Cochrane Library were systematically searched for studies published from January 1,2010 to February 28,*** were combined with fixed-effect model or random-effect model with specific *** analysis was conducted by the trim-and-fill method,and the Begger's and Egger's test were used to measure publication *** The meta-analysis included 16 original articles with 4632 very-low-birth-weight preterm *** respect to the intervention of Bifidobacterium,we estimated non-significant decrease in the morbidity of NEC with a risk ratio(RR)of 0.75[95%confidence internal(CI)0.56-1.01,P=0.06].Regarding the effect of Lactobacillus,there was no evidence of significant lower risk in the incidence of NEC(RR=0.67,95%CI 0.39-1.17,P=0.16).The use of mixture of probiotics(Bifidobacterium and Lactobacillus)reduced the risk of NEC in the probiotics group(RR=0.45,95%CI 0.25-0.80,P=0.007).Conclusion The mixture of Bifidobacterium and Lactobacillus could prevent the morbidity of NEC in very-low-birth-weight preterm *** Bifidobacterium or Lactobacillus alone did not show this effect.

关键词： Bifidobacterium Lactobacillus necrotizing enterocolitis Preterm infants

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necrotizing enterocolitis: A multifactorial disease with no cure

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World Journal of Gastroenterology 2008年第14期14卷 2142-2161页

作者： Kareena L Schnabl John E Van Aerde Alan BR Thomson Michael T Clandinin Nutrition and Metabolism Research Groups Department of Medicine University of Alberta Edmonton T6G 2P5 Canada Department of Pediatrics University of Alberta Edmonton T6G 2P5 Canada Department of Medicine Division of Gastroenterology University of Alberta Edmonton T6G 2P5 Canada Alberta Institute for Human Nutrition University of Alberta Edmonton T6G 2P5 Canada

necrotizing enterocolitis is an inflammatory bowel disease of neonates with significant morbidity and mortality in preterm infants. Due to the multifactorial nature o the disease and limitations in disease models, early diagnosis remains challenging and the pathogenesis elusive. Although preterm birth, hypoxic-ischemic events formula feeding, and abnormal bacteria colonization are established risk factors, the role of genetics and vasoactive/inflammatory mediators is unclear Consequently, treatments do not target the specific underlying disease processes and are symptomatic and surgically invasive. Breast-feeding is the most effective preventative measure. Recent advances in the prevention of necrotizing enterocolitis have focused on bioactive nutrients and trophic factors in human milk. Developmen of new disease models including the aspect of prematurity that consistently predisposes neonates to the disease with multiple risk factors will improve our understanding of the pathogenesis and lead to discovery of innovative therapeutics.

关键词： necrotizing enterocolitis Diagnosis Pathogenesis Prevention Disease models Vasoactive/ inflammatory mediators

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Role of LPS/CD14/TLR4-mediated inflammation in necrotizing enterocolitis:Pathogenesis and therapeutic implications

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World Journal of Gastroenterology 2009年第38期15卷 4745-4752页

作者： Kwong L Chan Kwong F Wong John M Luk Department of Surgery The University of Hong Kong Division of Paediatric Surgery Queen Mary Hospital Department of Pharmacology and Department of Surgery National University Health SystemNational University of SingaporeMD11 #05-1210 Medical Drive

AIM:To establish the roles of lipopolysaccharide (LPS)/CD14/toll-like receptor 4 (TLR4)-mediated inflammation in a rat model of human necrotizing enterocolitis (NEC).METHODS: Six pairs of intestinal samples from human NEC were collected before and after recovery for histological and molecular analysis of inflammatory cytokines and signaling components. In the rat NEC model, we isolated 10-cm jejunum segments and divided them into six groups (n=6) for sham operation, treatment with LPS, bowel distension, combined bowel distension and LPS stimulation, and two therapeutic groups. The potential eff icacy of a recombinant CD18 peptide and a monoclonal CD14 antibody was evaluated in the latter two groups. The serum and tissue levels of several inflammatory mediators were quantified by real-time polymerase chain reaction, ELISA and ***: Human acute phase NEC tissues displayed significant increases (P<0.05) in levels of TLR4, CD14, myeloid differentiation protein (MD)-2, tumor necrosis factor (TNF)-α and nuclear factor-κB when compared to those after recovery. The histological and inflammatory picture of human NEC was reproduced in rats that were treated with combined bowel distension and LPS, but not in the sham-operated and other control rats. Serum levels of interleukin-6 and TNF-α were also elevated. The NEC pathology was attenuated by treating the NEC rats with a monoclonal CD14 antibody or an LPS-neutralizing ***:LPS and distension are required to produce the histological and inflammatory features of NEC. A potential treatment option is blocking LPS activation and leukocyte infi ltration.

关键词： CD14 antigen Lipopolysaccharide necrotizing enterocolitis Pathogenesis Therapy Toll-like receptor 4

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Development of necrotizing enterocolitis after blood transfusion in very premature neonates

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World Journal of Pediatrics 2023年第1期19卷 68-75页

作者： Travis L.Odom Jessica Eubanks Nusiebeh Redpath Erica Davenport Dmitry Tumin Uduak S.Akpan Department of Pediatrics University of Texas Health Sciences Campus7703 Floyd Curl DriveSan AntonioTX 78229-3900USA Department of Pediatrics Brody School of Medicine at EastCarolina UniversityGreenvilleNCUSA ECU Health Medical Center GreenvilleNCUSA

Background Prior studies report conflicting evidence on the association between packed red blood cell(PRBC)transfu-sions and necrotizing enterocolitis(NEC),especially in early weeks of life where transfusions are frequent and spontaneous intestinal perforation can mimic *** primary objective of this study was to evaluate the association between PRBC transfusions and NEC after day of life(DOL)14 in very premature *** A retrospective cohort analysis of very premature neonates was conducted to investigate association between PRBC transfusions and NEC after DOL *** endpoints were PRBC transfusions after DOL 14 until the date of NEC diagnosis,discharge,or *** ranked-sum and Fisher's exact tests,Cox proportional hazards regression,and Kaplan-Meier curves were used to analyze *** Of 549 premature neonates,186(34%)received transfusions after DOL 14 and nine(2%)developed NEC(median DOL=38;interquartile range=32-46).Of the nine with NEC after DOL 14,all were previously transfused(P<0.001);therefore,hazard of NEC could not be *** hoc analysis of patients from DOL 10 onward included five additional patients who developed NEC between DOL 10 and DOL 14,and the hazard of NEC increased by a factor of nearly six after PRBC transfusion(hazard ratio=5.76,95%confidence interval=1.02-32.7;P=0.048).Conclusions Transfusions were strongly associated with NEC after DOL *** studies are needed to determine if restrictive transfusion practices can decrease incidence of NEC after DOL 14.

关键词： necrotizing enterocolitis Packed red blood cells Transfusions Very low birth weight infants

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Neonatal necrotizing enterocolitis caused by umbilical arterial catheter-associated abdominal aortic embolism:A case report

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World Journal of Clinical Cases 2021年第22期9卷 6557-6565页

作者： Xi Huang Yan-Ling Hu Yuan Zhao Qiong Chen Ying-Xin Li Department of Neonatal Nursing West China Second University HospitalSichuan University/West China School of NursingSichuan UniversityChengdu 610041Sichuan ProvinceChina Key Laboratory of Birth Defects and Related Diseases of Women and Children Sichuan UniversityMinistry of EducationChengdu 610041Sichuan ProvinceChina

BACKGROUND Reports of necrotizing enterocolitis(NEC)caused by umbilical arterial catheter(UAC)-associated abdominal aortic embolism in neonates are ***,we report the case of an extremely low birth weight(ELBW)infant with NEC caused by UAC-associated abdominal aortic *** SUMMARY A female infant,aged 21 min and weighing 830 g at 28+6 wk of gestational age,was referred to our hospital because of premature birth and shallow *** patient was diagnosed with ELBW,neonatal respiratory distress syndrome,neonatal intrauterine infection,and neonatal *** arterial and venous catheters were inserted on the day after birth and were removed 9 d later,according to the doctor’s *** 48 h after extubation,the patient’s manifestations included poor responsiveness,heart rate range of 175-185/min,and currant jelly ***,we considered a diagnosis of *** determine the cause,we used B-mode ultrasound,which revealed a partial abdominal aortic embolism(2 cm×0.3 cm)and abdominal *** patient was treated with nil per os,gastrointestinal decompression,anti-infective therapy,blood transfusion,and low-molecular-weight heparin sodium q12h for anticoagulant therapy(from May 20 to June 1,the dosage of low-molecular-weight heparin sodium was adjusted according to the anti-Xa activity during treatment).On the 67th day after admission,the patient fully recovered and was *** The abdominal aortic thrombosis in this patient was considered to be catheter related,which requires immediate treatment once *** choice of treatment should be determined according to the location of the thrombus and the patient’s condition.

关键词： Umbilical arterial catheter Abdominal aortic thrombosis necrotizing enterocolitis Neonate Case report

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Predictive scores for mortality in full-term infants with necrotizing enterocolitis: experience of a tertiary hospital in Southwest China

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世界儿科杂志:英文版 2016年第2期12卷 202-208页

作者： Yu Zhang Ji-Kun Ma Hong Wei Xiao-Wen Li Lu-Quan Li Jia-Lin Yu Department of Neonatology Children's Hospital of Chongqing Medical UniversityMinistry of Education Key Laboratory of Child Development and DisordersKey Laboratory of Pediatrics in Chongqing and Chongqing International Science and Technology Cooperation Center for Child Development and DisordersChongqingChina

Background: Although many risk factors for mortalityof necrotizing enterocolitis (NEC) were investigated,most of them were obtained from preterm infants, andfew works focused on the prognostic risk factors in fullterminfants. This study aimed to identify risk factors anddevelop a prediction score model for mortality in fulltermneonates with ***: The risk factors were analyzed retrospectivelyby bivariate and multivariate logistic regression analysis in153 full-term neonates with NEC, who were hospitalizedin Children's Hospital of Chongqing Medical Universityfrom 2000 to 2013. A prediction score model was developedaccording to the regression coeffi cients of risk ***: The mortality of the infants was 19.6%(30/153). The non-survivors had a younger age of diagnosisand advanced stage of NEC (P<0.05). They had a higherprevalence of respiratory failure, intestinal perforation,peritonitis and other complications, compared with thesurvivors (P<0.05). On the day of diagnosis, the nonsurvivorswere more likely to have abnormal laboratoryindicators than survivors (P<0.05). Age at diagnosis [oddsratio (OR)=0.91, 95% confidence interval (CI)=0.836-0.99], respiratory failure (OR=2.76, 95% CI=1.10-6.92),and peritonitis (OR=26.36, 95% CI=7.52-173.92) hadsignificant independent contributions to death. A scoremodel predicting death was developed, and the area underthe receiver operating characteristic curve was 0.869 (95%CI=0.803-0.935). All infants with scores ≥8 ***: Younger age at diagnosis, peritonitis,and respiratory failure might be risk factors for themortality of full-term infants with NEC. Infants with apredictive score of 8 were at high risk for death.

关键词： necrotizing enterocolitis neonate predictive score model prognosis

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Intestinal microbiome changes in an infant with right atrial isomerism and recurrent necrotizing enterocolitis:A case report and review of literature

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World Journal of Clinical Cases 2022年第29期10卷 10583-10599页

作者： Aleksandra Kaplina Ekaterina Zaikova Artem Ivanov Yulia Volkova Tatiana Alkhova Vladimir Nikiforov Alexander Latypov Marina Khavkina Tatiana Fedoseeva Tatiana Pervunina Yulia Skorobogatova Svetlana Volkova Vladimir Ulyantsev Olga Kalinina Stanislav Sitkin Natalia Petrova Research Laboratory of Physiology and Diseases of Newborns Almazov National Medical Research CentreSt.Petersburg 197341Russia Research Laboratory of Autoimmune and Autoinflammatory Diseases Almazov National Medical Research CentreSt.Petersburg 197341Russia Vladimir Ulyantsev International Laboratory of Computer TechnologiesITMO UniversitySt.Petersburg 197101Russia Department of Cardiovascular Surgery for Children Almazov National Medical Research CentreSt.Petersburg 197341Russia Department of Neonatal Physiology with an ICU Ward Almazov National Medical Research CentreSt.Petersburg 197341Russia Pediatric Cardiac Intensive Care Unit Almazov National Medical Research CentreSt.Petersburg 197341Russia Neonatal and Preterm Special Care Unit(2nd Stage Care) Almazov National Medical Research CentreSt.Petersburg 197341Russia Institute of Perinatology and Pediatrics Almazov National Medical Research CentreSt.Petersburg 197341Russia Express Laboratory of Perinatal Centre Almazov National Medical Research CentreSt.Petersburg 197341Russia Clinical Diagnostic Laboratory Almazov National Medical Research CentreSt.Petersburg 197341Russia Epigenetics and Metagenomics Group Institute of Perinatology and PediatricsAlmazov National Medical Research CentreSt.Petersburg 197341Russia Department of Internal Diseases Gastroenterology and DieteticsNorth-Western State Medical University named after I.I.MechnikovSt.Petersburg 191015Russia

BACKGROUND necrotizing enterocolitis(NEC)is a multifactorial disease that predominantly affects premature *** dysbiosis plays a critical role in NEC pathogenesis in premature *** main risk factor for NEC in term infants is mesenteric hypoperfusion associated with ductaldependent congenital heart disease(CHD)that eventually leads to intestinal *** incidence of NEC in neonates with critical CHD is 6.8%-13%.However,the role of the intestinal microbiome in NEC pathogenesis in infants with ductal-dependent CHD remains *** SUMMARY A male term neonate with right atrial isomerism underwent modified Blalock-Taussig shunt placement on the 14^(th)day of life and had persistent mesenteric hypoperfusion after *** patient had episodes of NEC stageⅡA on the 1^(st)and 28^(th)days after cardiac *** microbial composition was analyzed before and after cardiac surgery by sequencing region V4 of the 16S rRNA *** surgery,species belonging to genera Veillonella and Clostridia and class Gammaproteobacteria were detected,Bifidobacteriaceae showed a low *** first NEC episode was associated with postoperative hemodynamic instability,intestinal ischemiareperfusion injury during cardiopulmonary bypass,and a high abundance of Clostridium paraputrificum(Clostridium sensu stricto I)(56.1%).Antibacterial therapy after the first NEC episode resulted in increased abundance of Gammaproteobacteria,decreased abundance of Firmicutes,and low alpha *** changes in the microbial composition promoted the growth of Clostridium sensu strictoⅠ(72.0%)before the second NEC *** A high abundance of Clostridium sensu strictoⅠand mesenteric hypoperfusion may have contributed to NEC in the present case.

关键词： necrotizing enterocolitis Congenital heart disease Ivemark syndrome Heterotaxy Right atrial isomerism Intestinal microbiome Case report

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Outcome in neonates with necrotizing enterocolitis and patent ductus arteriosus

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世界儿科杂志:英文版 2016年第1期12卷 55-59页

作者： Ulf Kessler Franzisca Schulte Dietmar Cholewa Mathias Nelle Stephan C.Schaefer Peter M.Klimek Steffen Berger Department of Pediatric Surgery InselspitalBern University Hospital and University of BernSwitzerland Division of Neonatology Department of PediatricsInselspitalBern University Hospital and University of BernSwitzerland Institute of Pathology InselspitalUniversity of BernBernSwitzerland Department of Surgery HFR Fribourg-Cantonal HospitalSwitzerland

Background:There is no agreement of the influence of patent ductus arteriosus(PDA)on outcomes in patients with necrotizing enterocolitis(NEC).In this study,we assessed the infl uence of PDA on NEC ***:A retrospective study of 131 infants with established NEC was ***(death,disease severity,need for surgery,hospitalization duration),as well as multiple clinical parameters were compared between NEC patients with no congenital heart disease(n=102)and those with isolated PDA(n=29).Univariate,multivariate and stepwise logistic regression analyses were ***:Birth weight and gestational age were significantly lower in patients with PDA[median(95%CI):1120 g(1009-1562 g),28.4 wk(27.8-30.5 wk)]than in those without PDA[median(95%CI):1580 g(1593-1905 g),32.4 wk(31.8-33.5 wk);P<0.05].The risk of NEC-attributable fatality was higher in NEC patients with PDA(35%)than in NEC patients without PDA(14%)[univariate odds ratio(OR)=3.3,95%CI:1.8-8.6,P<0.05;multivariate OR=2.4,95%CI:0.82-2.39,P=0.111].Significant independent predictors for nonsurvival within the entire cohort were advanced disease severity stage III(OR=27.9,95%CI:7.4-105,P<0.001)and birth weight below 1100 g(OR=5.7,95%CI:1.7-19.4,P<0.01).Conclusions:In patients with NEC,the presence of PDA is associated with an increased risk of ***,when important differences between the two study groups are controlled,only birth weight and disease severity may independently predict mortality.

关键词： congenital heart disease necrotizing enterocolitis neonatal mortality patent ductus arteriosus

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