Modulating the crosstalk between macrophage and Th17: potential mechanism of natural products on acute lung injury

Sepsis is a life-threatening multiple organ dysfunction syndrome caused by the imbalance of the immune response to infection,featuring complex and variable conditions,and is one of the leading causes of mortality in ICU patients.Lung injury is a common organ damage observed in sepsis patients.Macrophages and Th17 cells,as crucial components of innate and adaptive immunity,play pivotal roles in the development of sepsis-induced acute lung injury(ALI).This review summarizes the alterations and mechanisms of macrophages and Th17 cells in sepsis-induced ALI.By focusing on the“cross-talk”between macrophages and Th17 cells,this review aims to provide a solid theoretical foundation for further exploring the therapeutic targets of traditional Chinese medicine formulas in the treatment of sepsis complicated with ALI,thereby offering insights and guidance for the clinical application of traditional Chinese medicine in managing sepsis-associated ALI.

MicroRNA-451 from Human Umbilical Cord-Derived Mesenchymal Stem Cell Exosomes Inhibits Alveolar Macrophage Autophagy via Tuberous Sclerosis Complex 1/Mammalian Target of Rapamycin Pathway to Attenuate Burn-Induced Acute Lung Injury in Rats

Objective Our previous studies established that microRNA(miR)-451 from human umbilical cord mesenchymal stem cell-derived exosomes(hUC-MSC-Exos)alleviates acute lung injury(ALI).This study aims to elucidate the mechanisms by which miR-451 in hUC-MSC-Exos reduces ALI by modulating macrophage autophagy.Methods Exosomes were isolated from hUC-MSCs.Severe burn-induced ALI rat models were treated with hUC-MSC-Exos carrying the miR-451 inhibitor.Hematoxylin-eosin staining evaluated inflammatory injury.Enzyme-linked immunosorbnent assay measured lipopolysaccharide(LPS),tumor necrosis factor-α,and interleukin-1βlevels.qRT-PCR detected miR-451 and tuberous sclerosis complex 1(TSC1)expressions.The regulatory role of miR-451 on TSC1 was determined using a dual-luciferase reporter system.Western blotting determined TSC1 and proteins related to the mammalian target of rapamycin(mTOR)pathway and autophagy.Immunofluorescence analysis was conducted to examine exosomes phagocytosis in alveolar macrophages and autophagy level.Results hUC-MSC-Exos with miR-451 inhibitor reduced burn-induced ALI and promoted macrophage autophagy.MiR-451 could be transferred from hUC-MSCs to alveolar macrophages via exosomes and directly targeted TSC1.Inhibiting miR-451 in hUC-MSC-Exos elevated TSC1 expression and inactivated the mTOR pathway in alveolar macrophages.Silencing TSC1 activated mTOR signaling and inhibited autophagy,while TSC1 knockdown reversed the autophagy from the miR-451 inhibitor-induced.Conclusion miR-451 from hUC-MSC exosomes improves ALI by suppressing alveolar macrophage autophagy through modulation of the TSC1/mTOR pathway,providing a potential therapeutic strategy for ALI.

Impact of interleukin 6 levels on acute lung injury risk and disease severity in critically ill sepsis patients

BACKGROUND Sepsis is a life-threatening condition characterized by a dysregulation of the host response to infection that can lead to acute lung injury(ALI)and multiple organ dysfunction syndrome(MODS).Interleukin 6(IL-6)is a pro-inflammatory cytokine that plays a crucial role in the pathogenesis of sepsis and its complications.AIM To investigate the relationship among plasma IL-6 levels,risk of ALI,and disease severity in critically ill patients with sepsis.METHODS This prospective and observational study was conducted in the intensive care unit of a tertiary care hospital between January 2021 and December 2022.A total of 83 septic patients were enrolled.Plasma IL-6 levels were measured upon admission using an enzyme-linked immunosorbent assay.The development of ALI and MODS was monitored during hospitalization.Disease severity was evaluated by Acute Physiology and Chronic Health Evaluation II(APACHE II)and Sequential Organ Failure Assessment(SOFA)scores.RESULTS Among the 83 patients with sepsis,38(45.8%)developed ALI and 29(34.9%)developed MODS.Plasma IL-6 levels were significantly higher in patients who developed ALI than in those without ALI(median:125.6 pg/mL vs 48.3 pg/mL;P<0.001).Similarly,patients with MODS had higher IL-6 levels than those without MODS(median:142.9 pg/mL vs 58.7 pg/mL;P<0.001).Plasma IL-6 levels were strongly and positively correlated with APACHE II(r=0.72;P<0.001)and SOFA scores(r=0.68;P<0.001).CONCLUSIONElevated plasma IL-6 levels in critically ill patients with sepsis were associated with an increased risk of ALI andMODS.Higher IL-6 levels were correlated with greater disease severity,as reflected by higher APACHE II andSOFA scores.These findings suggest that IL-6 may serve as a biomarker for predicting the development of ALI anddisease severity in patients with sepsis.

Mogroside IIE,an in vivo metabolite of sweet agent,alleviates acute lung injury via Pla2g2a-EGFR inhibition

In the face of increasingly serious environmental pollution,the health of human lung tissues is also facing serious threats.Mogroside IIE(M2E)is the main metabolite of sweetening agents mogrosides from the anti-tussive Chinese herbal Siraitia grosvenori.The study elucidated the anti-inflammatory action and molecular mechanism of M2E against acute lung injury(ALI).A lipopolysaccharide(LPS)-induced ALI model was established in mice and MH-S cells were employed to explore the protective mechanism of M2E through the western blotting,co-immunoprecipitation,and quantitative real time-PCR analysis.The results indicated that M2E alleviated LPS-induced lung injury through restraining the activation of secreted phospholipase A2 type IIA(Pla2g2a)-epidermal growth factor receptor(EGFR).The interaction of Pla2g2a and EGFR was identified by co-immunoprecipitation.In addition,M2E protected ALI induced with LPS against inflammatory and damage which were significantly dependent upon the downregulation of AKT and m TOR via the inhibition of Pla2g2a-EGFR.Pla2g2a may represent a potential target for M2E in the improvement of LPS-induced lung injury,which may represent a promising strategy to treat ALI.

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.

Research Progress on the Pathogenesis of Acute Lung Injury(ALI)

In this review,the databases searched were PubMed and Web of Science.It is believed that the main causes of acute lung injury(ALI)and acute respiratory distress syndrome(ARDS)are inflammatory response disorders,excessive oxidative stress,cell death,endoplasmic reticulum stress,coagulation dysfunction,and weakened aquaporin function.

Periplaneta Americana Extract Ameliorates LPS-induced Acute Lung Injury Via Reducing Inflammation and Oxidative Stress

Objective Acute lung injury(ALI)is an acute clinical syndrome characterized by uncontrolled inflammation response,which causes high mortality and poor prognosis.The present study determined the protective effect and underlying mechanism of Periplaneta americana extract(PAE)against lipopolysaccharide(LPS)-induced ALI.Methods The viability of MH-S cells was measured by MTT.ALI was induced in BALB/c mice by intranasal administration of LPS(5 mg/kg),and the pathological changes,oxidative stress,myeloperoxidase activity,lactate dehydrogenase activity,inflammatory cytokine expression,edema formation,and signal pathway activation in lung tissues and bronchoalveolar lavage fluid(BALF)were examined by H&E staining,MDA,SOD and CAT assays,MPO assay,ELISA,wet/dry analysis,immunofluorescence staining and Western blotting,respectively.Results The results revealed that PAE obviously inhibited the release of proinflammatory TNF-α,IL-6 and IL-1βby suppressing the activation of MAPK/Akt/NF-κB signaling pathways in LPS-treated MH-S cells.Furthermore,PAE suppressed the neutrophil infiltration,permeability increase,pathological changes,cellular damage and death,pro-inflammatory cytokines expression,and oxidative stress upregulation,which was associated with its blockage of the MAPK/Akt/NF-κB pathway in lung tissues of ALI mice.Conclusion PAE may serve as a potential agent for ALI treatment due to its anti-inflammatory and anti-oxidative properties,which correlate to the blockage of the MAPK/NF-κB and AKT signaling pathways.

Glycolysis and acute lung injury:A review

Acute lung injury is featured as diffuse pulmonary edema and persistent hypoxemia caused by lung or systemic injury.It is believed that these pathological changes are associated with damage to the alveolar epithelium and vascular endothelium,recruitment of inflammatory cells,and inflammatory factor storms.In recent years,the metabolic reprogramming of lung parenchymal cells and immune cells,particularly alterations in glycolysis,has been found to occur in acute lung injury.Inhibition of glycolysis can reduce the severity of acute lung injury.Thus,this review focuses on the interconnection between acute lung injury and glycolysis and the mechanisms of interaction,which may bring hope for the treatment of acute lung injury.

Extracellular vesicles in the pathogenesis and treatment of acute lung injury

Acute lung injury(ALI)and acute respiratory distress syndrome(ARDS)are common life-threatening lung diseases associated with acute and severe inflammation.Both have high mortality rates,and despite decades of research on clinical ALI/ARDS,there are no effective therapeutic strategies.Disruption of alveolar-capillary barrier integrity or activation of inflammatory responses leads to lung inflammation and injury.Recently,studies on the role of extracellular vesicles(EVs)in regulating normal and pathophysiologic cell activities,including inflammation and injury responses,have attracted attention.Injured and dysfunctional cells often secrete EVs into serum or bronchoalveolar lavage fluid with altered cargoes,which can be used to diagnose and predict the development of ALI/ARDS.EVs secreted by mesenchymal stem cells can also attenuate inflammatory reactions associated with cell dysfunction and injury to preserve or restore cell function,and thereby promote cell proliferation and tissue regeneration.This review focuses on the roles of EVs in the pathogenesis of pulmonary inflammation,particularly ALI/ARDS.

Study of the anti-inflammatory effect of the Traditional Mongolian Medicine Hohgardi-9 in acute lung injury

Background:Hohgardi-9 is a well-known traditional Mongolian drug that relieves cough and removes phlegm.Although it is widely used to treat lung diseases clinically,Hohgardi-9’s bioactive constituents and mechanism of action are unknown.In this study,we explored the bioactive compounds in Hohgardi-9 and the mechanism underlying its therapeutic effect against acute lung injury(ALI).Methods:We obtained the main components of Hohgardi-9 and analyzed the targets related to ALI by searching the traditional Chinese medicine systems pharmacology database and existing literature.Then,we constructed the compound-target network using Cytoscape 3.8.0 software to obtain the bioactive compounds in Hohgardi-9 against ALI.We used a string database to investigate the interaction between the possible protein targets of Hohgardi-9.We also performed Gene Ontology function annotation and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis to predict its anti-ALI mechanism.Further,to verify the therapeutical effects of Hohgardi-9,we used an ALI rat model and analyzed the components of Hohgardi-9 found in the rat plasma using ultra-high-performance liquid chromatography coupled with Q-Exactive mass spectrometry.Results:The network pharmacology and plasma component analysis showed that Hohgardi-9 contained 31 potentially bioactive components,including quercetin,herbacetin,izoteolin,and columbinetin acetate,which affected the NF-κB,TLR,and TNF signaling pathways via key targets,such as RELA(p65)and TLR4.The in vivo experiments using hematoxylin and eosin staining revealed that Hohgardi-9 significantly improved lung tissue injury and pulmonary edema in ALI rats.Simultaneously,Hohgardi-9 significantly reduced the expression levels of genes encoding inflammatory factors,such as TRL4,TNF-α,IL-1β,and ICAM1,in the lungs of ALI rats.Conclusion:Hohgardi-9 alleviated ALI by inhibiting inflammation-related gene expression through its active ingredients,such as quercetin and herbacetin.

Network pharmacology and molecular docking to explore Polygoni Cuspidati Rhizoma et Radix treatment for acute lung injury

BACKGROUND Polygoni Cuspidati Rhizoma et Radix(PCRR),a well-known traditional Chinese medicine(TCM),inhibits inflammation associated with various human diseases.However,the anti-inflammatory effects of PCRR in acute lung injury(ALI)and the underlying mechanisms of action remain unclear.AIM To determine the ingredients related to PCRR for treatment of ALI using multiple databases to obtain potential targets for fishing.METHODS Recognized and candidate active compounds for PCRR were obtained from Traditional Chinese Medicine Systems Pharmacology,STITCH,and PubMed databases.Target ALI databases were built using the Therapeutic Target,DrugBank,DisGeNET,Online Mendelian Inheritance in Man,and Genetic Association databases.Network pharmacology includes network construction,target prediction,topological feature analysis,and enrichment analysis.Bioinformatics resources from the Database for Annotation,Visualization and Integrated Discovery were utilized for gene ontology biological process and Kyoto Encyclopedia of Genes and Genomes network pathway enrichment analysis,and molecular docking techniques were adopted to verify the combination of major active ingredients and core targets.RESULTS Thirteen bioactive compounds corresponding to the 433 PCRR targets were identified.In addition,128 genes were closely associated with ALI,60 of which overlapped with PCRR targets and were considered therapeutically relevant.Functional enrichment analysis suggested that PCRR exerted its pharmacological effects in ALI by modulating multiple pathways,including the cell cycle,cell apoptosis,drug metabolism,inflammation,and immune modulation.Molecular docking results revealed a strong associative relationship between the active ingredient and core target.CONCLUSION PCRR alleviates ALI symptoms via molecular mechanisms predicted by network pharmacology.This study proposes a strategy to elucidate the mechanisms of TCM at the network pharmacology level.

Multiomics reveal human umbilical cord mesenchymal stem cells improving acute lung injury via the lung-gut axis

BACKGROUND Acute lung injury(ALI)and its final severe stage,acute respiratory distress syndrome,are associated with high morbidity and mortality rates in patients due to the lack of effective specific treatments.Gut microbiota homeostasis,including that in ALI,is important for human health.Evidence suggests that the gut microbiota improves lung injury through the lung-gut axis.Human umbilical cord mesenchymal cells(HUC-MSCs)have attractive prospects for ALI treatment.This study hypothesized that HUC-MSCs improve ALI via the lung-gut microflora.AIM To explore the effects of HUC-MSCs on lipopolysaccharide(LPS)-induced ALI in mice and the involvement of the lung-gut axis in this process.METHODS C57BL/6 mice were randomly divided into four groups(18 rats per group):Sham,sham+HUC-MSCs,LPS,and LPS+HUC-MSCs.ALI was induced in mice by intraperitoneal injections of LPS(10 mg/kg).After 6 h,mice were intervened with 0.5 mL phosphate buffered saline(PBS)containing 1×10^(6) HUC-MSCs by intraperitoneal injections.For the negative control,100 mL 0.9%NaCl and 0.5 mL PBS were used.Bronchoalveolar lavage fluid(BALF)was obtained from anesthetized mice,and their blood,lungs,ileum,and feces were obtained by an aseptic technique following CO_(2) euthanasia.Wright’s staining,enzyme-linked immunosorbent assay,hematoxylin-eosin staining,Evans blue dye leakage assay,immunohistochemistry,fluorescence in situ hybridization,western blot,16S rDNA sequencing,and non-targeted metabolomics were used to observe the effect of HUC-MSCs on ALI mice,and the involvement of the lung-gut axis in this process was explored.One-way analysis of variance with post-hoc Tukey’s test,independent-sample Student’s t-test,Wilcoxon rank-sum test,and Pearson correlation analysis were used for statistical analyses.RESULTS HUC-MSCs were observed to improve pulmonary edema and lung and ileal injury,and decrease mononuclear cell and neutrophil counts,protein concentrations in BALF and inflammatory cytokine levels in the serum,lung,and ileum of ALI mice.Especially,HUC-MSCs decreased Evans blue concentration and Toll-like receptor 4,myeloid differentiation factor 88,p-nuclear factor kappa-B(NF-κB)/NF-κB,and p-inhibitorαof NF-κB(p-IκBα)/IκBαexpression levels in the lung,and raised the pulmonary vascular endothelial-cadherin,zonula occludens-1(ZO-1),and occludin levels and ileal ZO-1,claudin-1,and occludin expression levels.HUC-MSCs improved gut and BALF microbial homeostases.The number of pathogenic bacteria decreased in the BALF of ALI mice treated with HUCMSCs.Concurrently,the abundances of Oscillospira and Coprococcus in the feces of HUS-MSC-treated ALI mice were significantly increased.In addition,Lactobacillus,Bacteroides,and unidentified_Rikenellaceae genera appeared in both feces and BALF.Moreover,this study performed metabolomic analysis on the lung tissue and identified five upregulated metabolites and 11 downregulated metabolites in the LPS+MSC group compared to the LPS group,which were related to the purine metabolism and the taste transduction signaling pathways.Therefore,an intrinsic link between lung metabolite levels and BALF flora homeostasis was established.CONCLUSION This study suggests that HUM-MSCs attenuate ALI by redefining the gut and lung microbiota.

Lung ultrasound for the early diagnosis of acute lung injury:A case report

BACKGROUND The extensive availability of ultrasound(US)technology has increased its use for point-of-care applications in many health care settings.During anaesthesia and surgery,acute respiratory failure or pulmonary oedema are common lifethreatening events that,if not recognized and treated appropriately,result in a high mortality rate.CASE SUMMARY We report a patient under anaesthesia whose lung US examination showed multiple vertical artefacts(B-lines)in the lung tissue,indicating pulmonary oedema.The respiratory state improved with the resolution of the pulmonary oedema after our treatment.CONCLUSION We believe that US of the lungs may be a useful tool for dynamic respiratory monitoring at the bedside during anaesthesia.

Effects of Yue-Bi-Tang on water metabolism in severe acute pancreatitis rats with acute lung-kidney injury

BACKGROUND The complications acute lung injury and acute kidney injury caused by severe inflammation are the main reasons of high mortality of severe acute pancreatitis(SAP).These two complications can both lead to water metabolism and acid-base balance disorders,which could act as additional critical factors affecting the disease trend.Aquaporins(AQPs),which can regulate the transmembrane water transport,have been proved to participate in the pathophysiological process of SAP and the associated complications,such as acute lung injury and acute kidney injury.Thus,exploring herbs that can effectively regulate the expression of AQP in SAP could benefit the prognosis of this disease.AIM To determine whether Yue-Bi-Tang(YBT)can regulate the water metabolism in rats with severe acute pancreatitis via regulating the expression of aquaporins.METHODS Sprague-Dawley rats were randomly divided into three groups,sham operation group(SOG),model group(MG),and treatment group(TG).SAP was induced with 3.5%sodium taurocholate in the MG and TG.Rats in the TG were administered with YBT while SOG and MG rats were given the same volume of saline.Blood and tissue samples were harvested to detect serum inflammatory cytokines,histopathological changes,malondialdehyde and superoxide dismutase in the lung,and protein and mRNA expression of kidney injury molecule-1,α-smooth muscle actin,and vimentin in the kidney,and AQP1 and 4 in the lung,pancreas,and kidney.RESULTS The serum interleukin-10,tumor necrosis factorα,and creatinine levels were higher in the MG than in the SOG.Tumor necrosis factorαlevel in the TG was lower than that in the MG.Malondialdehyde level in lung tissues was higher than in the SOG.The pathological scores and edema scores of the pancreas,lung,and kidney tissues in the MG were all higher than those in the SOG and TG.The protein expression of AQP4 in lung tissues and AQP1 in kidney tissues in the MG were higher than those in the SOG and TG.The expression of vimentin was significantly higher in the MG than in the SOG.The expression of AQP1 mRNA in the lung and kidney,and AQP4 mRNA in the kidney was up-regulated in the MG compared to the SOG.CONCLUSION YBT might regulate water metabolism to reduce lung and kidney edema of SAP rats via decreasing AQP expression,and alleviate the tissue inflammatory injury.

Dexmedetomidine Alleviates Pulmonary Edema by Upregulating AQP1 and AQP5 Expression in Rats with Acute Lung Injury Induced by Lipopolysaccharide

This study aims to elucidate the mechanisms by which dexmedetomidine alleviates pulmonary edema in rats with acute lung injury induced by lipopolysaccharide （LPS）. Male Wistar rats were randomly divided into five groups： normal saline control （NS） group, receiving intravenous 0.9% normal saline （5 mL/kg）; LPS group, receiving intravenous LPS （10 mg/kg）; small-dose dexmedetomidine （S） group, treated with a small dose of dexmedetomidine （0.5 μg·kg^-1·h^-1）; medium-dose dexmedetomidine （M） group, treated with a medium dose of dexmedetomidine （2.5 μg·kg^-1·h^-1）; high-dose dexmedetomidine （H） group, treated with a high dose of dexmedetomidine （5μg·kg^-1·h^-1）. The rats were sacrificed 6 h after intravenous injection of LPS or NS, and the hmgs were removed for evaluating histological characteristics and determining the lung wet/dry weight ratio （W/D）. The levels of tumor necrosis factor-alpha （TNF-α） and interleukin-1β （IL-1β） in the lung tissues were assessed by enzyme-linked immunosorbent assay （ELISA）. The mRNA and protein expression levels of aquaporin-1 （AQP1） and aquaporin-5 （AQP5） were detected by RT-PCR, immunohistochemistry, and Western blot- ting. The lung tissues from the LPS groups were significantly damaged, which were less pronounced in the H group but not in the small-dose dexmedetomidine group or medium-dose dexmedetomidine group. The W/D and the concentrations of TNF-α and IL-1β in the pulmonary tissues were increased in the LPS group as compared with those in NS group, which were reduced in the H group but not in S group or M group （P〈0.01）. The expression of AQP1 and AQP5 was lower in the LPS group than in the NS group, and significantly increased in the H group but not in the S group or M group （P〈0.01）. Our findings suggest that dexmedetomidine may alleviate pulmonary edema by increasing the expression of AQP-1 and AQP-5.

Circulating miRNAs as biomarkers for severe acute pancreatitis associated with acute lung injury

AIM To identify circulating micro(mi)RNAs as biological markers for prediction of severe acute pancreatitis(SAP) with acute lung injury(ALI).METHODS Twenty-four serum samples were respectively collected and classified as SAP associated with ALI and SAP without ALI, and the mi RNA expression profiles were determined by microarray analysis. These mi RNAs were validated by quantitative reverse transcriptionpolymerase chain reaction, and their putative targets were predicted by the online software Target Scan, mi Randa and Pic Tar database. Gene ontology(GO) and Kyoto encyclopedia of genes and genomes(commonly known as KEGG) were used to predict their possible functions and pathways involved.RESULTS We investigated 287 mi RNAs based on microarray data analysis. Twelve mi RNAs were differentially expressed in the patients with SAP with ALI and those with SAP without ALI. Hsa-mi R-1260 b, 762, 22-3 p, 23 b and 23 a were differently up-regulated and hsa-mi R-550 a*, 324-5 p, 484, 331-3 p, 140-3 p, 342-3 p and 150 were differently down-regulated in patients with SAP with ALI compared to those with SAP without ALI. In addition, 85 putative target genes of the significantly dysregulated mi RNAs were found by Target Scan, mi Randa and Pic Tar. Finally, GO and pathway network analysis showed that they were mainly enriched in signal transduction, metabolic processes, cytoplasm and cell membranes.CONCLUSION This is the first study to identify 12 circulating mi RNAs in patients with SAP with ALI, which may be biomarkers for prediction of ALI after SAP.

Therapeutic effects of Caspase-1 inhibitors on acute lung injury in experimental severe acute pancreatitis

AIM： To assess the therapeutic effect of Caspase-1 inhibitors （ICE-I） on acute lung injury （ALI） in experimental severe acute pancreatitis （SAP）. METHODS： Forty-two SD rats were randomly divided into 3 groups： healthy controls （HC, n = 6）; SAP-S group （n = 18）; SAP-ICE-i group （n = 18）. SAP was induced by retrograde infusion of 5% sodium taurocholate into the bile-pancreatic duct. HC rats underwent the same surgical procedures and duct cannulation without sodium taurocholate infusion, in SAP-S group, rats received the first intraperitoneal injection of isotonic saline 2 h after induction of acute pancreatitis and a repeated injection after 12 h. In SAP-ICE-I group, the rats were firstly given ICE inhibitors intraperitoneally 2 h after induction of pancreatitis. As in SAP-S group, the injection was repeated at 12 h. Serum 1L-1β was measured by EUSA. Intrapulmonary expression of Caspase-1, IL-1β and IL-18 mRNA were detected by semi-quantitative RT-PCR. The wet/dry weight ratios and histopathological changes of the lungs were also evaluated. RESULTS： Serum IL-1β levels in SAP-S group were 276.77 ± 44.92 pg/mL at 6 h, 308.99 ± 34.95 pg/mL at 12 h, and 311.60 ± 46.51 pg/mL at 18 h, which were increased significantly （P 〈 0.01, vs HC）. in SAP- ICE-I group, those values were decreased significantly （P 〈 0.01, vs SAP-S）. intrapulmonary expression of Caspase-1, IL-1β and IL-18 mRNA were observed in the HC group, while they were increased significantly in the SAP-S group （P 〈 0.01, vs HC）. The expression of IL-lβ and IL-18 mRNA were decreased significantly in the SAP- ICE-I group （P 〈 0.01, vs SAP-S）, whereas Caspase-1 mRNA expression had no significant difference （P 〉 0.05）. The wet/dry weight ratios of the lungs in the SAP-S group were increased significantly （P 〈 0.05 at 6 h, P 〈 0.01 at 12 h and 18 h, vs HC） and they were decreased significantly in the SAP-ICE-I group （P 〈 0.05, vs SAP-S）.Caspase-1 inhibitors ameliorated the severity of ALl in SAP.CONCLUSION： Caspase-1 activation, and overproduction of IL-1β and IL-18 play an important role in the course of ALI, and Caspase-1 inhibition is effective for the treatment of ALI in experimental SAP.

Pathogenesis of acute lung injury in rats with severe acute pancreatitis

BACKGROUND: Acute lung injury (ALI) is the most common and severe complication of severe acute pancreatitis (SAP). The elucidation of the mechanism of ALI contributes to the diagnosis and treatment of the illness. In this study, we studied the pathogenesis of ALI in rats with severe acute pancreatitis. METHODS: The rats were sacrificed at 1, 3, 5, 6, 9 and 12 hours after the establishment of the model of SAP. Pancreas and lung tissues were obtained for pathological study, and examination of microvascular permeability and myeloperoxidase (MPO) examination. The gene expressions of tumor necrosis factor-α (TNF-α) and intercellular adhesion molecule-1 (ICAM-1) in the pancreas and lung tissues were detected by reverse transcriptase-polymerase chain reaction (RT-PCR). RESULTS: After the establishment of the SAP model, the degree of pancreatic and lung injury increased gradually along with the gradual increase of MPO activity and micro-vascular permeability. Gene expressions of TNF-α and ICAM-1 in the pancreas rose at 1 hour and peaked at 7 hours. In contrast, their gene expression in the lungs rose slightly at 1 hour and peaked at 9-12 hours. CONCLUSION: An obvious time window existed between SAP and lung injury, which is beneficial to the early prevention of the development of ALI.

Effect of resveratrol on microcirculation disorder and lung injury following severe acute pancreatitis in rats

AIM: To investigate the mechanism of resveratrol underlying the microcirculation disorder and lung injury following severe acute pancreatitis (SAP). METHODS: Twenty-four rats were divided into 3 groups (SAP, sham and resveratrol groups) randomly. SAP model was established by injecting 4% sodium taurocholate l mL/kg through puncturing pancreatic ducts. Sham (control) group (8 rats) was established by turning over the duodenum. Resveratrol was given at 0.1 mg/kg b.m. intraperitoneally. Rats were sacrificed 9 h after SAP was induced. Blood samples were obtained for hemorrheological examination. Lung tissues were used for pathological observation, and examination of microvascular permeability, dry/wet ratio and myeloperoxidase (MPO) activity. Gene expression of intercellular adhesion molecule-1 (ICAM-1) was detected by RT-PCR. RESULTS: Compared with SAP group, resveratrol relieved the edema and infiltration of leukocytes in the lungs. Resveratrol improved markers of hemorrheology: high VTB (5.77±1.18 mPas vs9.49±1.34 mPas), low VTB (16.12±3.20 mPas vs30.91±7.28 mPas), PV (4.69±1.68 mPas vs 8.00±1.34 mPas), BSR (1.25±0.42 mm/h vs50.03±0.03 mm/h), VPC (54.67±3.08% vs 62.17±3.39%), fibrinogen (203.2?7.8 g/ L vs 51.3±19.1 g/L), original hemolysis (0.45±0.02 vs 0.49±0.02), and complete hemolysis (0.41±0.02 vs 0.43±0.02) (P<0.05). Resveratrol decreased the OD ratio of ICAM-1 gene (0.800±0.03 vs 1.188±0.10), dry/wet ratio (0.74±0.02 vs 0.77±0.03), microvascular permeability (0.079±0.006 vs 0.112±0.004) and MPO activity (4.42±0.32 vs 5.03±0.51) significantly (P<0.05). CONCLUSION: Resveratrol can improve the microcirculation disorder of the lung by decreasing leukocyte-endothelial interaction, reducing blood viscosity, improving the decrease of blood flow, and stabilizing erythrocytes in SAP rats. It may be a potential candidate to treat SAP and its severe complications (ALI).

Proteasome inhibitor ameliorates severe acute pancreatitis and associated lung injury of rats

AIM: To observe the effect of proteasome inhibitor MG-132 on severe acute pancreatitis (SAP) and associated lung injury of rats. METHODS: Male adult SD rats were randomly divided into SAP group, sham-operation group, and MG-132 treatment group. A model of SAP was established by injection of 5% sodium taurocholate into the biliary- pancreatic duct of rats. The MG-132 group was pretreated with 10 mg/kg MG-132 intraperitoneally (ip) 30 min before the induction of pancreatitis. The changes in serum amylase, myeloperoxidase (MPO) activity of pancreatic and pulmonary tissue were measured. The TNF-α level in pancreatic cytosolic fractions was assayed with an enzyme-linked immunosorbent assay (ELISA) kit. Meanwhile, the pathological changes in both pancreatic and pulmonary tissues were also observed. RESULTS: MG-132 significantly decreased serum amylase, pancreatic weight/body ratio, pancreatic TNF-α level, pancreatic and pulmonary MPO activity (P < 0.05). Histopathological examinations revealed that pancreatic and pulmonary samples from rats pretreated with MG-132 demonstrated milder edema, cellular damage, and inflammatory activity (P < 0.05). CONCLUSION: The proteasome inhibitor MG-132 shows a protective effect on severe acute pancreatitis and associated lung injury of rats.