14 research outputs found

    Hyperoxemia and excess oxygen use in early acute respiratory distress syndrome : Insights from the LUNG SAFE study

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    Publisher Copyright: ¬© 2020 The Author(s). Copyright: Copyright 2020 Elsevier B.V., All rights reserved.Background: Concerns exist regarding the prevalence and impact of unnecessary oxygen use in patients with acute respiratory distress syndrome (ARDS). We examined this issue in patients with ARDS enrolled in the Large observational study to UNderstand the Global impact of Severe Acute respiratory FailurE (LUNG SAFE) study. Methods: In this secondary analysis of the LUNG SAFE study, we wished to determine the prevalence and the outcomes associated with hyperoxemia on day 1, sustained hyperoxemia, and excessive oxygen use in patients with early ARDS. Patients who fulfilled criteria of ARDS on day 1 and day 2 of acute hypoxemic respiratory failure were categorized based on the presence of hyperoxemia (PaO2 > 100 mmHg) on day 1, sustained (i.e., present on day 1 and day 2) hyperoxemia, or excessive oxygen use (FIO2 ‚Č• 0.60 during hyperoxemia). Results: Of 2005 patients that met the inclusion criteria, 131 (6.5%) were hypoxemic (PaO2 < 55 mmHg), 607 (30%) had hyperoxemia on day 1, and 250 (12%) had sustained hyperoxemia. Excess FIO2 use occurred in 400 (66%) out of 607 patients with hyperoxemia. Excess FIO2 use decreased from day 1 to day 2 of ARDS, with most hyperoxemic patients on day 2 receiving relatively low FIO2. Multivariate analyses found no independent relationship between day 1 hyperoxemia, sustained hyperoxemia, or excess FIO2 use and adverse clinical outcomes. Mortality was 42% in patients with excess FIO2 use, compared to 39% in a propensity-matched sample of normoxemic (PaO2 55-100 mmHg) patients (P = 0.47). Conclusions: Hyperoxemia and excess oxygen use are both prevalent in early ARDS but are most often non-sustained. No relationship was found between hyperoxemia or excessive oxygen use and patient outcome in this cohort. Trial registration: LUNG-SAFE is registered with ClinicalTrials.gov, NCT02010073publishersversionPeer reviewe

    Hyperoxemia and excess oxygen use in early acute respiratory distress syndrome: Insights from the LUNG SAFE study

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    Background: Concerns exist regarding the prevalence and impact of unnecessary oxygen use in patients with acute respiratory distress syndrome (ARDS). We examined this issue in patients with ARDS enrolled in the Large observational study to UNderstand the Global impact of Severe Acute respiratory FailurE (LUNG SAFE) study. Methods: In this secondary analysis of the LUNG SAFE study, we wished to determine the prevalence and the outcomes associated with hyperoxemia on day 1, sustained hyperoxemia, and excessive oxygen use in patients with early ARDS. Patients who fulfilled criteria of ARDS on day 1 and day 2 of acute hypoxemic respiratory failure were categorized based on the presence of hyperoxemia (PaO2 &gt; 100 mmHg) on day 1, sustained (i.e., present on day 1 and day 2) hyperoxemia, or excessive oxygen use (FIO2 ‚Č• 0.60 during hyperoxemia). Results: Of 2005 patients that met the inclusion criteria, 131 (6.5%) were hypoxemic (PaO2 &lt; 55 mmHg), 607 (30%) had hyperoxemia on day 1, and 250 (12%) had sustained hyperoxemia. Excess FIO2 use occurred in 400 (66%) out of 607 patients with hyperoxemia. Excess FIO2 use decreased from day 1 to day 2 of ARDS, with most hyperoxemic patients on day 2 receiving relatively low FIO2. Multivariate analyses found no independent relationship between day 1 hyperoxemia, sustained hyperoxemia, or excess FIO2 use and adverse clinical outcomes. Mortality was 42% in patients with excess FIO2 use, compared to 39% in a propensity-matched sample of normoxemic (PaO2 55-100 mmHg) patients (P = 0.47). Conclusions: Hyperoxemia and excess oxygen use are both prevalent in early ARDS but are most often non-sustained. No relationship was found between hyperoxemia or excessive oxygen use and patient outcome in this cohort. Trial registration: LUNG-SAFE is registered with ClinicalTrials.gov, NCT0201007

    Correction to: Potentially modifiable factors contributing to outcome from acute respiratory distress syndrome: the LUNG SAFE study (Intensive Care Medicine, (2016), 42, 12, (1865-1876), 10.1007/s00134-016-4571-5)

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    The members of the LUNG SAFE Investigators and the ESICM Trials Group were provided in such a way that they could not be indexed as collaborators on PubMed. The publisher apologizes for this error

    SQSTM1/p62 interacts with HDAC6 and regulates deacetylase activity.

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    Protein aggregates can form in the cytoplasm of the cell and are accumulated at aggresomes localized to the microtubule organizing center (MTOC) where they are subsequently degraded by autophagy. In this process, aggregates are engulfed into autophagosomes which subsequently fuse with lysosomes for protein degradation. A member of the class II histone deacetylase family, histone deacetylase 6(HDAC6) has been shown to be involved in both aggresome formation and the fusion of autophagosomes with lysosomes making it an attractive target to regulate protein aggregation. The scaffolding protein sequestosome 1(SQSTM1)/p62 has also been shown to regulate accumulation and autophagic clearance of protein aggregates. Recent studies have revealed colocalization of HDAC6 and p62 to ubiquitinated mitochondria, as well as, ubiquitinated protein aggregates associated with the E3 ubiquitin ligase TRIM50. HDAC6 deacetylase activity is required for aggresome formation and can be regulated by protein interaction with HDAC6. Due to their colocalization at ubiquitinated protein aggregates, we sought to examine if p62 specifically interacted with HDAC6 and if so, if this interaction had any effect on HDAC6 activity and/or the physiological function of cortactin-F-actin assembly. We succeeded in identifying and mapping the direct interaction between HDAC6 and p62. We further show that this interaction regulates HDAC6 deacetylase activity. Data are presented demonstrating that the absence of p62 results in hyperactivation of HDAC6 and deacetylation of őĪ-tubulin and cortactin. Further, upon induction of protein misfolding we show that p62 is required for perinuclear co-localization of cortactin-F-actin assemblies. Thus, our findings indicate that p62 plays a key role in regulating the recruitment of F-actin network assemblies to the MTOC, a critical cellular function that is required for successful autophagic clearance of protein aggregates

    p62 regulates physiological function of cortactin-F-actin assembly.

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    <p>(<b>A</b>) WT MEF cells, either untreated (a-f) or treated (g-l),with 5 ¬ĶM MG132 for 6 hours were fixed with paraformaldehyde. F-actin was stained with phalloidin-AF350. Endogenous cortactin was immuno-stained with Texas Red secondary antibody and endogenous HDAC6 immuno-stained with Oregon Green secondary antibody. Cells were analyzed with confocal microscopy. Panel identification is as follows: a and g ‚Äď actin; b and h ‚Äď cortactin; c and i ‚Äď HDAC6; d and j ‚Äď actin/cortactin; e and k ‚Äď actin/HDAC6; f and l ‚Äď cortactin/HDAC6. A fully merged image is shown to the right of each set of panels. (<b>B</b>) p62KO MEF cells, either untreated (a-f) or treated (g-l), with 5 ¬ĶM MG132 for 6 hours, were subjected to the same immunofluorescence procedure as described above.</p

    Mapping the interaction region on p62.

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    <p>(<b>A</b>) Schematic diagram of HA-tagged p62 deletion constructs. (<b>B</b>) HEK cells were transfected with full length FLAG-HDAC6 and HA-tagged p62 deletion mutants constructs. Full length p62 was myc-tagged. HDAC6 was captured with anti-FLAG antibody and co-precipitating myc-tagged full length p62 or HA-tagged p62 deletion constructs analyzed by Western blot with anti-HA antibody.</p

    p62 specifically interacts with HDAC6.

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    <p>(<b>A</b>) Lysates of HEK cells transfected or not with HA-HDAC6 were subjected to GST-p62 pulldown assay. Tagged constructs were captured on glutathione sepharose beads and analyzed by Western blot with anti-HA and anti-GST antibodies. (<b>B</b>) HEK cells were transfected with FLAG-HDAC6 and myc-p62 constructs. HDAC6 was immunoprecipitated with FLAG-tag antibody and presence of co-precipitating myc-p62 (included in highlighted box) analyzed by Western blot with anti-myc antibody. Presence of transfected constructs were confirmed in the whole cell lysate. (<b>C</b>) Endogenously expressed p62 and HDAC6 was examined in WT MEF cells by immunoprecipitation with p62 or HDAC6 antibodies and analyzed by Western blot with corresponding antibodies. (<b>D</b>) Endogenous HDAC6 and p62 localization was examined by immunofluorescence in WT MEF cells.</p

    Mapping the interaction region on HDAC6.

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    <p>(<b>A</b>) Schematic diagram of HA-tagged HDAC6 truncation constructs. (<b>B</b>) HEK cells were transfected with full length myc-p62 and HA-tagged HDAC6 deletion constructs. p62 was captured with anti-myc antibody and co-precipitating HA-tagged HDAC6 constructs analyzed by Western blot with anti-HA antibody.</p

    Correction to: Potentially modifiable factors contributing to outcome from acute respiratory distress syndrome: the LUNG SAFE study (Intensive Care Medicine, (2016), 42, 12, (1865-1876), 10.1007/s00134-016-4571-5)

    No full text
    Correction to: Intensive Care Med (2016) 42:1865-1876 DOI 10.1007/s00134-016-4571-5
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