Acute Respiratory Distress Research Articles

Possible Link between Gut Microbiota, Diet, and COVID-19 Infection

Background: Coronavirus disease 2019 (COVID-19) is a concern for world health since it may impact both the upper (nose, throat, sinuses) and lower (trachea, lungs) respiratory tracts. Death (at a rate of 10%), respiratory failure, multi-organ failure, and acute respiratory distress syndrome (ARDS) are among the problems that might arise. Recent years have seen a global spread of zoonotic coronaviruses, which have caused human epidemics such as MERS and SARS. Various clinical symptoms may be seen in this sickness because to the numerous changes in intestinal homeostasis caused by SARS-CoV-2. Because of the beneficial impact that probiotics have on the host immune system, gastrointestinal disorders may now be effectively treated. This article discusses the close relationship between what we eat, the bacteria in our gut, and the risk of contracting the COV-19 virus. Conclusion: The relationship between gut microbiota, dietary factors, and COVID-19 severity indicates that the microbiome may influence immune regulation. Imbalances in microbial communities and reduced diversity can intensify inflammation, potentially worsening COVID-19 outcomes. Strategies such as probiotics, prebiotics, and dietary changes might provide therapeutic benefits by improving gut health and strengthening immune defenses. However, further research is required to clarify these mechanisms and establish effective interventions.

ASIC1a regulates airway epithelial cell pyroptosis in acute lung injury by NLRP3-Caspase1-GSDMD pathway.

Acidosis is the most common complication that seriously affects the prognosis of acute respiratory distress syndrome (ARDS). Acid-sensitive ion channel 1a (ASIC1a) is activated in acidic environments to regulate inflammatory process. However, the role of ASIC1a in ARDS is unclear. In this study, we examined the expression of ASIC1a in airway epithelial cells in an acidic environment. We then investigated whether blocking ASIC1a could inhibit pyroptosis of airway epithelial cells and the molecular mechanism. In the mouse acute lung injury (ALI) model, we observed the changes of lung histopathology, arterial blood gas and pyroptosis related indexes after ASIC1a inhibition. Bronchoalveolar lavage fluid (BALF) from patients with ARDS were collected to explore the expression level of ASIC1a in ARDS patients. Inhibiting ASIC1a can reduce the airway epithelial cell pyroptosis induced by an extracellular acidic environment. ASIC1a can bind to PRKACA, and silencing ASIC1a and PRKACA can inhibit the occurrence of pyroptosis in airway epithelial cells. Compared with control group, arterial blood pH and PaO2 in ALI group were significantly reduced. The inflammation in the lungs is more intense, and the mRNA and protein of NLRP3, Caspase1 and GSDMD were increased, while ASIC1a specific blocker psalmotoxin-1 alleviated this phenomenon. The expression of ASIC1a in BALF of ARDS patients was significantly increased, especially in non-survival group. Acidic micro-environment can induce the increased expression of ASIC1a, and inhibition of ASIC1a can alleviate the inflammation and airway epithelial cell pyroptosis in ARDS. ASIC1a may be a new target for the treatment of ARDS.

Humanin-G Ameliorates Hemorrhage-Induced Acute Lung Injury in Mice Through AMPKα1-Dependent and -Independent Mechanisms

Background/Objectives: The severity of acute lung injury is significantly impacted by age and sex in patients with hemorrhagic shock. AMP-activated protein kinase (AMPK) is a crucial regulator of energy metabolism but its activity declines with aging. Humanin is a mitochondrial peptide that exerts cytoprotective effects in response to oxidative stressors and is associated with longevity. Using a mouse model of hemorrhagic shock that mimics the clinical condition of adult patients, we investigated whether treatment with a humanin analog, humanin-G, mitigates lung injury and whether its mechanisms of action are dependent on the catalytic AMPKα1 subunit activation. Methods: Male and female AMPKα1 wild-type (WT) and knock-out (KO) mice (8–13 months old) were subjected to hemorrhagic shock by blood withdrawal, followed by resuscitation with shed blood and lactated Ringer’s solution. The mice were treated with PEGylated humanin-G or vehicle and euthanized 3 h post-resuscitation. Results: Sex- and genotype-related differences were observed after hemorrhagic shock as lung neutrophil infiltration was more pronounced in the male AMPKα1 WT mice than the female WT mice; also, the male AMPKα1 KO mice experienced a significant decline in mean arterial blood pressure when compared to the male WT mice after resuscitation. The scores of histological lung injury were similarly elevated in all the male and female AMPKα1 WT and KO mice when compared to the control mice. At molecular analysis, acute lung injury was associated with the downregulation of AMPKα1/α2 catalytic subunits in the WT mice, whereas an increased activation of the signal transducer and activator of transcription-3 (STAT3) was observed in all the vehicle-treated groups. The in vivo administration of humanin-G ameliorated histological lung damage in all the groups of animals and ameliorated mean arterial blood pressure in the male AMPKα1 KO mice. The in vivo administration of humanin-G lowered lung neutrophil infiltration in the male and female AMPKα1 WT mice only but not in the KO mice. The beneficial results of humanin-G correlated with the lung cytosolic and nuclear activation of AMPKα in the male and female AMPKα1 WT groups, whereas STAT3 activation was not modified. Conclusions: In adult age, hemorrhage-induced acute lung injury manifests with sex-dependent characteristics. Humanin-G has therapeutic potential and the AMPKα1subunit is an important requisite for its inhibitory effects on lung leucosequestration, but not for the amelioration of lung alveolar structure or the hemodynamic effects of the peptide.

Pharmacokinetics of Enteral Lormetazepam in Mechanically Ventilated ICU Patients with COVID-19: An Adjunct Sedative Study.

During the coronavirus disease 2019 (COVID-19) pandemic, sedative prescriptions surged, leading to shortages of midazolam. This study investigates lormetazepam as an adjunct sedative alternative to midazolam for mechanically ventilated patients with COVID-19. We aimed to determine the clinical pharmacokinetics (PK) of enterally administered lormetazepam and provide dosing recommendations. Critically ill patients with acute respiratory distress syndrome (ARDS) or COVID-19 requiring mechanical ventilation were enrolled in April 2020. Lormetazepam 2 mg every 12 h was administered enterally. Blood samples were collected to quantify lormetazepam and its glucuronide. PK analysis was conducted using a one-compartment model with the Edsim++ KinPop plugin. The primary PK parameters (means ± coefficient of variation [CV] %) for absorption constant (Ka), volume of distribution (Vd/F), and clearance (CL/F) were 6.4 h-1, 207 L/70 kg, and 14.5 L/h/kg0.75, respectively. Vd/F and CL/F median values were 2.64 L/kg and 2.53 mL/kg/min, respectively, with a half-life of 10.7 h. Lormetazepam's median ratio to its glucuronide was 11.5. Trough-guided dosing suggested alternatives of 0.92 mg three times daily, 1.62 mg twice daily, or 5.36 mg once daily. This is the first study to report a validated PK model for enterally administered lormetazepam as a sedative adjunct in critically ill adults on mechanical ventilation for ARDS and COVID-19. The model was internally validated using a bootstrap procedure. Adequate lormetazepam concentrations were achieved at prescribed doses, with no significant alterations in clearance or half-life. This population model may aid in dose optimization and sedation management for future intensive care unit (ICU) patients.

Placental mesenchymal stem cells suppress inflammation and promote M2-like macrophage polarization through the IL-10/STAT3/NLRP3 axis in acute lung injury

IntroductionAcute lung injury (ALI) is a clinically severe respiratory disorder that currently lacks specific and effective pharmacotherapy. The imbalance of M1/M2 macrophage polarization is pivotal in the initiation and progression of ALI. Shifting macrophage polarization from the proinflammatory M1 phenotype to the anti-inflammatory M2 phenotype could be a potential therapeutic strategy. The intratracheal administration of placental mesenchymal stem cells (pMSCs) has emerged as a novel and effective treatment for ALI. This study aimed to investigate the role and downstream mechanisms of pMSCs in reprogramming macrophage polarization to exert anti-inflammatory effects in ALI.MethodsThe study used lipopolysaccharide (LPS) to induce inflammation in both cell and rat models of ALI. Intratracheal administration of pMSCs was tested as a therapeutic intervention. An expression dataset for MSCs cultured with LPS-treated macrophages was collected from the Gene Expression Omnibus database to predict downstream regulatory mechanisms. Experimental validation was conducted through in vitro and in vivo assays to assess pMSCs effects on macrophage polarization and inflammation.ResultsBoth in vitro and in vivo experiments validated that pMSCs promoted M2 macrophage polarization and reduced the release of inflammatory factors. Further analyses revealed that pMSCs activated the signal transducer and activator of transcription (STAT)3 signaling pathway by secreting interleukin (IL)-10, leading to increased STAT3 phosphorylation and nuclear translocation. This activation inhibited NLRP3 inflammasome activation, promoting M2 macrophage polarization and suppressing the inflammatory response.ConclusionThe study concluded that pMSCs alleviated lung injury in an LPS-induced ALI model by inhibiting M1 macrophage polarization and proinflammatory factor secretion, while promoting M2 macrophage polarization. This effect was mediated via the IL-10/STAT3/NLRP3 axis, presenting a novel therapeutic pathway for ALI treatment.

Fibroblast growth factor 10 alleviates LPS-induced acute lung injury by promoting recruited macrophage M2 polarization.

Acute lung injury (ALI) is characterized by damage to the alveoli and an overabundance of inflammation. Representing a serious inflammatory condition, ALI lacks a precise treatment approach. Despite the recognized benefit impacts of Fibroblast growth factor-10 (FGF10) on ALI, the underlying mechanisms remain unelucidated. To study the role of FGF10 in ALI, C57BL/6J mice were intratracheally injected with 5mg/kg Lipopolysaccharide (LPS) with FGF10 (5mg/kg) or an equal volume of PBS. Inflammatory factors were quantified in bronchoalveolar lavage fluid (BALF) and plasma using ELISA. RNA sequencing of F4/80+Ly6G- macrophages in BALF explored changes in macrophage phenotype and potential mechanisms. Macrophage polarization in BALF was assessed using qRT-PCR, flow cytometry, and Western blot analysis. In vitro, a Transwell co-culture of mouse lung epithelial cells (MLE12) and bone marrow macrophages (BMDM) validated the role of FGF10 in modulating LPS-induced macrophage phenotypic changes. FGF10 ameliorated LPS-induced ALI by diminishing pro-inflammatory factors (IL-1β, TNF-α, and IL-6) and the neutrophil accumulation in BALF. FGF10 also increased the levels of anti-inflammatory factor IL-10. The FGF10 intervention group exhibited enhanced gene expression of macrophage arginine biosynthesis marker (ARG1), and expression of M2-type marker CD206 in monocytes and macrophages. In addition, phosphorylated STAT3 expression increased in isolated monocyte-derived macrophages. Experiments in vitro confirmed that FGF10 could elevate macrophage M2 marker ARG1 expression through the JAK2/STAT3 pathway. FGF10 ameliorates acute LPS-induced lung injury by modulating the polarization of monocyte-derived macrophages recruited in the alveolar space to the M2 type.

Effects of acetaminophen use on mortality of patients with acute respiratory distress syndrome: secondary data mining based on the MIMIC-IV database.

Acetaminophen is a commonly used analgesic after surgery, and its impact on prognosis in patients with acute respiratory distress syndrome (ARDS) has not been studied. This study explores the association between the use of acetaminophen and the risk of mortality in patients with ARDS. In this retrospective cohort study, 3,227 patients with ARDS who had or had not received acetaminophen were obtained from the Medical Information Mart for Intensive Care IV, patients were divided into acetaminophen and non- acetaminophen groups. In-hospital mortality of ARDS patients was considered as primary end point. We used univariate and multivariate Cox regression analyses to assess the relationship of acetaminophen use and in-hospital mortality in patients with ARDS. Subgroup analysis was performed according to age, gender, and severity of ARDS. Of the total patients, 2,438 individuals were identified as acetaminophen users. The median duration of follow-up was 10.54 (5.57, 18.82) days. The results showed that the acetaminophen use was associated with a decreased risk of in-hospital mortality [hazard ratio (HR) = 0.67, 95% confidence interval (CI): 0.57-0.78]. Across various subgroups of patients with ARDS based on age, gender, and severity, acetaminophen use exhibited an association with reduced risk of in-hospital mortality. Acetaminophen use was associated with in-hospital mortality of patients with ARDS. Acetaminophen therapy may represent a promising therapeutic option for ARDS patients and warrants further investigation.

The development of a C5.0 machine learning model in a limited data set to predict early mortality in patients with ARDS undergoing an initial session of prone positioning.

Acute Respiratory Distress Syndrome (ARDS) has a high morbidity and mortality. One therapy that can decrease mortality is ventilation in the prone position (PP). Patients undergoing PP are amongst the sickest, and there is a need for early identification of patients at particularly high risk of death. These patients may benefit from an in-depth review of treatment or consideration of rescue therapies. We report the development of a machine learning model trained to predict early mortality in patients undergoing prone positioning as part of the management of their ARDS. Prospectively collected clinical data were analysed retrospectively from a single tertiary ICU. The records of patients who underwent an initial session of prone positioning whilst receiving invasive mechanical ventilation were identified (n = 131). The decision to perform prone positioning was based on the criteria in the PROSEVA study. A C5.0 classifier algorithm with adaptive boosting was trained on data gathered before, during, and after initial proning. Data was split between training (85% of data) and testing (15% of data). Hyperparameter tuning was achieved through a grid-search using a maximal entropy configuration. Predictions for 7-day mortality after initial proning session were made on the training and testing data. The model demonstrated good performance in predicting 7-day mortality (AUROC: 0.89 training, 0.78 testing). Seven variables were used for prediction. Sensitivity was 0.80 and specificity was 0.67 on the testing data set. Patients predicted to survive had 13.3% mortality, while those predicted to die had 66.67% mortality. Among patients in whom the model predicted patient would survive to day 7 based on their response, mortality at day 7 was 13.3%. Conversely, if the model predicted the patient would not survive to day 7, mortality was 66.67%. This proof-of-concept study shows that with a limited data set, a C5.0 classifier can predict 7-day mortality from a number of variables, including the response to initial proning, and identify a cohort at significantly higher risk of death. This can help identify patients failing conventional therapies who may benefit from a thorough review of their management, including consideration of rescue treatments, such as extracorporeal membrane oxygenation. This study shows the potential of a machine learning model to identify ARDS patients at high risk of early mortality following PP. This information can guide clinicians in tailoring treatment strategies and considering rescue therapies. Further validation in larger cohorts is needed.

Taraxerone inhibits M1 polarization and alleviates sepsis-induced acute lung injury by activating SIRT1.

Acute lung injury (ALI) is the most lethal disease associated with sepsis, and there is a lack of effective drug treatment. As the major cells of sepsis-induced ALI, macrophages polarize toward the proinflammatory M1 phenotype and secrete multiple inflammatory cytokines to accelerate the disease process through nuclear factor kappa-B (NF-κB) and NLR family pyrin domain containing 3 (NLRP3) inflammasome signaling pathways. Taraxerone, the main component of the Chinese medicinal Sedum, possesses numerous biological activities. However, uncertainty remains regarding the potential of taraxerone to protect against sepsis-induced ALI. This study aimed to investigate the effects and mechanisms of taraxerone against ALI. An animal model for ALI was established by cecal ligation and puncture and treated with taraxerone via intraperitoneal administration. The protective effect of taraxerone on the lungs was analyzed using H&E staining, dihydroethidium staining, ELISA kits, cell counting, myeloperoxidase kit, malondialdehyde kit, glutathione kit, superoxide dismutase kit and flow cytometry. Western blotting, RT-PCR, flow cytometry, co-immunoprecipitation, and immunofluorescence were used to investigate the regulatory of taraxerone on SIRT1. Our study demonstrates for the first time that taraxerone can activate SIRT1 in macrophages, promoting SIRT1 activity. This activation inhibited the NF-κB signaling pathway primarily through the dephosphorylation and deacetylation of p65. Simultaneously, taraxerone disrupted the NLRP3 inflammasome signaling pathway, thereby alleviating M1 polarization of macrophages and mitigating sepsis-induced pulmonary inflammation and oxidative stress. In vivo, EX527 was used to validate the anti-inflammatory and anti-oxidative stress effects of taraxerone mediated by SIRT1. SIRT1-mediated anti-inflammatory and anti-oxidative stress effects may be important targets for taraxerone in treating ALI.

The use of a heated helium-oxygen mixture in patients with severe COVID-19 and ARDS against the background of standard therapy and noninvasive ventilation

Introduction. One of the insufficiently studied methods of Acute Respiratory Distress Syndrome (ARDS) therapy is therapy with a heated helium-oxygen mixture. Due to physico-chemical properties, helium demonstrates high efficiency in the treatment of various diseases of the pulmonological profile.Aim. To study the effect of a heated helium-oxygen mixture on the course of a severe form of COVID-19 occurring with the development of ARDS.Materials and methods. The study involved 58 patients with severe and extremely severe coronavirus infection and ARDS, divided into the NVL + t-He/O2 group (n = 30) and the NVL+O2 control group (n = 28). In addition to standard treatment, patients of the NVL + t-He/O2 group received noninvasive ventilation (NVL) and therapy with a heated helium-oxygen mixture, according to clinical recommendations. In the main group, inhalations took place daily for 60 minutes per day for 5 days.Results. Against the background of therapy with a heated helium-oxygen mixture, a more intense increase in the level of lymphocytes was observed: 1.39 (1.09–1.66) × 109/l in the NVL + t-He/O2 group versus 1.02 (0.78–1.40) × 109/l (p = 0.02). Also, as a result of treatment, there was a significant decrease in RR, D-dimer and CRP in the study group: the level of RR (21 (20–22)/minute versus 22.5 (21–24)/minute, p = 0.003), D-dimer (0.44 (0.29–0.60) FEU ng/ml versus 0.79 (0.42–1.34) FEU ng/ml, p = 0.02) and CRP (1.1 (0.7–3.1)mg/l versus 16.6 (8.5–29.5) mg/l, p = 0.03), respectively. Similarly to the NVL + t-He/O2 group, an increase in the level of PaO2 and the oxygenation index was noted. In addition, there were significantly fewer patients with grade III and IV lung damage in the NVL + t-He/O2 group compared with the control (p = 0.05).Conclusion. The use of a heated helium-oxygen mixture in patients with severe COVID-19, occurring with the development of ARDS, against the background of standard therapy and NIV has shown its safety and effectiveness: there was a decrease in the intensity of inflammation, improved oxygenation and a reduction in the need for respiratory support.

Systemic Coagulation Derangement as an Early Sign of Oxygenator Failure in Veno-Venous Extracorporeal Membrane Oxygenation (VV ECMO) Without Anticoagulation

Background and Clinical Significance: Veno-venous extracorporeal membrane oxygenation (VV ECMO) has become a widely accepted supportive treatment for severe acute respiratory distress syndrome (ARDS) in intensive care units (ICUs). Although it has gained popularity, some of its aspects, including optimal anticoagulation management and the best means of monitoring hemostasis, remain unresolved. Thrombosis and bleeding are still important complications of ECMO. Case Presentation: A 44-year-old male patient, with no underlying conditions, was diagnosed with severe acute respiratory distress syndrome (ARDS) due to AH1N1 influenza. He presented severe hypoxemia despite the use of mechanical ventilation, neuromuscular blocking agent infusion and prone position. VV ECMO was used, and coagulation was stopped on ECLS day 6 due to severe pulmonary hemorrhage. The systemic hemostatic disorders found in this patient were difficult to differentiate from disseminated intravascular coagulation (DIC) or sepsis-induced coagulopathy (SIC), improved transiently after circuit exchange, and resolved only after discontinuation of ECMO. The patient was discharged fully conscious and cooperative, with no apparent neurological deficit. Conclusions: Systemic hemostatic abnormalities may precede oxygenator failure and mimic DIC or SIC. Timely oxygenator exchange may therefore be considered. However, it is a high-risk procedure, especially in fully ECLS-dependent patients.

Increased Circulating Extracellular Superoxide Dismutase Attenuates Platelet-Neutrophil Interactions.

Acute respiratory distress syndrome (ARDS) is a serious illness accounting for 10% of ICU admissions and high mortality of 31-45% with a paucity of pharmacologic treatment options. Dysregulated inflammation and oxidative stress are hallmark features of ARDS. We previously showed that transgenic mice expressing a naturally occurring polymorphism of the antioxidant enzyme extracellular superoxide dismutase (EC-SOD), are protected against Staphylococcus aureus (S. aureus) pneumonia, acute lung injury, and pulmonary neutrophilia. In this mouse strain, an R213G amino acid substitution leads to lower tissue binding affinity and elevated alveolar and plasma EC-SOD levels, though the redox-regulated mechanisms responsible for protection against S. aureus are not yet elucidated. Neutrophils are recruited to the areas of injury and inflammation, in part by activated platelets, which contain multiple redox-sensitive targets. Thus, we hypothesize that increased circulating EC-SOD due to the EC-SOD R213G variant protects against S. aureus pneumonia by reducing platelet activation and subsequent neutrophil recruitment to the lung. We demonstrate that, compared to WT mice with S. aureus pneumonia, platelet activation, formation of platelet-neutrophil aggregates (PNAs), and influx of neutrophils and PNAs into the lung are decreased in the infected R213G mice. Furthermore, pre-treatment with a MnTE-2-PyP SOD mimetic protects against S. aureus-induced platelet activation, pulmonary neutrophilia, and acute lung injury. Our data highlight the redox regulation of platelet activation as a driver of S. aureus-induced acute lung injury.

Abstract 4135700: Effects of Mitochondrial Dysfunction on Extracellular Vesicle Release and Subsequent Disruption of the Lung Vascular Endothelial Barrier

Background: Lung endothelial cell (EC) barrier disruption is a hallmark of acute lung injury (ALI), which is commonly caused by bacterial pneumonia. Alveolar epithelial cells (AEC) are the first line of defence against invading respiratory pathogens in the lungs and can mediate inflammatory signaling to the adjacent EC contributing to barrier disruption. We have previously demonstrated that pneumolysin (PLY), a major Streptococcus pneumoniae virulence factor, induces both mitochondrial dysfunction in lung AEC and release of large extracellular vesicles (EVs). These EVs, which are enriched with mitochondrial cargo, contribute to increased permeability of the lung EC barrier. Here, we investigate strategies to inhibit mitochondrial dysfunction in AEC and examine how these interventions impact EC barrier function. Methods: Human alveolar epithelial cells (A549) or immortalized AEC (Cell Biologics) were pre-treated with mitoTEMPO (mtROS scavenger), P110 (excessive fission inhibitor), or ensifentrine [dual phosphodiesterase (PDE) 3/4 inhibitor] prior to PLY treatment (100-300 ng/ml, 4 hrs). Mitochondrial function was assessed by the JC-1 assay. EVs were isolated from cell media and analyzed for their mitochondrial content (Tom20 and Tim23 expression). To assess their functional role, EVs were added to TNF-α treated human lung microvascular EC, and barrier function was then determined using the ECIS assay to measure transendothelial electrical resistance (TER). Results: PLY-induced mitochondrial dysfunction was reduced in the presence of mitoTempo or P110. EVs from PLY-treated AEC (EV PLY ; enriched mitochondrial content) exacerbated TNF-α-induced EC barrier permeability as indicated by the significant decrease in TER. EV PLY derived from MitoTEMPO or P110-pretreated AEC contained less mitochondrial cargo and resulted in less EC permeability after TNF-α. Compared to mitoTEMPO and P110, ensifentrine exhibited superior protection against mitochondrial dysfunction after PLY exposure. In addition, in the presence of ensifentrine, the quantity of EV release and their extracelllular mitochondrial content were both dramatically reduced. In contrast to control EV PLY , EV PLY from ensifentrine-pretreated AEC demonstrated no barrier disruptive properties. Conclusions: Mitochondrial dysfunction in AEC contributes to vascular endothelial injury in ALI through mechanisms involving the release of barrier-disruptive EVs, which can be effectively targeted by inhibiting PDE3/4.

Tracking inflammation resolution signatures in lungs after SARS-CoV-2 omicron BA.1 infection of K18-hACE2 mice.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes Coronavirus Disease 2019 (COVID-19), which can result in severe disease, often characterised by a 'cytokine storm' and the associated acute respiratory distress syndrome. However, many infections with SARS-CoV-2 are mild or asymptomatic throughout the course of infection. Although blood biomarkers of severe disease are well studied, less well understood are the inflammatory signatures in lung tissues associated with mild disease or silent infections, wherein infection and inflammation are rapidly resolved leading to sequelae-free recovery. Herein we described RNA-Seq and histological analyses of lungs over time in an omicron BA.1/K18-hACE2 mouse infection model, which displays these latter features. Although robust infection was evident at 2 days post infection (dpi), viral RNA was largely cleared by 10 dpi. Acute inflammatory signatures showed a slightly different pattern of cytokine signatures compared with severe infection models, and where much diminished 30 dpi and absent by 66 dpi. Cellular deconvolution identified significantly increased abundance scores for a number of anti-inflammatory pro-resolution cell types at 5/10 dpi. These included type II innate lymphoid cells, T regulatory cells, and interstitial macrophages. Genes whose expression trended downwards over 2-66 dpi included biomarkers of severe disease and were associated with 'cytokine storm' pathways. Genes whose expression trended upward during this period were associated with recovery of ciliated cells, AT2 to AT1 transition, reticular fibroblasts and innate lymphoid cells, indicating a return to homeostasis. Very few differentially expressed host genes were identified at 66 dpi, suggesting near complete recovery. The parallels between mild or subclinical infections in humans and those observed in this BA.1/K18-hACE2 mouse model are discussed with reference to the concept of "protective inflammation".

Evolution of the oxyhemoglobin dissociation curve in COVID-19 related ARDS patients

IntroductionSevere hypoxemia is the leading cause of admission in intensive care (ICU) in patients with COVID-19 related acute respiratory distress syndrome (ARDS). In these patients, several studies reported a left shift of the oxyhemoglobin dissociation curve associated with a lower mortality. However, these results are conflicting, as these studies include few patients and often no control groups. Moreover, the calculation of P50, representing the PaO2 value at which 50% of hemoglobin is saturated, is not corrected for factors known to influence it (pH, PaCO2 or temperature). For all of these reasons, we compared the corrected P50 between ICU patients with severe COVID-19 related ARDS on mechanical ventilation or not, and ARDS from other causes. We investigated the evolution of the corrected P50 during the first 3 days of ICU and its relationship with ICU mortality.Methods and PatientsWe retrospectively calculated the corrected P50 in three groups of patients: intubated and mechanically ventilated COVID-19 related ARDS, non-intubated COVID-19 related ARDS and intubated patients with ARDS due to other infectious causes. The corrected P50 was calculated, on the worst blood gas analysis on days 1 and 3 of ICU admission, by the formula of Hill but modified by Dash et al., controlled for pH, PaCO2 and temperature. We collected ICU mortality.Results463 blood gas analysis at days 1 and 3 from 214 ICU COVID-19 related ARDS patients (114 with intubation and 100 without) and 35 ICU patients with ARDS from other causes were analyzed. All patients were severely hypoxemic: PaO2/FiO2 of 76 [58-108] mmHg for intubated COVID-19, 79 [60-108] mmHg for non-intubated COVID-19 and 142 [78-197] mmHg for the third group (p < 0.001). The mortality rate was higher in intubated COVID-19 related ARDS patients (44.7 versus 14 versus 37% in ARDS from other causes; p < 0.001). The corrected P50 was significantly lower in COVID-19 patients, especially in non- intubated patients (21.2 [18.8–25.2] mmHg vs. 25.5 [19.2–30.3] mmHg in intubated patients; compared to ARDS from other causes: 27.2 [23.3-35.4] mmHg; p < 0.001. The corrected P50 does not change over the first 3 days, except for the non intubated COVID-19 related ARDS and is not correlated with ICU mortality (odds ratio = 0.98 [0.95-1.03]; p = 0.51), in contrast of PaO2/FiO2 and ICU gravity scores.ConclusionThe oxyhemoglobin dissociation curve at ICU admission was left shifting in severe COVID-19 related ARDS patients regardless of the type of ventilation. This deviation increases the third day only in non-intubated COVID-19 related ARDS and was not related to the outcome.

Association Between Packed Red Blood Cell Transfusion and Acute Lung Injury in Very Low Birth Weight Infants: A Self- Matched Longitudinal Study

Objective: One serious morbidity of packed red blood cell (pRBC) transfusion in very low birth weight infants (VLBW) is acute lung injury (ALI). This study aimed to determine the association between pRBC transfusion and changes in the level of respiratory support within 6 hours after transfusion (post-transfusion respiratory decompensation, PTRD) in VLBW infants. Additionally, this study assessed the possible association of bronchopulmonary dysplasia (BPD) with transfusions within the first 7 days of life and identified risk factors for PTRD.Material and Methods: This historical, time-based, self-matched cohort study was conducted on VLBW infants that received their first pRBC transfusion. ALI during the exposure period (0-6 hours after transfusion, PTRD) was compared with ALI occurrences in the pre- and post-exposure periods. Associations were evaluated using mixed effects logistic regression. Results: Five hundred and ten VLBW infants receiving pRBC transfusion were enrolled in the study. Twenty-six percent (132/510) of infants developed PTRD, compared with 17% and 9% developing ALI in pre- and post-exposure periods, respectively. Mixed-effects logistic regression indicated an increased risk during the exposure period compared with non-exposure periods [odds ratio (OR) (95% confidence interval (CI): 1.59 (1.22, 2.36) p-value=0.002, and 3.90 (2.62, 5.82) p-value<0.001, respectively]. Early, first pRBC transfusion within the first 7 days of life was not associated with BPD [adjusted odds ratio (aOR) 0.90 (0.26, 1.32) p-value=0.600]. Conclusion: First, pRBC transfusions were associated with PTRD in VLBW infants. BPD was not associated with transfusion within 7 days of life. Further studies should prospectively focus on the causal relationships leading to PTRD.

Autophagy in Acute Lung Injury.

Acute lung injury (ALI) is a critical condition marked by rapid-onset respiratory failure due to extensive inflammation and increased pulmonary vascular permeability, often progressing to acute respiratory distress syndrome (ARDS) with high mortality. Autophagy, a cellular degradation process essential for removing damaged organelles and proteins, plays a crucial role in regulating lung injury and repair. This review examines the protective role of autophagy in maintaining cellular function and reducing inflammation and oxidative stress in ALI. It underscores the necessity of precise regulation to fully harness the therapeutic potential of autophagy in this context. We summarize the mechanisms by which autophagy influences lung injury and repair, discuss the interplay between autophagy and apoptosis, and examine potential therapeutic strategies, including autophagy inducers, targeted autophagy signaling pathways, antioxidants, anti-inflammatory drugs, gene editing, and stem cell therapy. Understanding the role of autophagy in ALI could lead to novel interventions for improving patient outcomes and reducing mortality rates associated with this severe condition.

Personalized positive end-expiratory pressure in spontaneously breathing patients with acute respiratory distress syndrome by simultaneous electrical impedance tomography and transpulmonary pressure monitoring: a randomized crossover trial.

Personalized positive end-expiratory pressure (PEEP) might foster lung and diaphragm protection in patients with acute respiratory distress syndrome (ARDS) who are undergoing pressure support ventilation (PSV). We aimed to compare the physiologic effects of personalized PEEP set according to synchronized electrical impedance tomography (EIT) and driving transpulmonary pressure (∆PL) monitoring against a classical lower PEEP/FiO2 table in intubated ARDS patients undergoing PSV. A cross-over randomized multicenter study was conducted in 30 ARDS patients with simultaneous recording of the airway, esophageal and transpulmonary pressure, together with EIT during PSV. Following a decremental PEEP trial (18 cmH2O to 4 cmH2O), PEEPEIT-∆PL was identified as the level with the smallest difference between lung overdistension and collapse. A low PEEP/FiO2 table was used to select PEEPTABLE. Each PEEP strategy was applied for 20min, and physiologic data were collected at the end of each step. The PEEP trial was well tolerated. Median PEEPEIT-∆PL was higher than PEEPTABLE (10 [8-12] vs. 8 [5-10] cmH2O; P = 0.021) and, at the individual patient level, PEEPEIT-∆PL level differed from PEEPTABLE in all patients. Overall, PEEPEIT-∆PL was associated with lower dynamic ∆PL (P < 0.001) and pressure-time product (P < 0.001), but there was variability among patients. PEEPEIT-∆PL also decreased respiratory drive and effort (P < 0.001), improved regional lung mechanics (P < 0.05) and reversed lung collapse (P = 0.007) without increasing overdistension (P = 0.695). Personalized PEEP selected using synchronized EIT and transpulmonary pressure monitoring could be associated with reduced dynamic lung stress and metabolic work of breathing in ARDS patients undergoing PSV.

Management of sedation during weaning from mechanical ventilation.

Critically ill patients frequently require mechanical ventilation and often receive sedation to control pain, reduce anxiety, and facilitate patient-ventilator interactions. Weaning from mechanical ventilation is intertwined with sedation management. In this review, we analyze the current evidence for sedation management during ventilatory weaning, including level of sedation, timing of sedation weaning, analgesic and sedative choices, and sedation management in acute respiratory distress syndrome (ARDS). Despite a large body of evidence from the past 20 years regarding the importance of light sedation and paired spontaneous awakening and spontaneous breathing trials (SATs/SBTs) to promote ventilator weaning, recent studies show that implementation of these strategies lag in practice. The recent WEAN SAFE trial highlights the delay between meeting weaning criteria and first weaning attempt, with level of sedation predicting both delays and weaning failure. Recent studies show that targeted interventions around evidence-based practices for sedation weaning improve outcomes, though long-term sustainability remains a challenge. Light or no sedation strategies that prioritize analgesia prior to sedatives along with paired SATs/SBTs promote ventilator liberation. Dexmedetomidine may have a role in weaning for agitated patients. Further investigation is needed into optimal sedation management for patients with ARDS.

Effects of Vitamin C Supplements on Clinical Outcomes and Hospitalization Duration for Patients with Coronavirus Disease 2019 (COVID-19): A Systematic Review and Meta-Analysis.

Vitamin C has been used as an essential antioxidant to reduce the inflammatory response associated with pneumonia and acute respiratory distress syndrome in patients with the 2019 coronavirus disease (COVID-19), but its effect on clinical outcomes remains controversial and inconclusive. The purpose of this study was to conduct a meta-analysis and systematic review to assess the effects of vitamin C supplementation on the severity of COVID-19 in hospitalized patients. Web of Science, Embase, Cochrane Library, PubMed, CNKI, CSTJ, Wan fang, and CBM databases were searched for publications between January 2020 and December 2023 that met the inclusion criteria. The meta-analyses of outcomes in more than one study were performed using Review Manager software. Heterogeneity was evaluated using the I2 statistic. A randomized controlled trial, cohort studies, and retrospective studies in which vitamin C supplementation was supplemented as monotherapy or in combination, compared with placebo, no treatment, or other standard treatment without vitamin C were included. After screening, 22 studies, with a total of 6831 patients, were selected for assessment. Odds ratios (ORs) with 95% CIs were calculated using fixed- and random-effects models. The meta-analysis showed significant effects of vitamin C on alleviating clinical outcomes in patients with COVID-19 (OR = 0.76, 95% CI = 0.65-0.89, P = .0007) but no shortening of the length of hospitalization (OR = 1.16, 95% CI = -0.13-2.44, P = .08) compared with the control group. Notably, vitamin C supplements significantly reduced the mortality risk (OR = 0.64, 95% CI = 0.51-0.80, P = .0001) and the incidence of severity (OR = 0.59, 95% CI = 0.43-0.80, P = .0006) in COVID-19 patients. The findings suggest that vitamin C supplements may have a beneficial effect on clinical outcomes, as well as reducing severity and mortality in COVID-19 patients, but more clinical randomized controlled trials are needed to evaluate the role of vitamin C in treating COVID-19. PROSPERO registration no. CRD42023491517.