Protective mechanism of quercetin in alleviating sepsis-related acute respiratory distress syndrome based on network pharmacology and in vitro experiments

BACKGROUND:Sepsis-related acute respiratory distress syndrome(ARDS)has a high mortality rate,and no effective treatment is available currently.Quercetin is a natural plant product with many pharmacological activities,such as antioxidative,anti-apoptotic,and anti-inflammatory effects.This study aimed to elucidate the protective mechanism of quercetin against sepsis-related ARDS.METHODS:In this study,network pharmacology and in vitro experiments were used to investigate the underlying mechanisms of quercetin against sepsis-related ARDS.Core targets and signaling pathways of quercetin against sepsis-related ARDS were screened and were verified by in vitro experiments.RESULTS:A total of 4,230 targets of quercetin,360 disease targets of sepsis-related ARDS,and 211 intersection targets were obtained via database screening.Among the 211 intersection targets,interleukin-6(IL-6),tumor necrosis factor(TNF),albumin(ALB),AKT serine/threonine kinase 1(AKT1),and interleukin-1β(IL-1β)were identified as the core targets.A Gene Ontology(GO)enrichment analysis revealed 894 genes involved in the inflammatory response,apoptosis regulation,and response to hypoxia.Kyoto Encyclopedia of Genes and Genomes(KEGG)enrichment analysis identified 106 pathways.After eliminating and generalizing,the hypoxia-inducible factor-1(HIF-1),TNF,nuclear factor-κB(NF-κB),and nucleotide-binding and oligomerization domain(NOD)-like receptor signaling pathways were identified.Molecular docking revealed that quercetin had good binding activity with the core targets.Moreover,quercetin blocked the HIF-1,TNF,NF-κB,and NODlike receptor signaling pathways in lipopolysaccharide(LPS)-induced murine alveolar macrophage(MH-S)cells.It also suppressed the inflammatory response,oxidative reactions,and cell apoptosis.CONCLUSION:Quercetin ameliorates sepsis-related ARDS by binding to its core targets and blocking the HIF-1,TNF,NF-κB,and NOD-like receptor signaling pathways to reduce inflammation,cell apoptosis,and oxidative stress.

Outcomes of combined mitochondria and mesenchymal stem cellsderived exosome therapy in rat acute respiratory distress syndrome and sepsis

BACKGROUND The treatment of acute respiratory distress syndrome(ARDS)complicated by sepsis syndrome(SS)remains challenging.AIM To investigate whether combined adipose-derived mesenchymal-stem-cells(ADMSCs)-derived exosome(EXAD)and exogenous mitochondria(mitoEx)protect the lung from ARDS complicated by SS.METHODS In vitro study,including L2 cells treated with lipopolysaccharide(LPS)and in vivo study including male-adult-SD rats categorized into groups 1(sham-operated-control),2(ARDS-SS),3(ARDS-SS+EXAD),4(ARDS-SS+mitoEx),and 5(ARDS-SS+EXAD+mitoEx),were included in the present study.RESULTS In vitro study showed an abundance of mitoEx found in recipient-L2 cells,resulting in significantly higher mitochondrial-cytochrome-C,adenosine triphosphate and relative mitochondrial DNA levels(P<0.001).The protein levels of inflammation[interleukin(IL)-1β/tumor necrosis factor(TNF)-α/nuclear factor-κB/toll-like receptor(TLR)-4/matrix-metalloproteinase(MMP)-9/oxidative-stress(NOX-1/NOX-2)/apoptosis(cleaved-caspase3/cleaved-poly(ADP-ribose)polymerase)]were significantly attenuated in lipopolysaccharide(LPS)-treated L2 cells with EXAD treatment than without EXAD treatment,whereas the protein expressions of cellular junctions[occluding/β-catenin/zonula occludens(ZO)-1/E-cadherin]exhibited an opposite pattern of inflam-mation(all P<0.001).Animals were euthanized by 72 h post-48 h-ARDS induction,and lung tissues were harvested.By 72 h,flow cytometric analysis of bronchoalveolar lavage fluid demonstrated that the levels of inflam-matory cells(Ly6G+/CD14+/CD68+/CD11b/c+/myeloperoxidase+)and albumin were lowest in group 1,highest in group 2,and significantly higher in groups 3 and 4 than in group 5(all P<0.0001),whereas arterial oxygen-saturation(SaO2%)displayed an opposite pattern of albumin among the groups.Histopathological findings of lung injury/fibrosis area and inflammatory/DNA-damaged markers(CD68+/γ-H2AX)displayed an identical pattern of SaO2%among the groups(all P<0.0001).The protein expressions of inflammatory(TLR-4/MMP-9/IL-1β/TNF-α)/oxidative stress(NOX-1/NOX-2/p22phox/oxidized protein)/mitochondrial-damaged(cytosolic-cytochrome-C/dynamin-related protein 1)/autophagic(beclin-1/Atg-5/ratio of LC3B-II/LC3B-I)biomarkers exhibited a similar manner,whereas antioxidants[nuclear respiratory factor(Nrf)-1/Nrf-2]/cellular junctions(ZO-1/E-cadherin)/mitochondrial electron transport chain(complex I-V)exhibited an opposite manner of albumin among the groups(all P<0.0001).CONCLUSION Combined EXAD-mitoEx therapy was better than merely one for protecting the lung against ARDS-SS induced injury.

Outpatient insulin use in type 2 diabetes mellitus and acute respiratory distress syndrome outcomes:A retrospective cohort study

BACKGROUND The impact of type 2 diabetes mellitus(T2DM)on acute respiratory distress syndrome(ARDS)is debatable.T2DM was suspected to reduce the risk and complications of ARDS.However,during coronavirus disease 2019(COVID-19),T2DM predisposed patients to ARDS,especially those who were on insulin at home.AIMTo evaluate the impact of outpatient insulin use in T2DM patients on non-COVID-19 ARDS outcomes.METHODS We conducted a retrospective cohort analysis using the Nationwide Inpatient Sample database.Adult patients diagnosed with ARDS were stratified into insulin-dependent diabetes mellitus(DM)(IDDM)and non-insulindependent DM(NIDDM)groups.After applying exclusion criteria and matching over 20 variables,we compared cohorts for mortality,duration of mechanical ventilation,incidence of acute kidney injury(AKI),length of stay(LOS),hospitalization costs,and other clinical outcomes.RESULTS Following 1:1 propensity score matching,the analysis included 274 patients in each group.Notably,no statistically significant differences emerged between the IDDM and NIDDM groups in terms of mortality rates(32.8%vs 31.0%,P=0.520),median hospital LOS(10 d,P=0.537),requirement for mechanical ventilation,incidence rates of sepsis,pneumonia or AKI,median total hospitalization costs,or patient disposition upon discharge.CONCLUSION Compared to alternative anti-diabetic medications,outpatient insulin treatment does not appear to exert an independent influence on in-hospital morbidity or mortality in diabetic patients with non-COVID-19 ARDS.

Microvesicles derived from mesenchymal stem cells inhibit acute respiratory distress syndrome-related pulmonary fibrosis in mouse partly through hepatocyte growth factor

BACKGROUND Pulmonary fibrosis is one of the main reasons for the high mortality rate among acute respiratory distress syndrome(ARDS)patients.Mesenchymal stromal cell-derived microvesicles(MSC-MVs)have been shown to exert antifibrotic effects in lung diseases.AIM To investigate the effects and mechanisms of MSC-MVs on pulmonary fibrosis in ARDS mouse models.METHODS MSC-MVs with low hepatocyte growth factor(HGF)expression(siHGF-MSC-MVs)were obtained via lentivirus transfection and used to establish the ARDS pulmonary fibrosis mouse model.Following intubation,respiratory mechanics-related indicators were measured via an experimental small animal lung function tester.Homing of MSC-MVs in lung tissues was investigated by near-infrared live imaging.Immunohistochemical,western blotting,ELISA and other methods were used to detect expression of pulmonary fibrosis-related proteins and to compare effects on pulmonary fibrosis and fibrosis-related indicators.RESULTS The MSC-MVs gradually migrated and homed to damaged lung tissues in the ARDS model mice.Treatment with MSC-MVs significantly reduced lung injury and pulmonary fibrosis scores.However,low expression of HGF(siHGF-MSC-MVs)significantly inhibited the effects of MSC-MVs(P<0.05).Compared with the ARDS pulmonary fibrosis group,the MSC-MVs group exhibited suppressed expression of type I collagen antigen,type III collagen antigen,and the proteins transforming growth factor-βandα-smooth muscle actin,whereas the siHGF-MVs group exhibited significantly increased expression of these proteins.In addition,pulmonary compliance and the pressure of oxygen/oxygen inhalation ratio were significantly lower in the MSC-MVs group,and the effects of the MSC-MVs were significantly inhibited by low HGF expression(all P<0.05).CONCLUSION MSC-MVs improved lung ventilation functions and inhibited pulmonary fibrosis in ARDS mice partly via HGF mRNA transfer.

Clinical significance of platelet mononuclear cell aggregates in patients with sepsis and acute respiratory distress syndrome

BACKGROUND The diagnosis of sepsis combined with acute respiratory distress syndrome(ARDS)has increased owing to the enhanced awareness among medical profes-sionals and the continuous development of modern medical technologies,while early diagnosis of ARDS still lacks specific biomarkers.One of the main patho-genic mechanisms of sepsis-associated ARDS involves the actions of various pathological injuries and inflammatory factors,such as platelet and white blood cells activation,leading to an increase of surface adhesion molecules.These adhesion molecules further form platelet-white blood cell aggregates,including platelet-mononuclear cell aggregates(PMAs).PMAs has been identified as one of the markers of platelet activation,here we hypothesize that PMAs might play a potential biomarker for the early diagnosis of this complication.METHODS We selected 72 hospitalized patients diagnosed with sepsis as the study population between March 2019 and March 2022.Among them,30 patients with sepsis and ARDS formed the study group,while 42 sepsis patients without ARDS comprised the control group.After diagnosis,venous blood samples were imme-diately collected from all patients.Flow cytometry was employed to analyze the expression of PMAs,platelet neutrophil aggregates(PNAs),and platelet aggregates(PLyAs)in the serum.Additionally,the Acute Physiology and Chronic Health Evaluation(APACHE)II score was calculated for each patient,and receiver operating characteristic curves were generated to assess diagnostic value.RESULTS The study found that the levels of PNAs and PLyAs in the serum of the study group were higher than those in the control group,but the difference was not statistically significant(P>0.05).However,the expression of PMAs in the serum of the study group was significantly upregulated(P<0.05)and positively correlated with the APACHE II score(r=0.671,P<0.05).When using PMAs as a diagnostic indicator,the area under the curve value was 0.957,indicating a high diagnostic value(P<0.05).Furthermore,the optimal cutoff value was 8.418%,with a diagnostic sensitivity of 0.819 and specificity of 0.947.CONCLUSION In summary,the serum levels of PMAs significantly increase in patients with sepsis and ARDS.Therefore,serum PMAs have the potential to become a new biomarker for clinically diagnosing sepsis complicated by ARDS.

Mechanisms and Research Progress of Traditional Chinese Medicine Regulating NF-κB in the Treatment of Acute Lung Injury/Acute Respiratory Distress Syndrome

Acute lung injury(ALI)has multiple causes and can easily progress to acute respiratory distress syndrome(ARDS)if not properly treated.Nuclear factorκB(NF-κB)is a key pathway in the treatment of ALI/ARDS.By exploring the relevance of NF-κB and the pathogenesis of this disease,it was found that this disease was mainly associated with inflammation,dysfunction of the endothelial barrier,oxidative stress,impaired clearance of alveolar fluid,and coagulation disorders.Traditional Chinese medicine(TCM)has the characteristics of multitargeting,multipathway effects,and high safety,which can directly or indirectly affect the treatment of ALI/ARDS.This article summarizes the mechanism and treatment strategies of TCM in recent years through intervention in the NF-κB-related signaling pathways for treating ALI/ARDS.It provides an overview from the perspectives of Chinese herbal monomers,TCM couplet medicines,TCM injections,Chinese herbal compounds,and Chinese herbal preparations,offering insights into the prevention and treatment of ALI/ARDS with TCM.

Steroids in acute respiratory distress syndrome:A panacea or still a puzzle?

Acute respiratory distress syndrome(ARDS)is a unique entity marked by various etiologies and heterogenous pathophysiologies.There remain concerns regarding the efficacy of particular medications for each severity level apart from respiratory support.Among several pharmacotherapies which have been examined in the treatment of ARDS,corticosteroids,in particular,have demonstrated potential for improving the resolution of ARDS.Nevertheless,it is imperative to consider the potential adverse effects of hyperglycemia,susceptibility to hospital-acquired infections,and the development of intensive care unit acquired weakness when administering corticosteroids.Thus far,a multitude of trials spanning several decades have investigated the role of corticosteroids in ARDS.Further stringent trials are necessary to identify particular subgroups before implementing corticosteroids more widely in the treatment of ARDS.This review article provides a concise overview of the most recent evidence regarding the role and impact of corticosteroids in the management of ARDS.

Suppression of miR-17 Alleviates Acute Respiratory Distress-associated Lung Fibrosis by Regulating Mfn2

Objective Acute respiratory distress syndrome(ARDS)patients currently have relatively high mortality,which is associated with early lung fibrosis.This study aimed to investigate whether miR-17 suppression could alleviate ARDS-associated lung fibrosis by regulating Mfn2.Methods A mouse model of ARDS-related lung fibrosis was constructed via intratracheal instillation of bleomycin.The expression level of miR-17 in lung tissues was detected via quantitative real time polymerase chain reaction(qRT-PCR).In the ARDS mouse model of lung fibrosis,the mitigating effects of miR-17 interference were evaluated via tail vein injection of the miR negative control or the miR-17 antagomir.The pathological changes in the lung tissue were examined via HE staining and Masson’s trichrome staining,and the underlying molecular mechanism was investigated via ELISA,qRT-PCR and Western blotting.Results Bleomycin-induced pulmonary fibrosis significantly increased collagen deposition and the levels of hydroxyproline(HYP)and miR-17.Interfering with miR-17 significantly reduced the levels of HYP and miR-17 and upregulated the expression of Mfn2.The intravenous injection of the miR-17 antagomir alleviated lung inflammation and reduced collagen deposition.In addition,interference with miR-17 could upregulate LC3B expression,downregulate p62 expression,and improve mitochondrial structure.Conclusion Interfering with miR-17 can improve pulmonary fibrosis in mice by promoting mitochondrial autophagy via Mfn2.

Review:Acute lung injury/acute respiratory distress syndrome (ALI/ARDS): the mechanism,present strategies and future perspectives of therapies

Acute lung injury/acute respiratory distress syndrome （ALI/ARDS）, which manifests as non-cardiogcnic pulmonary edema, respiratory distress and hypoxemia, could be resulted from various processes that directly or indirectly injure the lung. Extensive investigations in experimental models and humans with ALI/ARDS have revealed many molecular mechanisms that offer therapeutic opportunities for cell or gene therapy. Herein the present strategies and future perspectives of the treatment for ALI/ARDS, include the ventilatory, pharmacological, as well as cell therapies.

Intestinal bacterial overgrowth in the early stage of severe acute pancreatitis is associated with acute respiratory distress syndrome

BACKGROUND In the early stage of acute pancreatitis(AP),a large number of cytokines induced by local pancreatic inflammation seriously damage the intestinal barrier function,and intestinal bacteria and endotoxins enter the blood,causing inflammatory storm,resulting in multiple organ failure,infectious complications,and other disorders,eventually leading to death.Intestinal failure occurs early in the course of AP,accelerating its development.As an alternative method to detect small intestinal bacterial overgrowth,the hydrogen breath test is safe,noninvasive,and convenient,reflecting the number of intestinal bacteria in AP indirectly.This study aimed to investigate the changes in intestinal bacteria measured using the hydrogen breath test in the early stage of AP to clarify the relationship between intestinal bacteria and acute lung injury(ALI)/acute respiratory distress syndrome(ARDS).Early clinical intervention and maintenance of intestinal barrier function would be highly beneficial in controlling the development of severe acute pancreatitis(SAP).AIM To analyze the relationship between intestinal bacteria change and ALI/ARDS in the early stage of SAP.METHODS A total of 149 patients with AP admitted to the intensive care unit of the Digestive Department,Xuanwu Hospital,Capital Medical University from 2016 to 2019 were finally enrolled,following compliance with the inclusion and exclusion criteria.The results of the hydrogen breath test within 1 wk of admission were collected,and the hydrogen production rates at admission,72 h,and 96 h were calculated.The higher the hydrogen production rates the more bacteria in the small intestine.First,according to the improved Marshall scoring system in the 2012 Atlanta Consensus on New Standards for Classification of Acute Pancreatitis,66 patients with a PaO2/FiO2 score≤1 were included in the mild AP(MAP)group,18 patients with a PaO2/FiO2 score≥2 and duration<48 h were included in the moderately SAP(MSAP)group,and 65 patients with a PaO2/FiO2 score≥2 and duration>48 h were included in the SAP group,to analyze the correlation between intestinal bacterial overgrowth and organ failure in AP.Second,ALI(PaO2/FiO2=2)and ARDS(PaO2/FiO2>2)were defined according to the simplified diagnostic criteria proposed by the 1994 European Union Conference.The MSAP group was divided into two groups according to the PaO2/FiO2 score:15 patients with PaO2/FiO2 score=2 were included in group A,and three patients with score>2 were included in group B.Similarly,the SAP group was divided into two groups:28 patients with score=2 were included in group C,and 37 patients with score>2 were included in group D,to analyze the correlation between intestinal bacterial overgrowth and ALI/ARDS in AP.RESULTS A total of 149 patients were included:66 patients in the MAP group,of whom 53 patients were male(80.3%)and 13 patients were female(19.7%);18 patients in the MSAP group,of whom 13 patients were male(72.2%)and 5 patients were female(27.8%);65 patients in the SAP group,of whom 48 patients were male(73.8%)and 17 patients were female(26.2%).There was no significant difference in interleukin-6 and procalcitonin among the MAP,MSAP,and SAP groups(P=0.445 and P=0.399,respectively).There was no significant difference in the growth of intestinal bacteria among the MAP,MSAP,and SAP groups(P=0.649).There was no significant difference in the growth of small intestinal bacteria between group A and group B(P=0.353).There was a significant difference in the growth of small intestinal bacteria between group C and group D(P=0.038).CONCLUSION Intestinal bacterial overgrowth in the early stage of SAP is correlated with ARDS.

Effects of fluid balance on prognosis of acute respiratory distress syndrome patients secondary to sepsis

BACKGROUND:Fluid management is crucial to acute respiratory distress syndrome(ARDS)secondary to sepsis.However,choices of fluid resuscitation strategies and fluid input volumes remain a thorny problem.Our study aimed to elucidate the relationship between fluid balance and prognosis of ARDS patients secondary to sepsis.METHODS:Our study included 322 sepsis patients from Ruijin Hospital between 2014 and 2018,and 84 patients were diagnosed as ARDS within 72 hours after onset of sepsis according to Berlin ARDS Defi nition.RESULTS:Among the 322 sepsis patients,84(26.1%)were complicated with ARDS within 72 hours.ARDS patients had a lower oxygenation index(PaO2/FiO2166.4±71.0 vs.255.0±91.2,P<0.05),longer duration of mechanical ventilation(11[6-24]days vs.0[0-0]days,P<0.05)than those without ARDS.Sepsis patients with ARDS showed daily positive net fl uid balance during seven days compared with those without ARDS who showed daily negative net fluid balance since the second day with signifi cant statistical differences.Among the 84 sepsis patients with ARDS,58(69.0%)died.Mean daily fl uid input volumes were much lower in survivors than in non-survivors(43.2±16.7 mL/kg vs.51.0±25.2 mL/kg,P<0.05)while output volumes were much higher in survivors(45.2±19.8 mL/kg vs.40.2±22.7 mL/kg,P<0.05).Using binary logistic regression analysis,we found that the mean daily fl uid balance was independently associated with mortality of sepsis patients complicating with ARDS(P<0.05).CONCLUSIONS:Early negative fluid balance is independently associated with a better prognosis of sepsis patients complicated with ARDS.

Changes in intestinal microflora in rats with acute respiratory distress syndrome

AIM: To implement high-throughput 16S rDNA sequencing to study microbial diversity in the fecal matter of rats with acute lung injury/acute respiratory distress syndrome (ALI/ARDS).

Acute lung injury and acute respiratory distress syndrome： experimental and clinical investigations

Acute lung injury （ALl） or acute respiratory distress syndrome （ARDS） can be associated with various disorders. Recent investigation has involved clinical studies in collaboration with clinical investigators and pathologists on the pathogenetic mechanisms of ALl or ARDS caused by various disorders. This literature review includes a brief historical retrospective of ALI/ARDS, the neurogenic pulmonary edema due to head injury, the long-term experimental studies and clinical investigations from our laboratory, the detrimental role of NO, the risk factors, and the possible pathogenetic mechanisms as well as therapeutic regimen for ALI/ARDS.

Effect of High Frequency Oscillatory Ventilation on EVLW and Lung Capillary Permeability of Piglets with Acute Respiratory Distress Syndrome Caused by Pulmonary and Extrapulmonary Insults

The effect of high frequency oscillatory ventilation（HFOV） at early stage on hemodynamic parameters, extravascular lung water（EVLW）, lung capillary permeability, CC16 and s ICAM-1 in piglets with pulmonary or extrapulmonary acute respiratory distress syndrome（ARDS） was explored. Central vein pressure（CVP） and pulse indicator continuous cardiac output（Pi CCO） were monitored in 12 anesthetized and intubated healthy piglets. Pulmonary ARDS（ARDSp） and extrapulmonary ARDS（ARDSexp） models were respectively established by lung lavage of saline solution and intravenous injection of oleic acid. Then the piglets received HFOV for 4 h. EVLW index（EVLWI）, EVLW/intratroracic blood volume（ITBV） and pulmonary vascular permeability index（PVPI） were measured before and after modeling（T0 and T1）, and T2（1 h）, T3（2 h）, T4（3 h） and T5（4 h） after HFOV. CC16 and s ICAM-1 were also detected at T1 and T5. Results showed at T1, T3, T4 and T5, EVLWI was increased more significantly in ARDSp group than in ARDSexp group（P〈0.05）. The EVLWI in ARDSp group was increased at T1（P=0.008）, and sustained continuously within 2 h（P=0.679, P=0.216）, but decreased at T4（P=0.007） and T5（P=0.037）. The EVLWI in ARDSexp group was also increased at T1（P=0.003）, but significantly decreased at T3（P=0.002） and T4（P=0.019）. PVPI was increased after modeling in both two groups（P=0.004, P=0.012）, but there was no significant change within 4 h（T5） under HFOV in ARDSp group, while PVPI showed the increasing trends at first, then decreased in ARDSexp group after HFOV. The changes of EVLW/ITBV were similar to those of PVPI. No significant differences were found in ΔEVLWI（P=0.13）, ΔPVPI（P=0.28） and ΔEVLW/ITBV between the two groups（P=0.63）. The significant decreases in both CC16 and s ICAM-1 were found in both two groups 4 h after HFOV, but there was no significant difference between the two groups. It was concluded that EVLWI and lung capillary permeability were markedly increased in ARDSp and ARDSexp groups. EVLW could be decreased 4 h after the HFOV treatment. HFOV, EVLW/ITBV and PVPI were increased slightly at first, and then decreased in ARDSexp group, while in ARDSp group no significant difference was found after modeling. No significant differences were found in the decreases in EVLW and lung capillary permeability 4 h after HFOV.

Lung recruitment maneuver effects on respiratory mechanics and extravascular lung water index in patients with acute respiratory distress syndrome

BACKGROUND：Animal experiments showed that recruitment maneuver （RM） and protective ventilation strategy of the lung could improve oxygenation and reduce extravascular lung water. This study was to investigate the effects of RM on respiratory mechanics and extravascular lung water index （EVLWI） in patients with acute respiratory distress syndrome （ARDS）. METHODS：Thirty patients with ARDS were randomized into a RM group and a non-RM group. In the RM group, after basic mechanical ventilation stabilized for 30 minutes, RM was performed and repeated once every 12 hours for 3 days. In the non-RM group, lung protective strategy was conducted without RM. Oxygenation index （PaO2/FiO2）, peak inspiratory pressure （PIP）, Plateau pressure （Pplat）, static pulmonary compliance （Cst） and EVLWI of patients before treatment and at 12, 24, 48, 72 hours after the treatment were measured and compared between the groups. Hemodynamic changes were observed before and after RM. One-way ANOVA, Student＇s t test and Fisher＇s exact test were used to process the data. RESULTS：The levels of PaO2/FiO2 and Cst increased after treatment in the two groups, but they were higher in the RM group than in the non-RM group （P〈0.05）. The PIP and Pplat decreased after treatment in the two groups, but they were lower in the RM group than in the non-RM group （P〈0.05）. The EVLWI in the two groups showed downward trend after treatment （P〈0.05）, and the differences were signifcant at all time points （P〈0.01）; the EVLWI in the RM group was lower than that in the non-RM group at 12, 24, 48 and 72 hours （P〈0.05 or P〈0.01）. Compared with pre-RM, hemodynamics changes during RM were significantly different （P〈0.01）; compared with pre-RM, the changes were not significantly different at 120 seconds after the end of RM （P〉0.05）. CONCLUSIONS： RM could reduce EVLWI, increase oxygenation and lung compliance. The effect of RM on hemodynamics was transient.

Effi cacy and safety of low-dose corticosteroids for acute respiratory distress syndrome:A systematic review and meta-analysis

BACKGROUND:There are confl icting results regarding whether corticosteroids have better effi cacy than placebo in acute respiratory distress syndrome(ARDS)patients.Therefore,we aim to further evaluate the effi cacy and safety of corticosteroids in adult ARDS patients.METHODS:The databases,including Medline,EMBASE,and Cochrane Central Register of Controlled Trials(CENTRAL)in the Cochrane Library,were searched from their inception to May 2,2020.Randomized controlled trials(RCTs)and observational cohort studies were selected to assess the use of corticosteroids in adult ARDS patients.The quality of the results was judged by the Grading of Recommendations Assessment,Development,and Evaluation(GRADE)methodology.The inverse-variance method with random or fixed effects modeling was used to compute pooled odds ratio(OR),standardized mean diff erence(SMD),and their 95%confi dence interval(CI).RESULTS:Eight eligible RCTs and six cohort studies were included.The use of corticosteroids was associated with reduced mortality(OR 0.57,95%CI 0.43-0.76,I2=35.1%,P=0.148)in ARDS patients,and the result was confirmed in the included cohort studies(OR 0.51,95%CI 0.27-0.95,I2=66.7%,P=0.010).The subgroup analysis stratified by the initiation time and duration of corticosteroid use showed that early ARDS and prolonged corticosteroid use had signifi cant survival benefits in the RCTs.The low-dose corticosteroid use was also associated with significantly more ventilator-free days and a reduced rate of new infections in ARDS patients.CONCLUSIONS:The low-dose corticosteroid therapy may be safe and reduce mortality,especially in patients with prolonged treatment and early ARDS.

Medical imaging for pancreatic diseases:Prediction of severe acute pancreatitis complicated with acute respiratory distress syndrome

In this editorial we comment on the article published in the recent issue of the World Journal of Gastroenterology[2022;28(19):2123-2136].We pay attention to how to construct a simpler and more reliable new clinical predictive model to early identify patients at high risk of acute respiratory distress syndrome(ARDS)associated with severe acute pancreatitis(SAP),and to early predict the severity of organ failure from chest computed tomography(CT)findings in SAP patients.As we all know,SAP has a sudden onset,is a rapidly changing condition,and can be complicated with ARDS and even multiple organ dysfunction syndrome,and its mortality rate has remained high.At present,there are many clinical scoring systems for AP,including the bedside index for severity in AP,acute physiology and chronic health evaluation II,systemic inflammatory response syndrome,Japanese severe score,quick sepsis-related organ failure assessment,etc.However,some of these scoring systems are complex and require multiple and difficult clinical parameters for risk stratification.Although the aforementioned biomarkers are readily available,their ability to predict ARDS varies.Accordingly,it is extremely necessary to establish a simple and valuable novel model to predict the development of ARDS in AP.In addition,the extra-pancreatic manifestations of AP patients often involve the chest,among which pleural effusion and pulmonary consolidation are the more common complications.Therefore,by measuring the semi-quantitative indexes of chest CT in AP patients,such as the amount of pleural effusion and the number of lobes involved as pulmonary consolidation,it has important reference value for the early diagnosis of SAP complicated with ARDS and is expected to provide a basis for the early treatment of ARDS.

Development and external validation of models to predict acute respiratory distress syndrome related to severe acute pancreatitis

BACKGROUND Acute respiratory distress syndrome(ARDS)is a major cause of death in patients with severe acute pancreatitis(SAP).Although a series of prediction models have been developed for early identification of such patients,the majority are complicated or lack validation.A simpler and more credible model is required for clinical practice.AIM To develop and validate a predictive model for SAP related ARDS.METHODS Patients diagnosed with AP from four hospitals located at different regions of China were retrospectively grouped into derivation and validation cohorts.Statistically significant variables were identified using the least absolute shrinkage and selection operator regression method.Predictive models with nomograms were further built using multiple logistic regression analysis with these picked predictors.The discriminatory power of new models was compared with some common models.The performance of calibration ability and clinical utility of the predictive models were evaluated.RESULTS Out of 597 patients with AP,139 were diagnosed with SAP(80 in derivation cohort and 59 in validation cohort)and 99 with ARDS(62 in derivation cohort and 37 in validation cohort).Four identical variables were identified as independent risk factors for both SAP and ARDS:heart rate[odds ratio(OR)=1.05;95%CI:1.04-1.07;P<0.001;OR=1.05,95%CI:1.03-1.07,P<0.001],respiratory rate(OR=1.08,95%CI:1.0-1.17,P=0.047;OR=1.10,95%CI:1.02-1.19,P=0.014),serum calcium concentration(OR=0.26,95%CI:0.09-0.73,P=0.011;OR=0.17,95%CI:0.06-0.48,P=0.001)and blood urea nitrogen(OR=1.15,95%CI:1.09-1.23,P<0.001;OR=1.12,95%CI:1.05-1.19,P<0.001).The area under receiver operating characteristic curve was 0.879(95%CI:0.830-0.928)and 0.898(95%CI:0.848-0.949)for SAP prediction in derivation and validation cohorts,respectively.This value was 0.892(95%CI:0.843-0.941)and 0.833(95%CI:0.754-0.912)for ARDS prediction,respectively.The discriminatory power of our models was improved compared with that of other widely used models and the calibration ability and clinical utility of the prediction models performed adequately.CONCLUSION The present study constructed and validated a simple and accurate predictive model for SAPrelated ARDS in patients with AP.

Biomarkers for patients with trauma associated acute respiratory distress syndrome

Trauma is a major factor that contributes to the risk for acute respiratory distress syndrome(ARDS).Biomarkers that predict the risk,diagnosis,treatment response and prognosis of ARDS after trauma have been widely investigated.In addition to their applications in clinical diagnosis and treatment,these biomarkers provide important insights into our understanding of the pathogenesis of ARDS.This review begins with a brief introduction regarding the incidence and pathogenesis of trauma-associated ARDS.Then,we focus on reviewing the clinical trials that have been designed to investigate the value of biomarkers in ARDS after trauma.Biomarkers with a confirmed value in ARDS have been organized on the basis of key pathogenic processes that are central to ARDS and are described in detail.Among these,angiopoietin 2(Ang-2),L-selectin,Clara cell protein 16(CC16),soluable receptor for advanced glycation end products(s RAGE),Surfactant protein D(SP-D),histones,mt DNAs and some biomarker panels had a certain association with the diagnosis and prognosis of trauma-related ARDS.Further investigations are needed regarding the design of trials,the best sampling approaches and the optimal combinations of the biomarker panels.

Mitofusion 2 Overexpression Decreased Proliferation of Human Embryonic Lung Fibroblasts in Acute Respiratory Distress Syndrome through Inhibiting RAS-RAF-1-ERK1/2 Pathway

Acute respiratory distress syndrome(ARDS)is one of the most fatal diseases worldwide.Pulmonary fibrosis occurs early in ARDS,and its severity plays a crucial role in ARDS mortality rate.Some studies suggested that fibroproliferation is an essential mechanism in ARDS.Mitofusion2(Mfn2)overexpression plays a role in inhibiting cell proliferation.However,the role and potential mechanism of Mfn2 on the proliferation of fibroblasts is still unknown.In this study,we aimed at exploring the effect of Mfn2 on the human embryonic lung fibroblasts(HELF)and discussed its related mechanism.The HELF were treated with the Mfn2 overexpressing lentivirus(adv-Mfn2).The cell cycle was detected by flow cytometry.MTT,PCR and Western blotting were used to investigate the effect of Mfn2 on the proliferation of the HELF,collagen expression,the RAS-RAF-1-ERK1/2 pathway and the expression of cycle-related proteins(p21,p27,Rb,Raf-1,p-Raf-1,Erk1/2 and p-Erk1/2).The co-immunoprecipitation assay was used to explore the interaction between Mfn2 and Ras.The results showed that the overexpression of Mfn2 inhibited the proliferation of the HELF and induced the cell cycle arrest at the G0/G1 phase.Meanwhile,Mfn2 also inhibited the expression of collagen I,p-Erk and p-Raf-1.In addition,an interaction between Mfn2 and Ras existed in the HELF.This study suggests that the overexpression of Mfn2 can decrease the proliferation of HELF in ARDS,which was associated with the inhibition of the RAS-RAF-1-ERK1/2 pathway.The results may offer a potential therapeutic intervention for patients with ARDS.