Correction: Lung Transcriptomics during Protective Ventilatory Support in Sepsis-Induced Acute Lung Injury.
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ABSTRACT:
SUBMITTER: Acosta-Herrera M
PROVIDER: S-EPMC4683088 | biostudies-literature | 2015
REPOSITORIES: biostudies-literature
Publications
Correction: Lung Transcriptomics during Protective Ventilatory Support in Sepsis-Induced Acute Lung Injury.
Acosta-Herrera Marialbert M Lorenzo-Diaz Fabian F Pino-Yanes Maria M Corrales Almudena A Valladares Francisco F Klassert Tilman E TE Valladares Basilio B Slevogt Hortense H Ma Shwu-Fan SF Villar Jesus J Flores Carlos C
PloS one 20151217 12
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Project description:Acute lung injury (ALI) is a severe inflammatory process of the lung. The only proven life-saving support is mechanical ventilation (MV) using low tidal volumes (LVT) plus moderate to high levels of positive end-expiratory pressure (PEEP). However, it is currently unknown how they exert the protective effects. To identify the molecular mechanisms modulated by protective MV, this study reports transcriptomic analyses based on microarray and microRNA sequencing in lung tissues from a clinically relevant animal model of sepsis-induced ALI. Sepsis was induced by cecal ligation and puncture (CLP) in male Sprague-Dawley rats. At 24 hours post-CLP, septic animals were randomized to three ventilatory strategies: spontaneous breathing, LVT (6 ml/kg) plus 10 cmH2O PEEP and high tidal volume (HVT, 20 ml/kg) plus 2 cmH2O PEEP. Healthy, non-septic, non-ventilated animals served as controls. After 4 hours of ventilation, lung samples were obtained for histological examination and gene expression analysis using microarray and microRNA sequencing. Validations were assessed using parallel analyses on existing publicly available genome-wide association study findings and transcriptomic human data. The catalogue of deregulated processes differed among experimental groups. The 'response to microorganisms' was the most prominent biological process in septic, non-ventilated and in HVT animals. Unexpectedly, the 'neuron projection morphogenesis' process was one of the most significantly deregulated in LVT. Further support for the key role of the latter process was obtained by microRNA studies, as four species targeting many of its genes (Mir-27a, Mir-103, Mir-17-5p and Mir-130a) were found deregulated. Additional analyses revealed 'VEGF signaling' as a central underlying response mechanism to all the septic groups (spontaneously breathing or mechanically ventilated). Based on this data, we conclude that a co-deregulation of 'VEGF signaling' along with 'neuron projection morphogenesis', which have been never anticipated in ALI pathogenesis, promotes lung-protective effects of LVT with high levels of PEEP.
| S-EPMC4492998 | biostudies-literature
Project description:PurposeThe efficacy of partial ventilatory support modes that allow spontaneous breathing in patients with acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) is unclear. The objective of this scoping review was to assess the effects of partial ventilatory support on mortality, duration of mechanical ventilation, and both hospital and intensive care unit (ICU) lengths of stay (LOS) for patients with ALI and ARDS; the secondary objective was to describe physiologic effects on hemodynamics, respiratory system and other organ function.MethodsMEDLINE (1966-2009), Cochrane, and EmBase (1980-2009) databases were searched using common ventilator modes as keywords and reference lists from retrieved manuscripts hand searched for additional studies. Two researchers independently reviewed and graded the studies using a modified Oxford Centre for Evidence-Based Medicine grading system. Studies in adult ALI/ARDS patients were included for primary objectives and pre-clinical studies for supporting evidence.ResultsTwo randomized controlled trials (RCTs) were identified, in addition to six prospective cohort studies, one retrospective cohort study, one case control study, 41 clinical physiologic studies and 28 pre-clinical studies. No study was powered to assess mortality, one RCT showed shorter ICU length of stay, and the other demonstrated more ventilator free days. Beneficial effects of preserved spontaneous breathing were mainly physiological effects demonstrated as improvement of gas exchange, hemodynamics and non-pulmonary organ perfusion and function.ConclusionsThe use of partial ventilatory support modalities is often feasible in patients with ALI/ARDS, and may be associated with short-term physiological benefits without appreciable impact on clinically important outcomes.
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Project description:The present study aims to reveal the molecular mechanism of peroxisome proliferator-activated receptor ? (PPAR?) on sepsis-induced acute lung injury (ALI). To do that, the rat injury model was established using cecal ligation and perforation (CLP) method, followed by different treatments, and the rats were divided into Sham group, CLP group, CLP + rosiglitazone (PPAR? agonist) group, CLP + GW9662 (PPAR? inhibitor) group, CLP + bpV (phosphatase and tensin homolog (PTEN) inhibitor) group, CLP + GW9662 + bpV group. Compared with Sham group, the mRNA and protein expression levels of PPAR? were down-regulated, the inflammation levels were elevated, and the apoptosis was increased in CLP group. After treatment with rosiglitazone, the protein expression level of PPAR? was significantly up-regulated, the phosphorylation level of PTEN/?-catenin pathway was decreased, the PTEN/?-catenin pathway was inhibited, the lung injury, inflammation and apoptosis were reduced. The opposite effect was observed after treatment with GW9662. Besides, bpV inhibited PTEN/?-catenin pathway, and relieved the lung tissue injury. The overexpression of PPAR? reduced inflammatory response and inhibited apoptosis in sepsis-induced ALI. Furthermore, PPAR? relieved the sepsis-induced ALI by inhibiting the PTEN/?-catenin pathway.
| S-EPMC7256673 | biostudies-literature
Project description:BACKGROUND:An on-going debate exists as to whether partial ventilatory support is lung protective in an acute phase of ARDS. So far, the effects of different respiratory efforts on the development of ventilator-associated lung injury (VALI) have been poorly understood. To test the hypothesis whether respiratory effort itself promotes VALI, acute lung injury (ALI) was induced in 48 Sprague Dawley rats by hydrochloric acid aspiration model. Hemodynamics, gas-exchange, and respiratory mechanics were measured after 4 h of ventilation in pressure control (PC), assist-control (AC), or pressure support with 100% (PS100), 60% (PS60), or 20% (PS20) of the driving pressure during PC. VALI was assessed by histological analysis and biological markers. RESULTS:ALI was characterized by a decrease in PaO2/FiO2 from 447 ± 75 to 235 ± 90 mmHg (p < 0.001) and dynamic respiratory compliance from 0.53 ± 0.2 to 0.28 ± 0.1 ml/cmH2O (p < 0.001). There were no differences in hemodynamics or respiratory function among groups at baseline or after 4 h of ventilation. The reduction of mechanical pressure support was associated with a compensatory increase in an inspiratory effort such that peak inspiratory transpulmonary pressures were equal in all groups. The diffuse alveolar damage score showed significant lung injury but was similar among groups. Pro- and anti-inflammatory proteins in the bronchial fluid were comparable among groups. CONCLUSIONS:In experimental ALI in rodents, the respiratory effort was increased by reducing the pressure support during partial ventilatory support. In the presence of a constant peak inspiratory transpulmonary pressure, an increased respiratory effort was not associated with worsening ventilator-associated lung injury measured by histologic score and biologic markers.
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Project description:BackgroundTo clarify the mechanism of notoginsenoside R1 in the treatment of septic acute lung injury (ALI) based on network pharmacological analysis, and to verify it in the model of septic ALI in rats.MethodsBased on database searching, the related targets of notoginsenoside R1 and ALI were identified, and the component-disease-target network was constructed. The core targets were screened by protein-protein interaction (PPI), and the functional enrichment of Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) was analyzed. The rat model of septic ALI was further established to investigate the pharmacological effects of notoginsenoside R1.ResultsNotoginsenoside R1 possibly affected ALI through 150 targets, of which 36 were core targets. GO semantic similarity analysis showed that notoginsenoside R1 might play a role in regulating interleukin 17 (IL-17) signal pathway, tumor necrosis factor (TNF) signal pathway and other key links by regulating MAPK1, MAPK3, IL-1β and other targets. The results of pharmacological experiments showed that notoginsenoside R1 could significantly reduce the wet:dry ratio of the lung in an animal model of ALI, improve the pathological injury of the lung, and reduce the content of IL-1β in serum and in bronchoalveolar lavage fluid (BALF) of experimental animals.ConclusionsNotoginsenoside R1 can inhibit pulmonary edema, reduce inflammation, and improve lung lesions through multiple targets and pathways to achieve the pharmacological effects in the treatment of septic ALI.
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Project description:Currently, the treatment for sepsis-induced acute lung injury mainly involves mechanical ventilation with limited use of drugs, highlighting the urgent need for new therapeutic options. As a pivotal aspect of acute lung injury, the pathologic activation and apoptosis of endothelial cells related to oxidative stress play a crucial role in disease progression, with NOX4 and Nrf2 being important targets in regulating ROS production and clearance. Echinacoside, extracted from the traditional Chinese herbal plant Cistanche deserticola, possesses diverse biological activities. However, its role in sepsis-induced acute lung injury remains unexplored. Moreover, although some studies have demonstrated the regulation of NOX4 expression by SIRT1, the specific mechanisms are yet to be elucidated. Therefore, this study aimed to investigate the effects of echinacoside on sepsis-induced acute lung injury and oxidative stress in mice and to explore the intricate regulatory mechanism of SIRT1 on NOX4. We found that echinacoside inhibited sepsis-induced acute lung injury and oxidative stress while preserving endothelial function. In vitro experiments demonstrated that echinacoside activated SIRT1 and promoted its expression. The activated SIRT1 was competitively bound to p22 phox, inhibiting the activation of NOX4 and facilitating the ubiquitination and degradation of NOX4. Additionally, SIRT1 deacetylated Nrf2, promoting the downstream expression of antioxidant enzymes, thus enhancing the NOX4-Nrf2 axis and mitigating oxidative stress-induced endothelial cell pathologic activation and mitochondrial pathway apoptosis. The SIRT1-mediated anti-inflammatory and antioxidant effects of echinacoside were validated in vivo. Consequently, the SIRT1-regulated NOX4-Nrf2 axis may represent a crucial target for echinacoside in the treatment of sepsis-induced acute lung injury.
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Project description:BackgroundBacterial infection is one of the most common causes of sepsis, with acute lung injury (ALI) being a related complication. Pterostilbene (PTS) is extracted from blueberries, peanuts, and grapes, and has numerous pharmacologic activities. The aim of the present study was to explore the underlying role of PTS protects against sepsis-mediated ALI.MethodsWe established a sepsis model induced by cecal ligation and puncture (CLP) in rats. The rats were randomly divided into five groups (n=5 each): sham group, CLP group, Dexmedetomidine group (Dex, 50 µg/kg) and PTS groups (25 and 50 mg/kg). Twenty-hours hours after CLP, PTS was intraperitoneally injected for 14 continuous days. The rats were killed, and blood and lung tissue were collected for pathological analysis and mRNA and protein detection.ResultsOur findings showed that PTS reduced the wet/dry ratio and ameliorated sepsis-induced pulmonary fibrosis (PF), which was associated with improvement of pathological damage in lung tissues. We also observed the inhibitory effect of PTS on apoptosis and release of inflammatory cytokines (i.e., tumor necrosis factor-α, interleukin-6, and monocyte chemotactic protein 1). In addition, PTS markedly suppressed the phosphorylation levels of Janus kinase-2 (JAK2) and signal transducer and activator of transcription 3 (STAT3).ConclusionsOur results indicated that PTS inhibited the PF, apoptosis, and inflammatory response via the JAK2/STAT3 pathway in a sepsis-induced ALI rat model, providing a candidate for drug therapy of sepsis-induced ALI.
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Project description:ObjectiveInflammation and oxidative stress play critical roles in sepsis-induced acute lung injury (ALI). Sprout4 (Spry4) is involved in regulating inflammation and tissue injury; however, its role and mechanism in sepsis-induced ALI remain elusive.MethodsMacrophage-specific Spry4 knockout (Spry4MKO), transgenic (Spry4MTG) mice and matched control littermates were generated and exposed to cecum ligation and puncture (CLP) surgery to establish bacterial sepsis-induced ALI. Bone marrow-derived macrophages (BMDMs) from Spry4MKO or Spry4MTG mice were isolated and subjected to lipopolysaccharide (LPS) stimulation to further validate the role of Spry4 in vitro. To verify the necessity of AMP-activated protein kinase (AMPK), Spry4 and AMPK double knockout mice and compound C were used in vivo and in vitro. BMDMs were treated with STO-609 to inhibit calcium/calmodulin-dependent protein kinase kinase 2 (CaMKK2).ResultsWe found that macrophage Spry4 was increased in CLP mice and positively correlated with sepsis-induced ALI. Macrophage Spry4 deficiency prevented, while macrophage Spry4 overexpression exacerbated sepsis-induced inflammation, oxidative stress and ALI in mice and BMDMs. Mechanistic studies revealed that macrophage Spry4 deficiency alleviated sepsis-induced ALI through activating CaMKK2/AMPK pathway.ConclusionOur study identify macrophage Spry4 as a promising predictive and therapeutic target of sepsis-induced ALI.
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Project description:BackgroundSepsis morbidity and mortality are aggravated by acute lung injury (ALI) or acute respiratory distress syndrome (ARDS). Mouse B-1a cells are a phenotypically and functionally unique sub-population of B cells, providing immediate protection against infection by releasing natural antibodies and immunomodulatory molecules. We hypothesize that B-1a cells ameliorate sepsis-induced ALI.MethodsSepsis was induced in C57BL/6 mice by cecal ligation and puncture (CLP). PBS or B-1a cells were adoptively transferred into the septic mice intraperitoneally. After 20 h of CLP, lungs were harvested and assessed by PCR and ELISA for pro-inflammatory cytokines (IL-6, IL-1β) and chemokine (MIP-2) expression, by histology for injury, by TUNEL and cleaved caspase-3 for apoptosis, and by myeloperoxidase (MPO) assay for neutrophil infiltration.ResultsWe found that septic mice adoptively transferred with B-1a cells significantly decreased the mRNA and protein levels of IL-6, IL-1β and MIP-2 in the lungs compared to PBS-treated mice. Mice treated with B-1a cells showed dramatic improvement in lung injury compared to PBS-treated mice after sepsis. We found apoptosis in the lungs was significantly inhibited in B-1a cell injected mice compared to PBS-treated mice after sepsis. B-1a cell treatment significantly down-regulated MPO levels in the lungs compared to PBS-treated mice in sepsis. The protective outcomes of B-1a cells in ALI was further confirmed by using B-1a cell deficient CD19-/- mice, which showed significant increase in the lung injury scores following sepsis as compared to WT mice.ConclusionsOur results demonstrate a novel therapeutic potential of B-1a cells to treat sepsis-induced ALI.
| S-EPMC6016888 | biostudies-literature
Project description:ObjectiveInflammation and oxidative stress contribute to the progression of sepsis-induced acute lung injury (ALI). SAM domain, SH3 domain and nuclear localization signals 1 (SAMSN1) is a signaling adaptor protein, and mainly regulates inflammatory response of various immune cells. The present study generates macrophage-specific SAMSN1-knockout (Samsn1MKO) and SAMSN1-transgenic (Samsn1MTG) mice to investigate its role and mechanism in sepsis-induced ALI.MethodsSamsn1MKO and Samsn1MTG mice were exposed to lipopolysaccharide (LPS) instillation or cecal ligation and puncture (CLP) surgery to induce sepsis-induced ALI. Bone marrow transplantation, cellular depletion and non-invasive adoptive transfer of bone marrow-derived macrophages (BMDMs) were performed to validate the role of macrophage SAMSN1 in sepsis-induced ALI in vivo. Meanwhile, BMDMs were isolated from Samsn1MKO or Samsn1MTG mice to further clarify the role of SAMSN1 in vitro.ResultsMacrophage SAMSN1 expression was increased in response to LPS stimulation, and negatively correlated with LPS-induced ALI in mice. Macrophage SAMSN1 deficiency exacerbated, while macrophage SAMSN1 overexpression ameliorated LPS-induced inflammation, oxidative stress and ALI in mice and in BMDMs. Mechanistically, we found that macrophage SAMSN1 overexpression prevented LPS-induced ALI though activating AMP-activated protein kinase α2 (AMPKα2) in vivo and in vitro. Further studies revealed that SAMSN1 directly bound to growth factor receptor bound protein 2-associated protein 1 (GAB1) to prevent its protein degradation, and subsequently enhanced protein kinase A (PKA)/AMPKα2 activation in a protein tyrosine phosphatase, non-receptor type 11 (PTPN11, also known as SHP2)-dependent manner. Moreover, we observed that macrophage SAMSN1 overexpression diminished CLP-induced ALI in mice.ConclusionOur study documents the protective role of macrophage SAMSN1 against sepsis-induced inflammation, oxidative stress and ALI through activating AMPKα2 in a GAB1/SHP2/PKA pathway, and defines it as a promising biomarker and therapeutic target to treat sepsis-induced ALI.
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