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 mechan...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.展开更多
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 ...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.展开更多
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 gr...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.展开更多
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...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.展开更多
BACKGROUND Acute lung injury(ALI)is a common and life-threatening complication of severe acute pancreatitis(SAP).There are currently limited effective treatment options for SAP and associated ALI.Calycosin(Cal),a bioa...BACKGROUND Acute lung injury(ALI)is a common and life-threatening complication of severe acute pancreatitis(SAP).There are currently limited effective treatment options for SAP and associated ALI.Calycosin(Cal),a bioactive constituent extracted from the medicinal herb Radix Astragali exhibits potent anti-inflammatory properties,but its effect on SAP and associated ALI has yet to be determined.AIM To identify the roles of Cal in SAP-ALI and the underlying mechanism.METHODS SAP was induced via two intraperitoneal injections of L-arg(4 g/kg)and Cal(25 or 50 mg/kg)were injected 1 h prior to the first L-arg challenge.Mice were sacrificed 72 h after the induction of SAP and associated ALI was examined histologically and biochemically.An in vitro model of lipopolysaccharide(LPS)-induced ALI was established using A549 cells.Immunofluorescence analysis and western blot were evaluated in cells.Molecular docking analyses were conducted to examine the interaction of Cal with HMGB1.RESULTS Cal treatment substantially reduced the serum amylase levels and alleviated histopathological injury associated with SAP and ALI.Neutrophil infiltration and lung tissue levels of neutrophil mediator myeloperoxidase were reduced in line with protective effects of Cal against ALI in SAP.Cal treatment also attenuated the serum levels and mRNA expression of pro-inflammatory cytokines tumor necrosis factor-α,interleukin-6,IL-1β,HMGB1 and chemokine(CXC motif)ligand 1 in lung tissue.Immunofluorescence and western blot analyses showed that Cal treatment markedly suppressed the expression of HMGB1 and phosphorylated nuclear factor-kappa B(NF-κB)p65 in lung tissues and an in vitro model of LPSinduced ALI in A549 cells suggesting a role for HGMB1 in the pathogenesis of ALI.Furthermore,molecular docking analysis provided evidence for the direct interaction of Cal with HGMB1.CONCLUSION Cal protects mice against L-arg-induced SAP and associated ALI by attenuating local and systemic neutrophil infiltration and inflammatory response via inhibition of HGMB1 and the NF-κB signaling pathway.展开更多
The expression of intercellular adhesion molecule-1 (ICAM-1) in the pathogenesis of heroin-induced acute lung injury (ALI) in rats was investigated. The model of ALI was established by intravenous injection of heroin ...The expression of intercellular adhesion molecule-1 (ICAM-1) in the pathogenesis of heroin-induced acute lung injury (ALI) in rats was investigated. The model of ALI was established by intravenous injection of heroin into tail vein in rats. Thirty-six rats were randomly divided into heroin-treated groups (1 h, 2 h, 4 h, 6 h and 24 h) and normal control group. Changes in histopathologic morphology and biological markers of ALI were measured. The expression of ICAM-1 in lung tissue was detected by using immunohistochemistry and RT-PCR. The results showed that the W/D ratio and protein contents in BALF of the heroin-treated groups were significantly higher than that of the control group (P<0.01). The histopathological changes in the lung tissue were more obvious in heroin-treated groups. The ICAM-1 protein and mRNA expression in the lung tissue of heroin-treated groups were significantly increased as compared with that of the control group (P<0.01), and correlated with the ALI parameters in a time-dependent manner. Increasing of ICAM-1 expression was involved in the formation of heroin-induced lung injury. Furthermore, the level of expression was positively correlated with the severity of lung injury.展开更多
BACKGROUND： Myeloid cell （TREM-1） is an important mediator of the signal transduction pathway in inflammatory response. In this study, a mouse model of acute lung injury （ALl） by intraperitoneal injection of lipo...BACKGROUND： Myeloid cell （TREM-1） is an important mediator of the signal transduction pathway in inflammatory response. In this study, a mouse model of acute lung injury （ALl） by intraperitoneal injection of lipopolysaccharide （LPS） was established to observe the expression pattern of TREM-1 in lung tissue and the role of TREM-1 in pulmonary inflammatory response to ALl.METHODS： Thirty BALB/C mice were randomly divided into a normal control group （n=6） and an ALl group （n=24）. The model of ALl was made by intraperitonal injection of LPS in dose of 10 mg/ kg. Specimens from peripheral blood and lung tissue were collected 6, 12, 24 and 48 hours after LPS injection. RT-PCR was used to detect TREM-1 mRNA, and ELISA was employed for detection of TREM-1 protein and TNF-a protein, and HE staining was performed for the pathological Smith lung scoring under a light microscope.RESULTS： The expressions of TREM-1 mRNAin lung tissue and blood of the ALl group 6, 12, 24, and 48 hours after injection of LPS were higher than those in the control group. The levels of TREM- 1 protein and the levels of TNF-a protein in lung tissue of the ALl group 6, 12, 24, and 48 hours after LPS injection were higher than those of the control group; the level of TREM-1 protein peaked 12 hours after LPS injection, but it was not significantly correlated with the expression of TREM-1 mRNA （P=0.14）; the TNF-a concentration was positively correlated with TREM-1 levels in lung tissue and with Smith pathological score （r=0.795, P=0.001 ：r=0.499, P=0.034）, but not with the expression of TREM-1 mRNA （P=0.176）.CONCLUSION： The expression of TREM-1 mRNA in lung tissue of mice with ALl is elevated, and the expression of TREM-1 mRNA is related to the level of TNF-a and the severity of inflammatory response to ALl. The expressions of the TREM-1 gene are not consistent with the levels of TREM-1 protein, suggesting a new functional protein involved in immune regulation.展开更多
Objective:The protective effect of Scutellaria baicalensis Stems and Polygonum Cuspidatum compatibility on lipopolysaccharide(LPS)-induced acute lung injury(ALI)in rats was studied by observing the expression of TRPV1...Objective:The protective effect of Scutellaria baicalensis Stems and Polygonum Cuspidatum compatibility on lipopolysaccharide(LPS)-induced acute lung injury(ALI)in rats was studied by observing the expression of TRPV1 and inflammatory cytokines.Methods:48 male SD rats were randomly divided into 6 groups:control group,model group,dexamethasone group(5mg/kg)and Scutellaria baicalensis Stems-Polygonum Cuspidatum(3.5,7 and 14g/kg).The administration group was gavaged for 7 days,and the control group and model group were given the same amount of 0.9%sodium chloride.On the 8th day,except the control group,rats in other groups were injected with 8mg/kg LPS through caudal vein to induce Ali model.Take the rat lung tissue 6 hours after modeling,and calculate the wet/dry weight ratio(W/D)of the rat lung tissue;HE staining to observe the pathological changes of lung tissue;Determine the content of tumor necrosis factor-α(TNF-α)and interleukin-1β(1L-1β)in alveolar lavage fluid(BALF)and the activity of superoxide dismutase(SOD)in serum;Detect the mRNA and protein expression levels of TRPV1 receptor in rat lung tissue.Results:Compared with the model group,Scutellaria baicalensis Stems-Polygonum Cuspidatum can significantly reduce the damage of lung tissue structure and bleeding state,W/D value and TNF-α、IL-1βThe content of TRPV1 decreased,the level of SOD increased,and the mRNA and protein expression of TRPV1 receptor decreased.Conclusion:The combination of Scutellaria baicalensis Stems-Polygonum has a protective effect on acute lung injury in rats,and its mechanism may be related to down-regulating the expression of TRPV1 and inhibiting the levels of TNF-αand IL-1βin inflammatory cells.展开更多
Objective To investigate whether pretreatment with α 1-AT can attenuate acute lung injury (ALI) in rabbits induced with endotoxin. Methods Thirty-two New Zealand rabbits were randomly assigned to four groups(n=8):1.I...Objective To investigate whether pretreatment with α 1-AT can attenuate acute lung injury (ALI) in rabbits induced with endotoxin. Methods Thirty-two New Zealand rabbits were randomly assigned to four groups(n=8):1.Infusion of endotoxin(Lipopolysaccharide,LPS 500μg/kg)without α 1-AT (group LPS).2.Infusion α 1-AT 120mg/kg at 15min before challenge with LPS(group LAV).3.Infusion of α 1-AT 120mg/kg(group AAT).4 Infusion of saline 4ml/kg as control (group NS).Arterial blood gases,peripheral leukocyte counts and airway pressure were recorded every 1h.Physiologic intrapulmonary shunting (Qs/Qt) was measured every 4h.After 8h the bloods were collected for measurement of plasma concentration and activity of α 1-AT.Then bronchoalveolar lavage fluid (BALF)was collected for measurement of concentrations of total protein (TP),interleukin-8(IL-8),tumor necrosis factor(TNF-α),the activities of elastase-like and α 1-AT,total phospholipids(TPL) and disaturated phosphatidylcholine (DSPC).In addition,the wet-to-dry lung weight ratio(W/D) was measured. Results After infusion of endotoxin,it was observed that PaO 2,peripheral luekocyte counts,total respiratory compliance progressively decreased and P peak and Qs/Qt increased comparing with the baseline values.In contrast to group NS,the increased plasma concentration but reduced activity of α 1-AT was found in group LPS.In the BALF,the activity of α 1-AT,TPL,DSPC/TPL were lower,but the concentrations of albumin,IL-8,TNF-α,and the activity of NE were higher.The ratio of W/D also increased.The pretreatment of α 1-AT attenuated the deterioration of oxygenation,the reduction of compliance and the deterioration of other physiological,biochemical parameters mentioned above. Conclusion Pretreatment with α 1-AT could attenuate endotoxin-induced lung injury in rabbits.Those beneficial effects of α 1-AT might be due in part to the inhibitory effect on neutrophil elastase.展开更多
To investigate the protective effect of curcumin on endotoxin-induced acute lung injury in rats, and explore the underlying mechanisms, 24 male Wistar rats were randomly divided into 4 experimental groups： sham-vehic...To investigate the protective effect of curcumin on endotoxin-induced acute lung injury in rats, and explore the underlying mechanisms, 24 male Wistar rats were randomly divided into 4 experimental groups： sham-vehicle （S）, sham-curcumin （C）, lipopolysaccharide （LPS）-vehicle （L）, and curcumin-lipopolysaccharide （C-L） groups. The wet/dry （W/D） weight ratio of the lung and bronchoalveolar lavage （BAL） fluid protein content were used as measures of lung injury. Neutrophil recruitment and activation were evaluated by BAL fluid cellularity and myeloperoxidase （MPO） activity in cell-free BAL and lung tissue. The levels of cytokine-induced neutrophil chemoattractant-1 （CINC-1） in lung tissues were measured by ELISA. were observed by using the HE staining. Our results the wet/dry weight ratio and protein content in BALE The histopathological changes of lung tissues showed that lung injury parameters, including were significantly higher in the L group than in the S group （P〈0.01）. In the L group, higher numbers of neutrophils and greater MPO activity in cell-free BAL and lung homogenates were observed when compared with the S group （P〈0.01）. There was a marked increase in CINC-1 levels in lung tissues in response to LPS challenge （P〈0.01, L group vs S group）. Curcumin pretreatment significantly attenuated LPS-induced changes in these indices. LPS caused extensive morphological lung damage, which was also lessened after curcumin pretreatment. All the above-mentioned parameters in the C group were not significantly different from those of the S group. It is concluded that curcumin pretreatment attenuates LPS-induced lung injury in rats. This beneficial effect of curcumin may involves, in part, inhibition of neutrophilic recruitment and activity, possibly through inhibition of lung CINC-1 expression.展开更多
Influenza viruses are common respiratory pathogens in humans and can cause serious infection that leads to the development of pneumonia.Due to their hostrange diversity,genetic and antigenic diversity,and potential to...Influenza viruses are common respiratory pathogens in humans and can cause serious infection that leads to the development of pneumonia.Due to their hostrange diversity,genetic and antigenic diversity,and potential to reassort genetically in vivo,influenza A viruses are continual sources of novel influenza strains that lead to the emergence of periodic epidemics and outbreaks in humans.Thus,newly emerging viral diseases are always major threats to public health.In March 2009,a novel influenza virus suddenly emerged and caused a worldwide pandemic.The novel pandemic influenza virus was genetically and antigenically distinct from previous seasonal human influenza A/H1N1 viruses;it was identified to have originated from pigs,and further genetic analysis revealed it as a subtype of A/H1N1,thus later called a swine-origin influenza virus A/H1N1.Since the novel virus emerged,epidemiological surveys and research on experimental animal models have been conducted,and characteristics of the novel influenza virus have been determined but the exact mechanisms of pulmonary pathogenesis remain to be elucidated.In this editorial,we summa-rize and discuss the recent pandemic caused by the novel swine-origin influenza virus A/H1N1 with a focus on the mechanism of pathogenesis to obtain an insight into potential therapeutic strategies.展开更多
Summary： To investigate the protective effect of genistein on endotoxin-induced acute lung injury in rats, and explore the underlying mechanisms, 32 male Sprague-Dawley rats were randomly divided into 4 experimental ...Summary： To investigate the protective effect of genistein on endotoxin-induced acute lung injury in rats, and explore the underlying mechanisms, 32 male Sprague-Dawley rats were randomly divided into 4 experimental groups： saline control, genistein alone, lipopolysaccaride alone, and genistein pretreatment. Each treatment group consisted of eight animals. Animals were observed for 6 h after LPS challenge, and the wet/dry （W/D） weight ratio of the lung and bronchoalveolar lavage fluid （BALF） protein content were used as a measure of lung injury. Neutrophil recruitment and activation were evaluated by BALF cellularity and myeloperoxidase （MP（）） activity. RT-PCR analysis was performed in lung tissue to assess gene expression of ICAM-1. The histopathological changes were also observed using the HE staining of lung tissue. Our results showed that lung injury parameters, including the wet/dry weight ratio and protein content in BALF, were significantly higher in the LPS alone group than in the saline control group （P〈0.01）. In the LPS alone group, a larger number of neutrophils and greater MPO activity in cell-free BAL and lung homogenates were observed when compared with the saline control group （P〈0.01）. There was a significant increase in lung ICAM-1 mRNA in response to LPS challenge （P〈0. 01, group L versus group S）. Genistein pretreatment significantly attenuated LPS-induced changes in these indices. LPS caused extensive lung damage, which was also lessened after genistein pretreatment. All above-mentioned parameters in the genistein alone group were not significantly different from those of the saline control group. It is concluded that genistein pretreatment attenuated LPS-induced lung injury in rats. This beneficial effect of genistein may involves, in part, an inhibition of neutrophilic recruitment and activity, possibly through an inhibition of lung ICAM-1 expression.展开更多
Cardiopulmonary bypass has been speculated to elicit systemic inflammation to initiate acute lung injury(ALI), including acute respiratory distress syndrome(ARDS), in patients after cardiac surgery. We previously foun...Cardiopulmonary bypass has been speculated to elicit systemic inflammation to initiate acute lung injury(ALI), including acute respiratory distress syndrome(ARDS), in patients after cardiac surgery. We previously found that post-operative patients showed an increase in endothelial cell-derived extracellular vesicles(eEVs) with components of coagulation and acute inflammatory responses. However, the mechanism underlying the onset of ALI owing to the release of e EVs after cardiopulmonary bypass, remains unclear. Plasma plasminogenactivated inhibitor-1(PAI-1) and eEV levels were measured in patients with cardiopulmonary bypass. Endothelial cells and mice(C57BL/6,Toll-like receptor 4 knockout(TLR4^(-/-))) and inducible nitric oxide synthase knockout(iNOS^(-/-)) were challenged with eEVs isolated from PAI-1-stimulated endothelial cells. Plasma PAI-1 and eEVs were remarkably enhanced after cardiopulmonary bypass. Plasma PAI-1 elevation was positively correlated with the increase in eEVs. The increase in plasma PAI-1 and eEV levels was associated with post-operative ARDS. The eEVs derived from PAI-1-stimulated endothelial cells could recognize TLR4 to stimulate a downstream signaling cascade identified as the Janus kinase 2/3(JAK2/3)-signal transducer and activator of transcription 3(STAT3)-interferon regulatory factor 1(IRF-1)pathway, along with i NOS induction, and cytokine/chemokine production in vascular endothelial cells and C57BL/6 mice, ultimately contributing to ALI. ALI could be attenuated by JAK2/3 or STAT3 inhibitors(AG490 or S3I-201, respectively), and was relieved in TLR4-/-and iNOS-/-mice. eEVs activate the TLR4/JAK3/STAT3/IRF-1 signaling pathway to induce ALI/ARDS by delivering follistatin-like protein 1(FSTL1), and FSTL1 knockdown in eEVs alleviates eEV-induced ALI/ARDS. Our data thus demonstrate that cardiopulmonary bypass may increase plasma PAI-1 levels to induce FSTL1-enriched eEVs, which target the TLR4-mediated JAK2/3/STAT3/IRF-1 signaling cascade and form a positive feedback loop, leading to ALI/ARDS after cardiac surgery. Our findings provide new insight into the molecular mechanisms and therapeutic targets for ALI/ARDS after cardiac surgery.展开更多
Background Intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) are two important cytokines in inflammatory response, which may induce rolling and adhesion of both leukocytes and l...Background Intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) are two important cytokines in inflammatory response, which may induce rolling and adhesion of both leukocytes and lymphocytes, while modulating vascular permeability at the same time. These adhesion molecules usually serve as surrogate markers of activation and injury of vascular endothelial cells. Tumor necrosis factor-α (TNF-α) is a key factor to induce the expression and production of the above cell adhesion molecules. However, it remains to be elucidated whether exogenous ubiquitin exerts any effect on the cytokines in sepsis-induced ALI. Methods Sixty mice were devided randomly into five groups with twelve mice in each group, i.e. CLP group, SHAM group, UB1 group (10 mg/kg), UB2 group (5 mg/kg) and UB3 group(1 mg/kg). Mice of SHAM group underwent sham operation, and other four groups underwent CLP. Six hours after surgery, mice of three UB groups received ubiquitin by caudal vein injection while CLP and SHAM group received vehicle. Seven hours after surgery, blood and lungs of all mice were collected. ICAM-1, VCAM-1 and TNF-α level of 9% lung homogenate and serum TNF-α level were measured by ELISA. Results Pulmonary ICAM-1, VCAM-1 and TNF-α level of three UB groups were lower than CLP and SHAM group, and there were several comparisons with a statistically significant difference. Serum TNF-α level of three UB groups were slightly lower than CLP group, but far higher than SHAM group. Pulmonary ICAM-1 level, VCAM-1 level and serum TNF-α level of UB3 group were lower than UB1 and UB2 group, and there was a significant difference in VCAM-1 between UB3 and UB1 group. Pulmonary TNF-α level of UB3 group was slightly higher than UB1 and UB2 group.展开更多
To the Editor:Acute lung injury(ALI)is a debilitating lung disease characterized by pulmonary edema,diffuse alveolar damage,and uncontrolled neutrophil infiltration^(1).Severe cases of ALI can potentially lead to the ...To the Editor:Acute lung injury(ALI)is a debilitating lung disease characterized by pulmonary edema,diffuse alveolar damage,and uncontrolled neutrophil infiltration^(1).Severe cases of ALI can potentially lead to the development of acute respiratory distress syndrome(ARDS),which can lead to impaired respiratory function,multiorgan dysfunction,and an extremely high mortality rate^(2-4).ALI may be caused by various factors,including aspiration,severe pneumonia,sepsis,trauma,fatty embolism,pancreatitis,and blood transfusion^(3).Current clinical approaches to treating ALI/ARDS include mechanical ventilation,extracorporeal membrane oxygenation(ECMO),and other supportive therapies^(5,6).Therefore,ALI/ARDS is an urgent problem that needs to be addressed in the field of respiratory critical care and innovative mechanisms and therapies^(6).展开更多
Acute lung injury(ALI)is a severe inflammatory condition with a high mortality rate,often precipitated by sepsis.The pathophysiology of ALI involves complex mechanisms,including inflammation,oxidative stress,and ferro...Acute lung injury(ALI)is a severe inflammatory condition with a high mortality rate,often precipitated by sepsis.The pathophysiology of ALI involves complex mechanisms,including inflammation,oxidative stress,and ferroptosis,a novel form of regulated cell death.This study explores the therapeutic potential of andrographolide(AG),a bioactive compound derived from Andrographis,in mitigating Lipopolysaccharide(LPS)-induced inflammation and ferroptosis.Our research employed in vitro experiments with RAW264.7 macrophage cells and in vivo studies using a murine model of LPS-induced ALI.The results indicate that AG significantly suppresses the production of pro-inflammatory cytokines and inhibits ferroptosis in LPS-stimulated RAW264.7 cells.In vivo,AG treatment markedly reduces lung edema,decreases inflammatory cell infiltration,and mitigates ferroptosis in lung tissues of LPS-induced ALI mice.These protective effects are mediated via the modulation of the Toll-like receptor 4(TLR4)/Kelch-like ECH-associated protein 1(Keap1)/Nuclear factor erythroid 2-related factor 2(Nrf2)signaling pathway.Molecular docking simulations identified the binding sites of AG on the TLR4 protein(Kd value:-33.5 kcal·mol^(-1)),and these interactions were further corroborated by Cellular Thermal Shift Assay(CETSA)and SPR assays.Collectively,our findings demonstrate that AG exerts potent anti-inflammatory and anti-ferroptosis effects in LPS-induced ALI by targeting TLR4 and modulating the Keap1/Nrf2 pathway.This study underscores AG's potential as a therapeutic agent for ALI and provides new insights into its underlying mechanisms of action.展开更多
基金supported by the tenth batch of"3221"industrial innovation and scientific research projects in Bengbu City(beng talent[2020]No.8)the 2021 Bengbu Medical College Science and Technology Project[Natural Science,Project Number:2021byzd217].
文摘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.
基金supported by National Natural Science Foundation of China(No.81960351)High-level Talent Fund of Hainan Province(No.822RC835).
文摘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.
基金supported by a grant from Technical Research and Development Fund of Shenzhen(No.JCYJ20140416122812032)
文摘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.
文摘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.
文摘BACKGROUND Acute lung injury(ALI)is a common and life-threatening complication of severe acute pancreatitis(SAP).There are currently limited effective treatment options for SAP and associated ALI.Calycosin(Cal),a bioactive constituent extracted from the medicinal herb Radix Astragali exhibits potent anti-inflammatory properties,but its effect on SAP and associated ALI has yet to be determined.AIM To identify the roles of Cal in SAP-ALI and the underlying mechanism.METHODS SAP was induced via two intraperitoneal injections of L-arg(4 g/kg)and Cal(25 or 50 mg/kg)were injected 1 h prior to the first L-arg challenge.Mice were sacrificed 72 h after the induction of SAP and associated ALI was examined histologically and biochemically.An in vitro model of lipopolysaccharide(LPS)-induced ALI was established using A549 cells.Immunofluorescence analysis and western blot were evaluated in cells.Molecular docking analyses were conducted to examine the interaction of Cal with HMGB1.RESULTS Cal treatment substantially reduced the serum amylase levels and alleviated histopathological injury associated with SAP and ALI.Neutrophil infiltration and lung tissue levels of neutrophil mediator myeloperoxidase were reduced in line with protective effects of Cal against ALI in SAP.Cal treatment also attenuated the serum levels and mRNA expression of pro-inflammatory cytokines tumor necrosis factor-α,interleukin-6,IL-1β,HMGB1 and chemokine(CXC motif)ligand 1 in lung tissue.Immunofluorescence and western blot analyses showed that Cal treatment markedly suppressed the expression of HMGB1 and phosphorylated nuclear factor-kappa B(NF-κB)p65 in lung tissues and an in vitro model of LPSinduced ALI in A549 cells suggesting a role for HGMB1 in the pathogenesis of ALI.Furthermore,molecular docking analysis provided evidence for the direct interaction of Cal with HGMB1.CONCLUSION Cal protects mice against L-arg-induced SAP and associated ALI by attenuating local and systemic neutrophil infiltration and inflammatory response via inhibition of HGMB1 and the NF-κB signaling pathway.
文摘The expression of intercellular adhesion molecule-1 (ICAM-1) in the pathogenesis of heroin-induced acute lung injury (ALI) in rats was investigated. The model of ALI was established by intravenous injection of heroin into tail vein in rats. Thirty-six rats were randomly divided into heroin-treated groups (1 h, 2 h, 4 h, 6 h and 24 h) and normal control group. Changes in histopathologic morphology and biological markers of ALI were measured. The expression of ICAM-1 in lung tissue was detected by using immunohistochemistry and RT-PCR. The results showed that the W/D ratio and protein contents in BALF of the heroin-treated groups were significantly higher than that of the control group (P<0.01). The histopathological changes in the lung tissue were more obvious in heroin-treated groups. The ICAM-1 protein and mRNA expression in the lung tissue of heroin-treated groups were significantly increased as compared with that of the control group (P<0.01), and correlated with the ALI parameters in a time-dependent manner. Increasing of ICAM-1 expression was involved in the formation of heroin-induced lung injury. Furthermore, the level of expression was positively correlated with the severity of lung injury.
文摘BACKGROUND： Myeloid cell （TREM-1） is an important mediator of the signal transduction pathway in inflammatory response. In this study, a mouse model of acute lung injury （ALl） by intraperitoneal injection of lipopolysaccharide （LPS） was established to observe the expression pattern of TREM-1 in lung tissue and the role of TREM-1 in pulmonary inflammatory response to ALl.METHODS： Thirty BALB/C mice were randomly divided into a normal control group （n=6） and an ALl group （n=24）. The model of ALl was made by intraperitonal injection of LPS in dose of 10 mg/ kg. Specimens from peripheral blood and lung tissue were collected 6, 12, 24 and 48 hours after LPS injection. RT-PCR was used to detect TREM-1 mRNA, and ELISA was employed for detection of TREM-1 protein and TNF-a protein, and HE staining was performed for the pathological Smith lung scoring under a light microscope.RESULTS： The expressions of TREM-1 mRNAin lung tissue and blood of the ALl group 6, 12, 24, and 48 hours after injection of LPS were higher than those in the control group. The levels of TREM- 1 protein and the levels of TNF-a protein in lung tissue of the ALl group 6, 12, 24, and 48 hours after LPS injection were higher than those of the control group; the level of TREM-1 protein peaked 12 hours after LPS injection, but it was not significantly correlated with the expression of TREM-1 mRNA （P=0.14）; the TNF-a concentration was positively correlated with TREM-1 levels in lung tissue and with Smith pathological score （r=0.795, P=0.001 ：r=0.499, P=0.034）, but not with the expression of TREM-1 mRNA （P=0.176）.CONCLUSION： The expression of TREM-1 mRNA in lung tissue of mice with ALl is elevated, and the expression of TREM-1 mRNA is related to the level of TNF-a and the severity of inflammatory response to ALl. The expressions of the TREM-1 gene are not consistent with the levels of TREM-1 protein, suggesting a new functional protein involved in immune regulation.
基金Discipline Innovation Team of Shaanxi University of Traditional Chinese Medicine(No.2019-QN02)Project of Shaanxi Provincial Department of Education(Research and Development of Scutellaria Baicalensis Stem and Leaf and Honeysuckle Vine Anti Livestock and Poultry Infection Products)(No.20JC012)。
文摘Objective:The protective effect of Scutellaria baicalensis Stems and Polygonum Cuspidatum compatibility on lipopolysaccharide(LPS)-induced acute lung injury(ALI)in rats was studied by observing the expression of TRPV1 and inflammatory cytokines.Methods:48 male SD rats were randomly divided into 6 groups:control group,model group,dexamethasone group(5mg/kg)and Scutellaria baicalensis Stems-Polygonum Cuspidatum(3.5,7 and 14g/kg).The administration group was gavaged for 7 days,and the control group and model group were given the same amount of 0.9%sodium chloride.On the 8th day,except the control group,rats in other groups were injected with 8mg/kg LPS through caudal vein to induce Ali model.Take the rat lung tissue 6 hours after modeling,and calculate the wet/dry weight ratio(W/D)of the rat lung tissue;HE staining to observe the pathological changes of lung tissue;Determine the content of tumor necrosis factor-α(TNF-α)and interleukin-1β(1L-1β)in alveolar lavage fluid(BALF)and the activity of superoxide dismutase(SOD)in serum;Detect the mRNA and protein expression levels of TRPV1 receptor in rat lung tissue.Results:Compared with the model group,Scutellaria baicalensis Stems-Polygonum Cuspidatum can significantly reduce the damage of lung tissue structure and bleeding state,W/D value and TNF-α、IL-1βThe content of TRPV1 decreased,the level of SOD increased,and the mRNA and protein expression of TRPV1 receptor decreased.Conclusion:The combination of Scutellaria baicalensis Stems-Polygonum has a protective effect on acute lung injury in rats,and its mechanism may be related to down-regulating the expression of TRPV1 and inhibiting the levels of TNF-αand IL-1βin inflammatory cells.
文摘Objective To investigate whether pretreatment with α 1-AT can attenuate acute lung injury (ALI) in rabbits induced with endotoxin. Methods Thirty-two New Zealand rabbits were randomly assigned to four groups(n=8):1.Infusion of endotoxin(Lipopolysaccharide,LPS 500μg/kg)without α 1-AT (group LPS).2.Infusion α 1-AT 120mg/kg at 15min before challenge with LPS(group LAV).3.Infusion of α 1-AT 120mg/kg(group AAT).4 Infusion of saline 4ml/kg as control (group NS).Arterial blood gases,peripheral leukocyte counts and airway pressure were recorded every 1h.Physiologic intrapulmonary shunting (Qs/Qt) was measured every 4h.After 8h the bloods were collected for measurement of plasma concentration and activity of α 1-AT.Then bronchoalveolar lavage fluid (BALF)was collected for measurement of concentrations of total protein (TP),interleukin-8(IL-8),tumor necrosis factor(TNF-α),the activities of elastase-like and α 1-AT,total phospholipids(TPL) and disaturated phosphatidylcholine (DSPC).In addition,the wet-to-dry lung weight ratio(W/D) was measured. Results After infusion of endotoxin,it was observed that PaO 2,peripheral luekocyte counts,total respiratory compliance progressively decreased and P peak and Qs/Qt increased comparing with the baseline values.In contrast to group NS,the increased plasma concentration but reduced activity of α 1-AT was found in group LPS.In the BALF,the activity of α 1-AT,TPL,DSPC/TPL were lower,but the concentrations of albumin,IL-8,TNF-α,and the activity of NE were higher.The ratio of W/D also increased.The pretreatment of α 1-AT attenuated the deterioration of oxygenation,the reduction of compliance and the deterioration of other physiological,biochemical parameters mentioned above. Conclusion Pretreatment with α 1-AT could attenuate endotoxin-induced lung injury in rabbits.Those beneficial effects of α 1-AT might be due in part to the inhibitory effect on neutrophil elastase.
文摘To investigate the protective effect of curcumin on endotoxin-induced acute lung injury in rats, and explore the underlying mechanisms, 24 male Wistar rats were randomly divided into 4 experimental groups： sham-vehicle （S）, sham-curcumin （C）, lipopolysaccharide （LPS）-vehicle （L）, and curcumin-lipopolysaccharide （C-L） groups. The wet/dry （W/D） weight ratio of the lung and bronchoalveolar lavage （BAL） fluid protein content were used as measures of lung injury. Neutrophil recruitment and activation were evaluated by BAL fluid cellularity and myeloperoxidase （MPO） activity in cell-free BAL and lung tissue. The levels of cytokine-induced neutrophil chemoattractant-1 （CINC-1） in lung tissues were measured by ELISA. were observed by using the HE staining. Our results the wet/dry weight ratio and protein content in BALE The histopathological changes of lung tissues showed that lung injury parameters, including were significantly higher in the L group than in the S group （P〈0.01）. In the L group, higher numbers of neutrophils and greater MPO activity in cell-free BAL and lung homogenates were observed when compared with the S group （P〈0.01）. There was a marked increase in CINC-1 levels in lung tissues in response to LPS challenge （P〈0.01, L group vs S group）. Curcumin pretreatment significantly attenuated LPS-induced changes in these indices. LPS caused extensive morphological lung damage, which was also lessened after curcumin pretreatment. All the above-mentioned parameters in the C group were not significantly different from those of the S group. It is concluded that curcumin pretreatment attenuates LPS-induced lung injury in rats. This beneficial effect of curcumin may involves, in part, inhibition of neutrophilic recruitment and activity, possibly through inhibition of lung CINC-1 expression.
文摘Influenza viruses are common respiratory pathogens in humans and can cause serious infection that leads to the development of pneumonia.Due to their hostrange diversity,genetic and antigenic diversity,and potential to reassort genetically in vivo,influenza A viruses are continual sources of novel influenza strains that lead to the emergence of periodic epidemics and outbreaks in humans.Thus,newly emerging viral diseases are always major threats to public health.In March 2009,a novel influenza virus suddenly emerged and caused a worldwide pandemic.The novel pandemic influenza virus was genetically and antigenically distinct from previous seasonal human influenza A/H1N1 viruses;it was identified to have originated from pigs,and further genetic analysis revealed it as a subtype of A/H1N1,thus later called a swine-origin influenza virus A/H1N1.Since the novel virus emerged,epidemiological surveys and research on experimental animal models have been conducted,and characteristics of the novel influenza virus have been determined but the exact mechanisms of pulmonary pathogenesis remain to be elucidated.In this editorial,we summa-rize and discuss the recent pandemic caused by the novel swine-origin influenza virus A/H1N1 with a focus on the mechanism of pathogenesis to obtain an insight into potential therapeutic strategies.
文摘Summary： To investigate the protective effect of genistein on endotoxin-induced acute lung injury in rats, and explore the underlying mechanisms, 32 male Sprague-Dawley rats were randomly divided into 4 experimental groups： saline control, genistein alone, lipopolysaccaride alone, and genistein pretreatment. Each treatment group consisted of eight animals. Animals were observed for 6 h after LPS challenge, and the wet/dry （W/D） weight ratio of the lung and bronchoalveolar lavage fluid （BALF） protein content were used as a measure of lung injury. Neutrophil recruitment and activation were evaluated by BALF cellularity and myeloperoxidase （MP（）） activity. RT-PCR analysis was performed in lung tissue to assess gene expression of ICAM-1. The histopathological changes were also observed using the HE staining of lung tissue. Our results showed that lung injury parameters, including the wet/dry weight ratio and protein content in BALF, were significantly higher in the LPS alone group than in the saline control group （P〈0.01）. In the LPS alone group, a larger number of neutrophils and greater MPO activity in cell-free BAL and lung homogenates were observed when compared with the saline control group （P〈0.01）. There was a significant increase in lung ICAM-1 mRNA in response to LPS challenge （P〈0. 01, group L versus group S）. Genistein pretreatment significantly attenuated LPS-induced changes in these indices. LPS caused extensive lung damage, which was also lessened after genistein pretreatment. All above-mentioned parameters in the genistein alone group were not significantly different from those of the saline control group. It is concluded that genistein pretreatment attenuated LPS-induced lung injury in rats. This beneficial effect of genistein may involves, in part, an inhibition of neutrophilic recruitment and activity, possibly through an inhibition of lung ICAM-1 expression.
基金supported by the National Key Research and Development Program of China(2021YFA0805100)the National Natural Science Foundation of China(81830013,81770241,81970363,82000362,92268202,81170271,81370370,81490531,81670392,81600382)+6 种基金the National Natural Science Foundation of China Distinguished Young Scholar Grant(81325001)“973 Project”from the Ministry of Science and Technology of China(2009CB522104)Guangdong Basic and Applied Basic Research Foundation,China(2019B1515120092)the Science and Technology Planning Project of Guangzhou,China(202103000016)the Changjiang Scholars Program from the Ministry of Education of Chinathe Sun Yat-sen University Clinical Research 5010 Programthe Program of National Key Clinical Specialties。
文摘Cardiopulmonary bypass has been speculated to elicit systemic inflammation to initiate acute lung injury(ALI), including acute respiratory distress syndrome(ARDS), in patients after cardiac surgery. We previously found that post-operative patients showed an increase in endothelial cell-derived extracellular vesicles(eEVs) with components of coagulation and acute inflammatory responses. However, the mechanism underlying the onset of ALI owing to the release of e EVs after cardiopulmonary bypass, remains unclear. Plasma plasminogenactivated inhibitor-1(PAI-1) and eEV levels were measured in patients with cardiopulmonary bypass. Endothelial cells and mice(C57BL/6,Toll-like receptor 4 knockout(TLR4^(-/-))) and inducible nitric oxide synthase knockout(iNOS^(-/-)) were challenged with eEVs isolated from PAI-1-stimulated endothelial cells. Plasma PAI-1 and eEVs were remarkably enhanced after cardiopulmonary bypass. Plasma PAI-1 elevation was positively correlated with the increase in eEVs. The increase in plasma PAI-1 and eEV levels was associated with post-operative ARDS. The eEVs derived from PAI-1-stimulated endothelial cells could recognize TLR4 to stimulate a downstream signaling cascade identified as the Janus kinase 2/3(JAK2/3)-signal transducer and activator of transcription 3(STAT3)-interferon regulatory factor 1(IRF-1)pathway, along with i NOS induction, and cytokine/chemokine production in vascular endothelial cells and C57BL/6 mice, ultimately contributing to ALI. ALI could be attenuated by JAK2/3 or STAT3 inhibitors(AG490 or S3I-201, respectively), and was relieved in TLR4-/-and iNOS-/-mice. eEVs activate the TLR4/JAK3/STAT3/IRF-1 signaling pathway to induce ALI/ARDS by delivering follistatin-like protein 1(FSTL1), and FSTL1 knockdown in eEVs alleviates eEV-induced ALI/ARDS. Our data thus demonstrate that cardiopulmonary bypass may increase plasma PAI-1 levels to induce FSTL1-enriched eEVs, which target the TLR4-mediated JAK2/3/STAT3/IRF-1 signaling cascade and form a positive feedback loop, leading to ALI/ARDS after cardiac surgery. Our findings provide new insight into the molecular mechanisms and therapeutic targets for ALI/ARDS after cardiac surgery.
文摘Background Intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) are two important cytokines in inflammatory response, which may induce rolling and adhesion of both leukocytes and lymphocytes, while modulating vascular permeability at the same time. These adhesion molecules usually serve as surrogate markers of activation and injury of vascular endothelial cells. Tumor necrosis factor-α (TNF-α) is a key factor to induce the expression and production of the above cell adhesion molecules. However, it remains to be elucidated whether exogenous ubiquitin exerts any effect on the cytokines in sepsis-induced ALI. Methods Sixty mice were devided randomly into five groups with twelve mice in each group, i.e. CLP group, SHAM group, UB1 group (10 mg/kg), UB2 group (5 mg/kg) and UB3 group(1 mg/kg). Mice of SHAM group underwent sham operation, and other four groups underwent CLP. Six hours after surgery, mice of three UB groups received ubiquitin by caudal vein injection while CLP and SHAM group received vehicle. Seven hours after surgery, blood and lungs of all mice were collected. ICAM-1, VCAM-1 and TNF-α level of 9% lung homogenate and serum TNF-α level were measured by ELISA. Results Pulmonary ICAM-1, VCAM-1 and TNF-α level of three UB groups were lower than CLP and SHAM group, and there were several comparisons with a statistically significant difference. Serum TNF-α level of three UB groups were slightly lower than CLP group, but far higher than SHAM group. Pulmonary ICAM-1 level, VCAM-1 level and serum TNF-α level of UB3 group were lower than UB1 and UB2 group, and there was a significant difference in VCAM-1 between UB3 and UB1 group. Pulmonary TNF-α level of UB3 group was slightly higher than UB1 and UB2 group.
基金National Natural Science Foundation of China(No.82274069,82030116,and 82141212)China Postdoctoral Science Foundation(No.2022M720095 and 2023T160434)Young Elite Scientists Sponsorship Programby China Association of Chinese Medicine(No.2022-QNRC2-B09).
文摘To the Editor:Acute lung injury(ALI)is a debilitating lung disease characterized by pulmonary edema,diffuse alveolar damage,and uncontrolled neutrophil infiltration^(1).Severe cases of ALI can potentially lead to the development of acute respiratory distress syndrome(ARDS),which can lead to impaired respiratory function,multiorgan dysfunction,and an extremely high mortality rate^(2-4).ALI may be caused by various factors,including aspiration,severe pneumonia,sepsis,trauma,fatty embolism,pancreatitis,and blood transfusion^(3).Current clinical approaches to treating ALI/ARDS include mechanical ventilation,extracorporeal membrane oxygenation(ECMO),and other supportive therapies^(5,6).Therefore,ALI/ARDS is an urgent problem that needs to be addressed in the field of respiratory critical care and innovative mechanisms and therapies^(6).
基金supported by China-ASEAN International Innovative Center for Health Industry of Traditional Chinese Medicine(No.AD20297142)Guangxi Collaborative Innovation Center for Scientific Achievements Transformation and Applicationon Traditional Chinese Medicine(No.05020058)。
文摘Acute lung injury(ALI)is a severe inflammatory condition with a high mortality rate,often precipitated by sepsis.The pathophysiology of ALI involves complex mechanisms,including inflammation,oxidative stress,and ferroptosis,a novel form of regulated cell death.This study explores the therapeutic potential of andrographolide(AG),a bioactive compound derived from Andrographis,in mitigating Lipopolysaccharide(LPS)-induced inflammation and ferroptosis.Our research employed in vitro experiments with RAW264.7 macrophage cells and in vivo studies using a murine model of LPS-induced ALI.The results indicate that AG significantly suppresses the production of pro-inflammatory cytokines and inhibits ferroptosis in LPS-stimulated RAW264.7 cells.In vivo,AG treatment markedly reduces lung edema,decreases inflammatory cell infiltration,and mitigates ferroptosis in lung tissues of LPS-induced ALI mice.These protective effects are mediated via the modulation of the Toll-like receptor 4(TLR4)/Kelch-like ECH-associated protein 1(Keap1)/Nuclear factor erythroid 2-related factor 2(Nrf2)signaling pathway.Molecular docking simulations identified the binding sites of AG on the TLR4 protein(Kd value:-33.5 kcal·mol^(-1)),and these interactions were further corroborated by Cellular Thermal Shift Assay(CETSA)and SPR assays.Collectively,our findings demonstrate that AG exerts potent anti-inflammatory and anti-ferroptosis effects in LPS-induced ALI by targeting TLR4 and modulating the Keap1/Nrf2 pathway.This study underscores AG's potential as a therapeutic agent for ALI and provides new insights into its underlying mechanisms of action.
