Factor In Acute Lung Injury Research Articles

Chest computed tomography for patients with sepsis in the emergency intensive care unit

Sepsis is a systemic inflammatory response syndrome (SIRS) caused by infection, which may lead to multiple organ dysfunction in susceptible patient. The most frequently involved organs/systems include the lung, kidney and circulation system. It is well established that sepsis is a risk factor for acute lung injury. While overt pulmonary infiltrates can be well captured by human operators, subtle structural changes of the lung might be ignored. Since the advantage of chest computed tomography (CT) is its capability of providing fine structural changes in high spatial resolution, the study of chest CT by means of computer science may provide further insights into the underlying pathophysiology. The integration of chest CT into the study of sepsis is limited partly due to the lack of well-curated database. The study aims to establish a database comprising detailed clinical tabular data, as well as the raw chest CT images. The database is intended to support a wide array of research studies involving radiomics in sepsis patients, helping to reduce barriers to the reproducibility of clinical research.

Role and Mechanism of Sialic Acid in Alleviating Acute Lung Injury through In Vivo and In Vitro Models.

Excessive inflammatory reactions are the most important pathological injury factor in acute lung injury (ALI). Our recent study found that sialic acid had an anti-colitis effect. In this study, the effect of sialic acid (SA) on acute lung inflammation was investigated. A lipopolysaccharide (LPS)-induced ALI animal model and LPS-stimulated HUVEC cell model were used to evaluate the anti-inflammatory effect of SA and study its molecular mechanisms. Compared with the LPS group, the lung index of the SA group decreased from 0.79 ± 0.05% to 0.58 ± 0.06% (LPS + 50 SA) and 0.62 ± 0.02% (LPS + 100 SA), with p < 0.01, suggesting that SA could improve the pulmonary edema of mice and alleviate LPS-induced lung injury. Transcriptome research identified 26 upregulated genes and 25 downregulated genes involved in the protection of SA against ALI. These genes are mainly related to the MAPK and NF-κB signaling pathways. Our study also proved that SA markedly downregulated the expression of inflammatory factors and blocked the JNK/p38/PPAR-γ/NF-κB pathway. Meanwhile, SA treatment also upregulated the expression of HO-1 and NQO1 in ALI mice. In vitro, SA obviously repressed the expressions of inflammatory cytokines and the JNK/p38-NF-κB/AP-1 pathway. SA also regulated the expression of oxidative stress-related genes through the Nrf2 pathway. Taken together, SA exhibits a protective role by modulating the anti-inflammatory and anti-oxidation pathways in ALI, and it may be a promising candidate for functional foods to prevent ALI.

Human Placental Mesenchymal Stem Cells-Exosomes Alleviate Endothelial Barrier Dysfunction via Cytoskeletal Remodeling through hsa-miR-148a-3p/ROCK1 Pathway.

Endothelial barrier disruption of human pulmonary vascular endothelial cells (HPVECs) is an important pathogenic factor for acute lung injury (ALI)/acute respiratory distress syndrome (ARDS). Mesenchymal stem cells-exosome (MSCs-Exo) represents an ideal carrier for cell-free therapy. The therapeutic implication and underlying mechanism of human placental MSCs-Exo (HPMSCs-Exo) in ALI/ARDS need to be further explored. HPMSCs-Exo was extracted from HPMSCs and characterized. Then, the therapeutic effects of exosomes were evaluated in ALI mice and HPVECs. RNA-sequencing was applied to reveal the miRNA profile of HPMSCs-Exo and differentially expressed genes (DEGs) in HPMSCs-Exo-pretreated HPVECs. The targets of miRNAs were predicted by bioinformatics methods and correlated to DEGs. Finally, the role of hsa-miR-148a-3p/ROCK1 pathway in HPVECs has been further discussed. The results showed that HPMSCs-Exo could downregulate Rho-associated coiled-coil-containing protein kinase 1 (ROCK1), upregulate the expression of zonula occludens-1 (ZO-1) and F-actin, promote HPVECs migration and tube formation, reduce cytoskeletal disorders and cell permeability, and thus improve ALI/ARDS. RNA-sequencing revealed the DEGs were mainly enriched in cell junction, angiogenesis, inflammation, and energy metabolism. HPMSCs-Exo contains multiple miRNAs which are associated with cytoskeletal function; the expression abundance of hsa-miR-148a-3p is the highest. Bioinformatic analysis identified ROCK1 as a target of hsa-miR-148a-3p. The overexpression of hsa-miR-148a-3p in HPMSCs-Exo promoted the migration and tube formation of HPVECs and reduced ROCK1 expression. However, the overexpression of ROCK1 on HPVECs reduced the therapeutic effect of HPMSCs-Exo. HPMSCs-Exo represents a protective regimen against endothelial barrier disruption of HPVECs in ALI/ARDS, and the hsa-miR-148a-3p/ROCK1 pathway plays an important role in this therapeutics implication.

Liensinine alleviates LPS-induced acute lung injury by blocking autophagic flux via PI3K/AKT/mTOR signaling pathway

Acute lung injury (ALI) is a major pathological problem characterized by severe inflammatory reactions and is a critical disease with high clinical morbidity and mortality. Liensinine, a major isoquinoline alkaloid, is extracted from the green embryos of mature Nelumbonaceae seeds. It has been reported to have an inhibitory effect on tumors. However, the effects of liensinine on ALI have not been reported to-date. The aim of this study was to explore the inhibitory effects of liensinine on lipopolysaccharide (LPS)-induced ALI and its possible mechanism. We found that liensinine significantly reduced LPS-induced ALI and reduced the production of inflammatory factors IL-6, IL-8, and TNF-α. In addition, liensinine blocked autophagic flux and increased the number of autophagosomes by upregulating LC3-II/I and p62 protein levels. More importantly, pretreatment with the early stages autophagy inhibitor 3-Methyladenine (3-MA) can reverse the inhibitory effects of liensinine on the secretion of inflammatory factors in ALI. The PI3K/AKT/mTOR pathway is involved in LPS-induced autophagy regulated by liensinine in ALI. In summary, this study suggests that liensinine inhibits the production of inflammatory factors in LPS-induced ALI by regulating autophagy via the PI3K/AKT/mTOR pathway, which may provide a new therapeutic strategy to alleviate ALI.

Predictive value of serum retinol binding protein in severity and complications of acute pancreatitis: a retrospective cohort study

Objectives Retinol binding protein (RBP) is associated with an increased risk of insulin resistance, metabolic syndrome, atherosclerosis and hypertension. This study aimed to evaluate serum RBP levels in patients with acute pancreatitis (AP). Methods The study included 1,871 AP patients, including 1,411 with mild AP (MAP), 244 with moderately severe AP (MSAP), and 186 with severe AP (SAP). Retrospective analysis was conducted on RBP concentrations and other clinical data of AP patients. Results AP patients were subgrouped by RBP level into low RBP (LRBP), normal RBP (NRBP), and high RBP (HRBP) groups. The LRBP group showed a significantly higher proportion of SAP patients than NRBP and HRBP groups. Additionally, the LRBP group had the highest BISAP and CTSI scores among the three groups; WBC and CRP levels in the NRBP group were significantly lower than those in the LRBP and HRBP groups. RBP was better at predicting acute necrotic collection (ANC) than other local complications, with an area under the curve (AUC) of 0.821. RBP was also an independent risk factor for acute lung injury (ALI) and ANC in AP patients. The AUC of RBP for predicting ALI was 0.829, with 30.45 mg/L as the optimal cutoff value, and the sensitivity and specificity were 59.70% and 96.50%, respectively. The AUC of RBP for predicting ANC was 0.821, with 28.35 mg/L as the optimal cutoff value, and the sensitivity and specificity were 61.20% and 95.50%, respectively. Conclusions Serum RBP had predictive value for AP severity, local and systemic complications.

Nigericin attenuates lipopolysaccharides induced sepsis and alleviates acute lung injury in in vivo model

Nigericin is a potent antibiotic derived from Streptomyces hygroscopicus which acts as a polyether ionophore. The anticancer property of nigericin was extensively studied, and it has been proven to inhibit cancer cell proliferation, progression, and invasion in prostate, colorectal, nasopharyngeal, and lung cancer. It also stimulates bacterial clearance in macrophages. The protective role of nigericin in sepsis, which is the foremost risk factor for acute lung injury and acute respiratory distress syndrome. Since bacteremia is frequently associated with lung injury, in this study we evaluated the potency of nigericin against an lipopolysaccharide (LPS)-induced sepsis mice model. BALB/c mice were challenged with intratracheal administration of LPS and simultaneously treated with 10 mg/kg and 20 mg/kg nigericin for 3 consecutive days. The mice were euthanized, and the lung tissue was excised to determine the lung wet/dry ratio. Bronchoalveolar lavage fluid was collected and assessed for protein content, LDH, and immune cell count. The antioxidant activity of nigericin was evaluated by measuring the MPO, MDA, SOD, and GSH activities in the lung tissues. The proinflammatory cytokines TNF-α and IL-6 were quantified to assess the anti-inflammatory potency against LPS-induced inflammation. iNOS, COX-2 and PGE-2 levels in lung tissue of nigericin-treated LPS-challenged mice were estimated to assess the immunomodulatory activity of nigericin. Finally, the antiapoptotic potency and cytoprotective effect of nigericin were analyzed by estimating apoptotic protein levels in lung tissue and assessing lung tissue histopathology with hematoxylin & eosin staining. Nigericin treatment significantly reduced immune cell infiltration, synthesis of proinflammatory cytokines, immunomodulatory proteins, and proapoptotic proteins in LPS-challenged mice. It also increased antioxidants and antiapoptotic protein Bcl2, thereby ameliorating lung tissue from LPS-induced inflammation. Our results indicate nigericin suppressed the LPS induced sepsis in an in vivo model and has the therapeutic potency to cure sepsis induced acute lung injury.

Activation of cannabinoid-2 receptor protects against Pseudomonas aeruginosa induced acute lung injury and inflammation

BackgroundBacterial pneumonia is a major risk factor for acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). Pseudomonas aeruginosa (PA), an opportunistic pathogen with an increasing resistance acquired against multiple drugs, is one of the main causative agents of ALI and ARDS in diverse clinical settings. Given the anti-inflammatory role of the cannabinoid-2 receptor (CB2R), the effect of CB2R activation in the regulation of PA-induced ALI and inflammation was tested in a mouse model as an alternative to conventional antibiotic therapy.MethodsIn order to activate CB2R, a selective synthetic agonist, JWH133, was administered intraperitoneally (i.p.) to C57BL/6J mice. Furthermore, SR144528 (a selective CB2R antagonist) was administered in combination with JWH133 to test the specificity of the CB2R-mediated effect. PA was administered intratracheally (i.t.) for induction of pneumonia in mice. At 24 h after PA exposure, lung mechanics were measured using the FlexiVent system. The total cell number, protein content, and neutrophil population in the bronchoalveolar lavage fluid (BALF) were determined. The bacterial load in the whole lung was also measured. Lung injury was evaluated by histological examination and PA-induced inflammation was assessed by measuring the levels of BALF cytokines and chemokines. Neutrophil activation (examined by immunofluorescence and immunoblot) and PA-induced inflammatory signaling (analyzed by immunoblot) were also studied.ResultsCB2R activation by JWH133 was found to significantly reduce PA-induced ALI and the bacterial burden. CB2R activation also suppressed the PA-induced increase in immune cell infiltration, neutrophil population, and inflammatory cytokines. These effects were abrogated by a CB2R antagonist, SR144528, further confirming the specificity of the CB2R-mediated effects. CB2R-knock out (CB2RKO) mice had a significantly higher level of PA-induced inflammation as compared to that in WT mice. CB2R activation diminished the excess activation of neutrophils, whereas mice lacking CB2R had elevated neutrophil activation. Pharmacological activation of CB2R significantly reduced the PA-induced NF-κB and NLRP3 inflammasome activation, whereas CB2KO mice had elevated NLRP3 inflammasome.ConclusionOur findings indicate that CB2R activation ameliorates PA-induced lung injury and inflammation, thus paving the path for new therapeutic avenues against PA pneumonia.

Cervical sympathetic trunk transection alleviates acute lung injury caused by intestinal obstruction via inhibition of phospholipase A2 in rats

BackgroundIntestinal obstruction can result in inflammatory injury to distant organs, especially the lungs. Stellate ganglion block (SGB) provides sympathetic nervous homeostasis and inhibits the systemic inflammatory response. This study aimed to investigate whether SGB can alleviate acute lung injury by inhibiting phospholipase A2 expression in rats.MethodsThirty healthy male Sprague–Dawley rats were divided into three groups: C group (sham-operated); CLP group (cecal ligation and puncture with intestinal obstruction), and cervical sympathetic trunk transection (CSTT) group (transection of the cervical sympathetic trunk following CLP).Arterial blood samples were obtained to determine the ratio of partial arterial pressure of oxygen (PaO2) to fraction of oxygen in inspired air (FiO2). Venous blood samples were used to evaluate the serum concentrations of chemokines, tumor necrosis factor (TNF)-α, interleukin (IL)-6, and IL-10 using enzyme-linked immunosorbent assays. Following euthanasia, the lungs were isolated to estimate the wet/dry lung weight (W/D) ratio, evaluate the pathological damage to lung tissues on microscopy, and determine secretory-type phospholipase A2 (sPLA2) expression using western blotting.ResultsRats in the CLP group showed increased fatigue, decreased activity levels, and coarse, gray hair. The levels of chemokines, TNF-α, and IL-6 in the CLP and CSTT groups were higher than those in the C group. However, the levels were lower in the CSTT group than those in the CLP group. IL-10 levels in the CLP group were higher and lower than those in the C and CSTT groups, respectively. W/D ratios and PaO2/FiO2 in the CLP and CSTT groups were higher than those in the C group, whereas these ratios in the CSTT group were lower than those in the CLP group. No lung injury was noted in group C, and the lung injury scores were lower in the CSTT group than those in the CLP group. sPLA2 expression levels in the CLP group were higher than those in the C group, whereas these levels in the CSTT group were lower than those in the CLP group.ConclusionssPLA2 overexpression in the lungs may be a pathogenic factor in acute lung injury. CSTT alleviated acute lung injury by inhibiting sPLA2 expression.

Sevoflurane anesthesia ameliorates LPS-induced acute lung injury (ALI) by modulating a novel LncRNA LINC00839/miR-223/NLRP3 axis

BackgroundSevoflurane is considered as a lung-protective factor in acute lung injury (ALI), but the underlying molecular mechanism remains largely unknown. The present study identified for the first time that sevoflurane ameliorated lipopolysaccharide (LPS)-induced ALI through regulating a novel long non-coding RNA LINC00839, and uncovered its regulatory mechanism.MethodsLPS-induced ALI models were established in mice or mouse pulmonary microvascular endothelial cells (MPVECs), and they were administered with sevoflurane. Real-Time quantitative PCR, western blot and bioinformatics analysis were performed to screen the aberrantly expressed long non-coding RNA and the downstream molecules in sevoflurane-treated ALI models, and their roles in the protection effect of sevoflurane were verified by functional recovery experiments.ResultsSevoflurane relieved LPS-induced lung injury, cell pyroptosis and inflammation in vitro and in vivo. LINC00839 was significantly suppressed by sevoflurane, and overexpression of LINC00839 abrogated the protective effects of sevoflurane on LPS-treated MPVECs. Mechanismly, LINC00839 positively regulated NOD-like receptor protein 3 (NLRP3) via sequestering miR-223. MiR-223 inhibitor reversed the inhibitory effects of LINC00839 knockdown on NLRP3-mediated pyroptosis in LPS-treated MPVECs. Furthermore, both miR-223 ablation and NLRP3 overexpression abrogated the protective effects of sevoflurane on LPS-treated MPVECs.ConclusionIn general, our work illustrates that sevoflurane regulates the LINC00839/miR-223/NLRP3 axis to ameliorate LPS-induced ALI, which might provide a novel promising candidate for the prevention of ALI.

Glycyrrhizic Acid Alleviates Lipopolysaccharide (LPS)-Induced Acute Lung Injury by Regulating Angiotensin-Converting Enzyme-2 (ACE2) and Caveolin-1 Signaling Pathway.

Acute lung injury (ALI) is mainly caused by severe infection, shock, trauma, and burn, which causes the extensive release of inflammatory factors and other mediators. As a major bioactive constituent of traditional Chinese herb licorice, glycyrrhizic acid (GA) plays an important effect on inflammatory regulation. Nevertheless, the exact mechanism of this effect remains unclear. The present study aims to explore the potential protective effect of GA on LPS-induced ALI. Our results showed that GA significantly attenuated LPS-induced ALI and decreased the production of inflammatory factors, including IL-1β, MCP-1, COX2, HMGB1, and adhesion molecules, such as E-selectin, VCAM-1, and modulated expression of angiotensin-converting enzyme 2 (ACE2). Moreover, treatment of ACE2 inhibitor (MLN-4760) reversed the effects of GA on the secretion of pro-inflammatory factors in ALI. Additionally, GA exerts its protective effect by regulating the ACE2 and caveolin-1/NF-κB signaling pathway. In conclusion, this study showed that GA alleviated LPS-induced ALI by upregulating ACE2 and inhibiting the caveolin-1/NF-κB signaling pathway.

Dexmedetomidine ameliorates renal ischemia reperfusion-mediated activation of the NLRP3 inflammasome in alveolar macrophages.

Renal ischemia-reperfusion (rI/R) is a risk factor for acute lung injury (ALI). Alveolar macrophages (AMs) activation mediated by rI/R-induced ALI is one of the pathogeneses associated with the development of ALI. In rI/R, α2-adrenergic receptor agonists have been indicated to be effective in decreasing urea nitrogen concentrations. In this study, we explored the underlying pathogenesis of the clinically obtainable α2-adrenergic receptor agonist dexmedetomidine (DEX) in protecting against rI/R -mediated AMs activation. We incubated AMs with the serum of sham and rI/R rats in the presence or absence of various concentrations of DEX. We used an enzyme-linked immunosorbent assay to detect the secretion levels of GSH, LDH, IL-18, IL-1β, and HMGB1 in the culture supernatant. We employed real-time polymerase chain reaction to assess the expression of NOX-4 mRNA, and western blotting to observe the protein levels of NOX-4, the NLRP3 inflammasome, AMPK, and eNOS. In addition, we used immunofluorescence to analyze ROS and MMP activity. Incubation of AMs with DEX suppressed rI/R-mediated cellular LDH production and ROS release. DEX also abolished the rI/R-mediated decrease in the activity of GSH and increased the levels of the rI/R-related NADPH oxidase protein NOX-4. Furthermore, DEX reduced the amelioration of the mitochondrial potential induced by rI/R. Our study showed that DEX inhibits rI/R-mediated levels of the NLRP3 inflammasome proteins ASC, NLRP3, HMGB1 and p20, and ameliorates rI/R-mediated AMPK signaling inactivation. Therefore, DEX reduces the levels of two mediators that are activated by the NLRP3 inflammasome: IL-18 and IL-1β. Finally, our study established that DEX mitigates the rI/R-mediated decrease in eNOS, demonstrating its protective functions against AMs activation. In conclusion, our study demonstrated that the protective action of DEX in AMs is induced through amelioration of HMGB1-NLRP3 inflammasome-AMPK signaling. Our results suggest that the anesthetic reagent DEX exerts beneficial effects to ameliorate rI/R-induced ALI.

COVID-19 As An Endothelial Disease and Its Relationship to Vascular Endothelial Growth Factor (VEGF) and Iodide

Recently, attention around COVID-19 has shifted from respiratory symptoms to endothelial and other symptoms. Angiotensin-converting enzyme 2 (ACE2) is the entry receptor for SARS-CoV-2. SARS-CoV-2 is known to downregulate ACE2. Vascular endothelial growth factors (VEGFs) are considered a key factor in acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). VEGF concentrations were observed to be significantly higher in both ICU and non-ICU COVID-19 patients than in healthy controls. Although VEGFs promote angiogenesis, neurogenesis and neuroprotection, they also induce vascular leakiness and permeability. ACE2 antagonizes VEGF-A to reduce vascular permeability during acute lung injury. Also in breast cancer cells, ACE2 downregulated the expression of VEGF-A. Since SARS-CoV-2 downregulates ACE2, it likely cancels the VEGF-A-antagonizing effect of ACE2, leading to upregulation of VEGF and thus increase of vascular permeability and aggravation of endothelial damage. VEGF might be upregulated also in normoxic conditions. Iodide is a VEGF modulator, increasing lymphatic system related VEGF-C/D expression while simultaneously suppressing endothelial cell related VEGF-A/B expression. It may thus revert VEGF-A/B increase caused by SARS-CoV-2 downregulation of ACE2. Protein kinase B (Akt) induces protective nitric oxide (NO) production in endothelial cells, including inhibition of thrombosis and platelet aggregation. In one study, excess iodide activated PI3K/Akt pathway. In addition, iodide was demonstrated to accumulate in upper airway secretions and inhibit viral infections by participating in a nonspecific, broad spectrum mechanism applicable to multiple types of viruses. Also, in a mouse model, iodide was observed to protect against ischemia-reperfusion injury, which may be relevant for e.g. COVID-19 associated acute limb ischemia. It has also been suggested that inorganic iodides act as antioxidants through an ancient direct mechanism. Recently, a computer simulation suggested that iodide may protect against SARS-CoV-2 directly by exhausting the electron donor property of the S protein by acting as a strong electron sink. There is initial evidence to warrant comprehensive clinical and basic research on the related pathways and possible benefits of iodide for treatment of COVID-19.

Blockade of equilibrative nucleoside transporter 1/2 protects against Pseudomonas aeruginosa-induced acute lung injury and NLRP3 inflammasome activation.

Pseudomonas aeruginosa infections are increasingly multidrug resistant and cause healthcare-associated pneumonia, a major risk factor for acute lung injury (ALI)/acute respiratory distress syndrome (ARDS). Adenosine is a signaling nucleoside with potential opposing effects; adenosine can either protect against acute lung injury via adenosine receptors or cause lung injury via adenosine receptors or equilibrative nucleoside transporter (ENT)-dependent intracellular adenosine uptake. We hypothesized that blockade of intracellular adenosine uptake by inhibition of ENT1/2 would increase adenosine receptor signaling and protect against P. aeruginosa-induced acute lung injury. We observed that P. aeruginosa (strain: PA103) infection induced acute lung injury in C57BL/6 mice in a dose- and time-dependent manner. Using ENT1/2 pharmacological inhibitor, nitrobenzylthioinosine (NBTI), and ENT1-null mice, we demonstrated that ENT blockade elevated lung adenosine levels and significantly attenuated P. aeruginosa-induced acute lung injury, as assessed by lung wet-to-dry weight ratio, BAL protein levels, BAL inflammatory cell counts, pro-inflammatory cytokines, and pulmonary function (total lung volume, static lung compliance, tissue damping, and tissue elastance). Using both agonists and antagonists directed against adenosine receptors A2AR and A2BR, we further demonstrated that ENT1/2 blockade protected against P. aeruginosa -induced acute lung injury via activation of A2AR and A2BR. Additionally, ENT1/2 chemical inhibition and ENT1 knockout prevented P. aeruginosa-induced lung NLRP3 inflammasome activation. Finally, inhibition of inflammasome prevented P. aeruginosa-induced acute lung injury. Our results suggest that targeting ENT1/2 and NLRP3 inflammasome may be novel strategies for prevention and treatment of P. aeruginosa-induced pneumonia and subsequent ARDS.

Inactivation of Nf-κb Pathway by Taxifolin Attenuates Sepsis-Induced Acute Lung Injury

Acute lung injury is a clinical syndrome consisting of a wide range of acute hypoxemic respiratory failure disorders. Sepsis is a serious complication caused by an excessive immune response to pathogen-induced infections, which has become a major predisposing factor for acute lung injury. Taxifolin is a natural flavonoid that shows diverse therapeutic benefits in inflammation- and oxidative stress-related diseases. In this study, we investigated the role of taxifolin in a mouse model of cecal ligation and puncture-induced sepsis. Cecal ligation and puncture-operated mice presented damaged alveolar structures, thickened alveolar walls, edematous septa, and hemorrhage compared to sham-treated controls. Cecal ligation and puncture mice also showed increased wet-to-dry (W/D) lung weight ratio and elevated total protein concentration and lactate dehydrogenase level in bronchoalveolar lavage fluid. Taxifolin treatment protected animals against sepsis-induced pulmonary damage and edema. Septic mice presented compromised antioxidant capacity, whereas the administration of taxifolin prior to cecal ligation and puncture surgery decreased malondialdehyde concentration and enhanced the levels of reduced glutathione and superoxide dismutase in mice with sepsis-induced acute lung injury. Moreover, cecal ligation and puncture-operated mice showed markedly higher levels of proinflammatory cytokines relative to sham-operated group, while taxifolin treatment effectively mitigated sepsis-induced inflammation in mouse lungs. Further investigation revealed that taxifolin suppressed the activation of the nuclear factor kappa-light-chain-enhancer of activated B cells signaling pathway in cecal ligation and puncture-challenged mice by regulating the phosphorylation of p65 and IκBα. In conclusion, our study showed that taxifolin alleviated sepsis-induced acute lung injury via the inhibition of nuclear factor kappa-light-chain-enhancer of activated B cells signaling pathway, suggesting the therapeutic potential of taxifolin in the treatment sepsis-induced acute lung injury.

Long non-coding RNA MALAT1 sponges miR-149 to promote inflammatory responses of LPS-induced acute lung injury by targeting MyD88.

Acute lung injury (ALI) caused by sepsis occurs early and the condition is severe, andis also an important reason for accelerating the death of patients. Increasing evidence has identified long non-coding RNA (lncRNA) metastasis associated in lung adenocarcinoma transcript 1 (MALAT1) as a regulator of ALI. However, the potential mechanism underlying MALAT1 on ALI still needs further identification. To explore the mechanisms of gene regulation expression mediated by MALAT1 through miR-149/MyD88 in lung injury inflammation, we constructed a lung injury inflammatory model using the lipopolysaccharides (LPS)-induced method and quantificated the cytokines and signaling cascade moleculesas well as miR-149. The MALAT1, myeloid differentiation factor 88 (MyD88), tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and IL-6 levels were significantly increased, and the nuclear factor-κB (NF-κB) pathway was activated, but the miR-149 level was decreased in the LPS-induced ALI model. miR-149 directly targeted both lncRNA MALAT1 and the MyD88 gene. Knockdown of MALAT1 down-regulated the levels of MyD88, TNF-α, IL-1β, and IL-6, and inhibited the NF-κB pathway. However, MALAT1 knockdown up-regulated the expression of miR-149. Overexpression of miR-149 down-regulated MyD88, TNF-α, IL-1β, and IL-6 levels, and inhibited the NF-κB pathway. MALAT1 acts as a pro-inflammatory factor in ALI via the miR-149/MyD88/NF-κB axis and is therefore a potential novel therapeutic target for ALI treatment.

Posttreatment With the Fatty Acid Amide Hydrolase Inhibitor URB937 Ameliorates One-Lung Ventilation–Induced Lung Injury in a Rabbit Model

BackgroundOne-lung ventilation (OLV)–induced inflammation is a risk factor for acute lung injury that is responsible for 20% of postoperative pulmonary complications after lung resection. Inflammation is an important trigger for acute lung injury. Fatty acid amide hydrolase (FAAH) is the major enzyme that degrades the endocannabinoid arachidonoylethanolamine (AEA), an important regulator of inflammation, and its downstream metabolites such as arachidonic acid (AA) are also involved in inflammation. Importantly, AEA is also found in lung parenchyma. However, it remains unclear whether pharmacological inhibition of FAAH inhibitor using compounds such as URB937 can attenuate OLV-induced lung injury. Materials and methodsNew Zealand white rabbits were anesthetized to establish a modified OLV-induced lung injury model. Twenty-four male rabbits were randomly divided into four groups (n = 6): TLV-S (2.5-h two-lung ventilation [TLV] + 1.5 mL/kg saline + 1-h TLV), OLV-S (2.5-h OLV + 1.5 mL/kg saline + 0.5-h OLV + 0.5-h TLV), U-OLV (1.5 mL/kg URB937 + 3.0-h OLV + 0.5-h TLV), and OLV-U (2.5-h OLV + 1.5 mL/kg URB937 + 0.5-h OLV + 0.5-h TLV). Arterial blood gases, lung wet/dry ratio, and lung injury score of the nonventilated lungs were measured. The levels of AEA, AA, prostaglandin I2 (PGI2), thromboxane A2 (TXA2), and leukotriene B4 (LTB4) in the nonventilated lung were also quantified. ResultsThe arterial oxygenation index (PaO2/FiO2) decreased after 0.5-h OLV in the three OLV groups. The PaO2/FiO2 in the OLV-U group was better than that in the OLV-S and U-OLV groups and was accompanied with reductions in the wet/dry ratio and lung injury scores of the nonventilated lungs. The FAAH inhibitor URB937 administered not before but 2.5 h after OLV attenuated OLV-induced lung injury by increasing AEA levels and reducing the levels of downstream metabolites including AA, PGI2, TXA2, and LTB4. ConclusionsPosttreatment with the FAAH inhibitor URB937 attenuated OLV-induced lung injury in rabbits and was associated with increased AEA levels and decreased levels of AA and its downstream metabolites.

Targeting allosteric site of AKT by 5,7-dimethoxy-1,4-phenanthrenequinone suppresses neutrophilic inflammation.

BackgroundAcute lung injury (ALI) is a severe life-threatening inflammatory disease. Neutrophil activation is a major pathogenic factor in ALI. Protein kinase B (PKB)/AKT regulates diverse cellular responses, but the significance in neutrophilic inflammation and ALI remains unknown.MethodsHuman neutrophils and neutrophil-like differentiated HL-60 (dHL-60) cells were used to examine the anti-inflammatory effects of 5,7-dimethoxy-1,4-phenanthrenequinone (CLLV-1). The therapeutic potential of CLLV-1 was determined in a mouse model of lipopolysaccharide (LPS)-induced ALI.FindingsCLLV-1 inhibited respiratory burst, degranulation, adhesion, and chemotaxis in human neutrophils and dHL-60 cells. CLLV-1 inhibited the phosphorylation of AKT (Thr308 and Ser473), but not of ERK, JNK, or p38. Furthermore, CLLV-1 blocked AKT activity and covalently reacted with AKT Cys310 in vitro. The AKT309–313 peptide-CLLV-1 adducts were determined by NMR or mass spectrometry assay. The alkylation agent-conjugated AKT (reduced form) level was also inhibited by CLLV-1. Significantly, CLLV-1 ameliorated LPS-induced ALI, neutrophil infiltration, and AKT activation in mice.InterpretationOur results identify CLLV-1 as a covalent allosteric AKT inhibitor by targeting AKT Cys310. CLLV-1 shows potent anti-inflammatory activity in human neutrophils and LPS-induced mouse ALI. Our findings provide a mechanistic framework for redox modification of AKT that may serve as a novel pharmacological target to alleviate neutrophilic inflammation.

Targeting Allosteric Site of AKT by 5,7-Dimethoxy-1,4-Phenanthrenequinone Suppresses Neutrophilic Inflammation

Background: Acute lung injury (ALI) is a severe life-threatening inflammatory disease. Neutrophil activation is a major pathogenic factor in ALI. Protein kinase B (PKB)/AKT regulates diverse cellular responses, but the significance in neutrophilic inflammation and ALI remains unknown. Methods: Human neutrophils and neutrophil-like differentiated HL-60 (dHL-60) cells were used to examine the anti-inflammatory effects of 5,7-dimethoxy-1,4-phenanthrenequinone (CLLV-1). The therapeutic potential of CLLV-1 was determined in a mouse model of lipopolysaccharide (LPS)-induced ALI. Findings: CLLV-1 inhibited respiratory burst, degranulation, adhesion, and chemotaxis in human neutrophils and dHL-60 cells. CLLV-1 inhibited the phosphorylation of AKT (Thr308 and Ser473), but not of ERK, JNK, or p38. Furthermore, CLLV-1 blocked AKT activity and covalently reacted with AKT Cys310 in vitro. The AKT309-313 peptide-CLLV-1 adducts were determined by NMR or mass spectrometry assay. The alkylation agent-conjugated AKT (reduced form) level was also inhibited by CLLV-1. Significantly, CLLV-1 ameliorated LPS-induced ALI, neutrophil infiltration, and AKT activation in mice. Interpretation: Our results identify CLLV-1 as a covalent allosteric AKT inhibitor by targeting AKT Cys310. CLLV-1 shows potent anti-inflammatory activity in human neutrophils and LPS-induced mouse ALI. Our findings provide a mechanistic framework for redox modification of AKT that may serve as a novel pharmacological target to alleviate neutrophilic inflammation. Funding Statement: This research was financial supported by the grants from the Ministry of Science Technology (MOST 106-2320-B-255-003-MY3 and MOST 104-2320-B-255-004-MY3), Ministry of Education (EMRPD1G0231 and EMRPD1H0381), and Chang Gung Memorial Hospital (CMRPF1F0011~3, CMRPF1F0061~3, CMRPF1G0241~3, and BMRP450), Taiwan. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Declaration of Interests: The authors declare that no competing interests exist. Ethics Approval Statement: The procedure of neutrophil isolation was approved by the Institutional Review Board at Chang Gung Memorial Hospital. ALI was induced by intra-tracheal spray of 2 mg/kg LPS (Escherichia coli 0111:B4) in seven to eight weeks old C57BL/6 male mice, according to the guidelines and approved by Institutional Animal Care and Use Committee of Chang Gung University, Taiwan.

Interleukin 1α (IL-1α) Promotes Pathogenic Immature Myeloid Cells and IL-1β Favors Protective Mature Myeloid Cells During Acute Lung Infection.

Bacterial pneumonia is a common risk factor for acute lung injury and sepsis-mediated death, but the mechanisms underlying the overt inflammation and accompanying pathology are unclear. Infiltration of immature myeloid cells and necrotizing inflammation mediate severe pathology and death during pulmonary infection with Francisella tularensis. However, eliciting mature myeloid cells provides protection. Yet, the host factors responsible for this pathologic immature myeloid cell response are unknown. Here, we report that while the influx of both mature and immature myeloid cells is strictly MyD88 dependent, the interleukin 1 (IL-1) receptor mediates an important dual function via its ligands IL-1α and IL-1β. Although IL-1β favors the appearance of bacteria-clearing mature myeloid cells, IL-1α contributes to lung infiltration by ineffective and pathologic immature myeloid cells. Finally, IL-1α and IL-1β are not the sole factors involved, but myeloid cell responses during acute pneumonia were largely unaffected by lung levels of interleukin 10, interleukin 17, CXCL1, granulocyte colony-stimulating factor, and granulocyte-macrophage colony-stimulating factor.

Predictive Value of Intraoperative Troponin I Elevation in Pediatric Living Donor Liver Transplant Recipients With Biliary Atresia.

Pediatric living donor liver transplantation is associated with slight alteration in cardiac enzymes without ongoing acute cardiac injury, but available information about the significance of these changes is limited. The aims of this study were to analyze the link between the anomalies of intraoperative serum cardiac troponin I (cTnI) and acute lung injury during the first week after liver transplantation. In this retrospective study, 123 children suffering from biliary atresia were enrolled. Several perioperative variables, particularly cTnI before operation and at 30 minutes of neohepatic phase were recorded. Sixty-four recipients were divided into high cTnI group (≥0.07 ng/mL) and 59 recipients composed normal cTnI group (<0.07 ng/mL). The clinical data between 2 groups were compared and the association between serum cTnI level and acute lung injury after living donor liver transplantation were evaluated by univariate and multivariate logistic regression analyses. The percentage of acute lung injury after pediatric living donor liver transplantation among high cTnI group and normal cTnI group was 34.3% and 11.9%, respectively. Intratransplant cTnI ≥ 0.07 ng/mL (odds ratio [OR], 3.475; 95% confidence interval [CI], 1.114-10.842) was the risk factors for acute lung injury after transplantation. The value of cTnI showed the close correlation with preoperative bilirubin (OR, 1.005; 95% CI, 1.002-1.008) and pretransplant albumin (OR, 0.915; 95% CI, 0.849-0.986). Intraoperative cTnI elevation was the significant prognostic risk factor in acute lung injury after pediatric living-donor liver transplantation for children with biliary atresia. And the value of cTnI was associated with preoperative bilirubin and albumin level.