Acute respiratory distress syndrome Sweeney, Rob Mac, PhD; McAuley, Daniel F, Prof
The Lancet (British edition),
11/2016, Letnik:
388, Številka:
10058
Journal Article
Recenzirano
Odprti dostop
Summary Acute respiratory distress syndrome presents as hypoxia and bilateral pulmonary infiltrates on chest imaging in the absence of heart failure sufficient to account for this clinical state. ...Management is largely supportive, and is focused on protective mechanical ventilation and the avoidance of fluid overload. Patients with severe hypoxaemia can be managed with early short-term use of neuromuscular blockade, prone position ventilation, or extracorporeal membrane oxygenation. The use of inhaled nitric oxide is rarely indicated and both β2 agonists and late corticosteroids should be avoided. Mortality remains at approximately 30%.
Acute respiratory distress syndrome (ARDS) is characterised by acute hypoxaemic respiratory failure with bilateral infiltrates on chest imaging, which is not fully explained by cardiac failure or ...fluid overload. ARDS is defined by the Berlin criteria. In this Series paper the diagnosis, management, outcomes, and long-term sequelae of ARDS are reviewed. Potential limitations of the ARDS definition and evidence that could inform future revisions are considered. Guideline recommendations, evidence, and uncertainties in relation to ARDS management are discussed. The future of ARDS strives towards a precision medicine approach, and the framework of treatable traits in ARDS diagnosis and management is explored.
Mesenchymal stromal cells (MSC) have been reported to improve bacterial clearance in preclinical models of Acute Respiratory Distress Syndrome (ARDS) and sepsis. The mechanism of this effect is not ...fully elucidated yet. The primary objective of this study was to investigate the hypothesis that the antimicrobial effect of MSC in vivo depends on their modulation of macrophage phagocytic activity which occurs through mitochondrial transfer. We established that selective depletion of alveolar macrophages (AM) with intranasal (IN) administration of liposomal clodronate resulted in complete abrogation of MSC antimicrobial effect in the in vivo model of Escherichia coli pneumonia. Furthermore, we showed that MSC administration was associated with enhanced AM phagocytosis in vivo. We showed that direct coculture of MSC with monocyte‐derived macrophages enhanced their phagocytic capacity. By fluorescent imaging and flow cytometry we demonstrated extensive mitochondrial transfer from MSC to macrophages which occurred at least partially through tunneling nanotubes (TNT)‐like structures. We also detected that lung macrophages readily acquire MSC mitochondria in vivo, and macrophages which are positive for MSC mitochondria display more pronounced phagocytic activity. Finally, partial inhibition of mitochondrial transfer through blockage of TNT formation by MSC resulted in failure to improve macrophage bioenergetics and complete abrogation of the MSC effect on macrophage phagocytosis in vitro and the antimicrobial effect of MSC in vivo. Collectively, this work for the first time demonstrates that mitochondrial transfer from MSC to innate immune cells leads to enhancement in phagocytic activity and reveals an important novel mechanism for the antimicrobial effect of MSC in ARDS. Stem Cells 2016;34:2210–2223
Antimicrobial effect of mesenchymal stromal cells (MSC) in acute respiratory distress syndrome (ARDS) is mediated in part by enhanced alveolar macrophage phagocytosis through TNT‐dependent mitochondrial transfer leading to improved macrophage bioenergetics. (A) In mouse E. coli pneumonia MSC treatment improved bacterial clearance in the lung (p = .02), alveolar macrophage(AM) depletion by liposomal clodronate significantly increased bacterial burden (p < .05) and abrogated MSC antimicrobial effect. (B) In E. coli pneumonia MSC treatment significantly increased the percentage of phagocytic AM compared to PBS suggesting improved AM phagocytosis (p = .01). (C) (i‐iii) transfer of mitochondria from MSC (MitoRed+) to primary human macrophages (MDM) (CD45+) through TNT‐like structures (arrows) (scale bar = 50 μm) (iv) Flow cytometry showing more than 90% of CD45+ MDM acquired MSC specific MitoRed fluorescence (APC+), indicating extensive mitochondrial transfer from MSC (4 hours of coculture) (v) In vivo 93% and 65% of AM were positive for MitoRed at 24 and 48 hours after MSC administration, respectively. (D) AM that had internalized MSC mitochondria (Mito+) showed a significantly higher phagocytic index in comparison to those without (p = .003). (E) Pretreatment of MSC with Cytochalasin B (500 nM) inhibited TNT formation and partially blocked mitochondrial transfer (scale bar = 50 μm). By flow cytometry pretreatment of MSC with Cytochalasin B resulted in approximately 50% abrogation in the MitoRed MFI of macrophages (p < .05). (F) Coculture with untreated but not Cytochalasin B pretreated MSC significantly enhanced MDM levels of mitochondrial ATP turnover (p < .05). (G) Pretreatment of MSC with Cytochalasin B abrogated MSC antibacterial effect in the in vivo E. coli pneumonia model (p < .05).
Extracorporeal membrane oxygenation (ECMO) is a technology capable of providing short-term mechanical support to the heart, lungs or both. Over the last decade, the number of centres offering ECMO ...has grown rapidly. At the same time, the indications for its use have also been broadened. In part, this trend has been supported by advances in circuit design and in cannulation techniques. Despite the widespread adoption of extracorporeal life support techniques, the use of ECMO remains associated with significant morbidity and mortality. A complication witnessed during ECMO is the inflammatory response to extracorporeal circulation. This reaction shares similarities with the systemic inflammatory response syndrome (SIRS) and has been well-documented in relation to cardiopulmonary bypass. The exposure of a patient's blood to the non-endothelialised surface of the ECMO circuit results in the widespread activation of the innate immune system; if unchecked this may result in inflammation and organ injury. Here, we review the pathophysiology of the inflammatory response to ECMO, highlighting the complex interactions between arms of the innate immune response, the endothelium and coagulation. An understanding of the processes involved may guide the design of therapies and strategies aimed at ameliorating inflammation during ECMO. Likewise, an appreciation of the potentially deleterious inflammatory effects of ECMO may assist those weighing the risks and benefits of therapy.
Purpose
Using latent class analysis (LCA), we have consistently identified two distinct subphenotypes in four randomized controlled trial cohorts of ARDS. One subphenotype has hyper-inflammatory ...characteristics and is associated with worse clinical outcomes. Further, within three negative clinical trials, we observed differential treatment response by subphenotype to randomly assigned interventions. The main purpose of this study was to identify ARDS subphenotypes in a contemporary NHLBI Network trial of infection-associated ARDS (SAILS) using LCA and to test for differential treatment response to rosuvastatin therapy in the subphenotypes.
Methods
LCA models were constructed using a combination of biomarker and clinical data at baseline in the SAILS study (
n
= 745). LCA modeling was then repeated using an expanded set of clinical class-defining variables. Subphenotypes were tested for differential treatment response to rosuvastatin.
Results
The two-class LCA model best fit the population. Forty percent of the patients were classified as the “hyper-inflammatory” subphenotype. Including additional clinical variables in the LCA models did not identify new classes. Mortality at day 60 and day 90 was higher in the hyper-inflammatory subphenotype. No differences in outcome were observed between hyper-inflammatory patients randomized to rosuvastatin therapy versus placebo.
Conclusions
LCA using a two-subphenotype model best described the SAILS population. The subphenotypes have features consistent with those previously reported in four other cohorts. Addition of new class-defining variables in the LCA model did not yield additional subphenotypes. No treatment effect was observed with rosuvastatin. These findings further validate the presence of two subphenotypes and demonstrate their utility for patient stratification in ARDS.
Early clinical data from studies of the NVX-CoV2373 vaccine (Novavax), a recombinant nanoparticle vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that contains the ...full-length spike glycoprotein of the prototype strain plus Matrix-M adjuvant, showed that the vaccine was safe and associated with a robust immune response in healthy adult participants. Additional data were needed regarding the efficacy, immunogenicity, and safety of this vaccine in a larger population.
In this phase 3, randomized, observer-blinded, placebo-controlled trial conducted at 33 sites in the United Kingdom, we assigned adults between the ages of 18 and 84 years in a 1:1 ratio to receive two intramuscular 5-μg doses of NVX-CoV2373 or placebo administered 21 days apart. The primary efficacy end point was virologically confirmed mild, moderate, or severe SARS-CoV-2 infection with an onset at least 7 days after the second injection in participants who were serologically negative at baseline.
A total of 15,187 participants underwent randomization, and 14,039 were included in the per-protocol efficacy population. Of the participants, 27.9% were 65 years of age or older, and 44.6% had coexisting illnesses. Infections were reported in 10 participants in the vaccine group and in 96 in the placebo group, with a symptom onset of at least 7 days after the second injection, for a vaccine efficacy of 89.7% (95% confidence interval CI, 80.2 to 94.6). No hospitalizations or deaths were reported among the 10 cases in the vaccine group. Five cases of severe infection were reported, all of which were in the placebo group. A post hoc analysis showed an efficacy of 86.3% (95% CI, 71.3 to 93.5) against the B.1.1.7 (or alpha) variant and 96.4% (95% CI, 73.8 to 99.5) against non-B.1.1.7 variants. Reactogenicity was generally mild and transient. The incidence of serious adverse events was low and similar in the two groups.
A two-dose regimen of the NVX-CoV2373 vaccine administered to adult participants conferred 89.7% protection against SARS-CoV-2 infection and showed high efficacy against the B.1.1.7 variant. (Funded by Novavax; EudraCT number, 2020-004123-16.).
Galectin-3 Inhibition in COVID-19 Reddy, Kiran; Nichol, Alistair; McAuley, Daniel F
American journal of respiratory and critical care medicine,
01/2023, Letnik:
207, Številka:
2
Journal Article
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