Acute Respiratory Distress Research Articles

Predictive Value of the PaO2/FIO2 Ratio for Mortality in Patients with Acute Respiratory Distress Syndrome: A Systematic Review and Meta-analysis.

Background Despite the controversy regarding its clinical utility, the PaO2/FIO2 ratio has been used to define the severity of acute respiratory distress syndrome (ARDS). This systematic review and meta-analysis (SRMA) details summary estimates of the predictive performance of PaO2/FIO2 ratio in predicting mortality in patients with ARDS. Methods To clarify the integrated diagnostic accuracy, we included studies in which the study population comprised patients with ARDS in any clinical setting, included adult patients (≥18 years old), and evaluated mortality. The MEDLINE and Cochrane Central Registry of Controlled Trials databases were searched for articles in English. We performed SRMA on the accuracy of the diagnostic prognostic tests using the Quality Assessment of Diagnostic Accuracy Studies-2 tool to evaluate the risk of bias. We obtained summary point estimates of sensitivity and specificity and calculated the area under the receiver operating characteristic (AUROC) curve of the summary receiver operating characteristic curve with 95% confidence intervals (CIs). Results Twenty-eight trials with 38270 patients were included in the quality assessment. Most of the studies were conducted in intensive-care units. Overall, the risk of bias is high. For PaO2/FIO2 of 100 and 200 the pooled sensitivity, specificity, and AUROC were 44.8% (95% CI, 38.1%-51.7%), 70.6% (95% CI, 65.9%-74.9%), 0.60 (0.58-0.64) and 83.9% (95% CI, 78.9%-87.8%), 26.1% (95% CI, 20.8%-32.1%), 0.64 (0.60-0.69), respectively. Conclusion The PaO2/FIO2 ratio alone did not have impressive prediction accuracy for mortality in patients with ARDS and might not be able to be used solely as a clinical prognostic tool.

Survival difference in patients treated with extracorporeal membrane oxygenation in COVID-19 vs. non-COVID ARDS: a systematic review and meta-analysis.

The COVID-19 pandemic has emphasized the need for effective management of severe acute respiratory distress syndrome (ARDS) using veno-venous extracorporeal membrane oxygenation (VV-ECMO). This meta-analysis aims to compare the effectiveness and outcomes of ECMO in patients with COVID-19 ARDS versus those with non-COVID ARDS, assessing its role in different respiratory virus infections. A systematic search was conducted in PubMed, Web of Science, and other relevant databases up to June 30, 2023, to identify studies comparing ECMO use in COVID-19 and non-COVID ARDS cases. This analysis adheres to PRISMA guidelines, with studies rigorously selected based on predefined inclusion and exclusion criteria and assessed for bias using validated tools. The meta-analysis included 24 studies with 2,121 patients, revealing that non-COVID ARDS patients treated with ECMO had a lower mortality risk compared to those with COVID-19 ARDS. Specifically, the overall pooled risk difference in survival was -0.11 (95% CI: -0.17 to -0.05, P<0.001), indicating a statistically significant advantage for non-COVID patients. The standardized mean difference for ECMO duration was significantly longer in COVID-19 patients (SMD=0.70, 95% CI: 0.32 to 1.08, P<0.001), reflecting more prolonged treatment needs. ECMO serves as a vital intervention in severe ARDS, with differential effectiveness observed between COVID-19 and non-COVID patients. The study's findings underline the need for precise patient selection and tailored ECMO application across different viral etiologies. These insights are crucial for enhancing clinical strategies and resource allocation during ongoing and future pandemics.

Immediate postinjury extracorporeal carbon dioxide removal reduces ventilator requirements and mitigates acute respiratory distress syndrome in swine.

Awareness of ventilator-induced lung injury contributed to increased use of extracorporeal interventions, but not immediately after injury, before acute respiratory distress syndrome (ARDS) ensues. Our objective was to evaluate the role of venovenous extracorporeal carbon dioxide removal (ECCO2R) in management of mechanically ventilated swine with smoke inhalation injury and 40% body surface area burns. Yorkshire swine (n = 29, 43.2 ± 0.5 kg) underwent anesthesia, instrumentation, severe smoke inhalation, and 40% body surface area burns, followed by 72 hours of round-the-clock intensive care unit care with mechanical ventilation, fluids, pressors, bronchoscopic cast removal, computer tomography scans, and arterial blood assays. Within 1 hour after injury, animals received ECCO2R with either MiniLung (Xenios AG, Heilbronn, Germany; n = 10) or Hemolung (ALung Technologies, Pittsburgh, PA; n = 10), or no ECCO2R in injured controls (INJC, n = 12). Immediate postinjury ECCO2R reduced minute ventilation (p < 0.001) and prevented ARDS in 37.5% of MiniLung and 11.1% of Hemolung animals. Time to ARDS (partial pressure of arterial oxygen to fraction of inspired oxygen ratio below 300) was shortest (14 ± 2.2 hours) in INJC, intermediate (21.6 ± 3.5 hours) in Hemolung (HEMO), and most delayed in MiniLung (31.1 ± 7.2 hours, p = 0.0121, log-rank test vs. INJC). Driving pressure was lower in MiniLung versus INJC (p < 0.0001) and HEMO versus INJC (p = 0.0005) at 48 hours. Extracorporeal CO2 removal reduced systemic levels of tumor necrosis factor α versus INJC. In swine with severe smoke inhalation and burns, immediate postinjury ECCO2R reduced ventilator settings, delayed or prevented ARDS, and reduced its severity. Proactive early percutaneous ECCO2R initiation via simplified, purpose-built devices should be considered as a low-maintenance lung injury management approach with significant disease modifying clinical benefit potential.

Dexamethasone alleviates acute lung injury in a rat model with venovenous extracorporeal membrane oxygenation support

BackgroundIn recent years, dexamethasone (Dex) has been used to treat acute respiratory distress syndrome (ARDS) in patients with COVID-19 and achieved promising outcomes. Venovenous extracorporeal membrane oxygenation (VV ECMO) support...

Severe community-acquired pneumonia compared to severe community-acquired Acinetobacter baumannii pneumonia in Reunion Island: A retrospective study.

Acinetobacter baumannii (Ab) has emerged in the last decades as a cause of community-acquired pneumonia (CAP) in tropical and subtropical regions. We previously conducted the first investigation on this topic in France with a case series of severe CAP-Ab in Reunion Island over an eight-year period. In the present work, we aim to highlight the specific aspects of CAP-Ab by comparing our case series with an historical cohort (PAC_RUN), obtained by retrospective chart review (2016-2021) of severe community-acquired pneumonia cases on Reunion Island, in which CAP-Ab was ruled out. During the study period, eight CAP-Ab cases were identified, giving an incidence of 0.1 cases per 100,000 people/year, and an incidence of 16.5 cases per 100,000 people/year for non-Ab-related CAP (n = 761). By comparing with non-Ab-related CAP, patients had more excessive alcohol use (75% vs. 25.6%, p = 0.005) and lower body mass index (21 vs. 24 kg/m2, p = 0.004). Six cases (75%) of CAP-Ab occurred during the rainy season (p = 0.06). Mortality was higher (62.5% vs. 24.3%, p = 0.02) and time to death was shorter (median 2 days vs. 7, p = 0.009) in the CAP-Ab group. Bacteraemic pneumonia was strongly associated with CAP-Ab (62.5% vs. 15.7%, p = 0.004). Significant differences were found in the need for renal replacement therapy (75% vs. 17.2%, p < 0.001), catecholamine use (100% vs. 54.5%, p = 0.01) and use of invasive mechanical ventilation (100% vs. 62.7%, p = 0.03). Also, in the proportion of severe acute respiratory distress syndrome (62.5% vs. 23.2%, p = 0.02), septic shock (100% vs. 40.6%, p < 0.001), and cardiogenic shock (87.5% vs. 15.9%, p < 0.001). Compared to severe non-Ab-related CAP, severe CAP-Ab is characterised by higher mortality, associated with a high frequency of multiple organ failure. Excessive alcohol consumption and malnutrition seem to be risk factors. To improve outcomes, broader spectrum antibiotic therapy must be immediately proposed when CAP-Ab is suspected.

Human adenovirus type 7 (HAdV-7) infection induces pulmonary vascular endothelial injury through the activation of endothelial autophagy

BackgroundHAdV-7 is a prevalent pathogen that can cause severe pneumonia in children. Previous studies have shown a significant increase in serum levels of vascular permeability factor (VPF/VEGF) and viral load in pediatric patients with fatal HAdV-7 infection, suggesting potential damage to the pulmonary vascular endothelium. Further research is necessary to elucidate the underlying mechanism.MethodsThe human lung microvascular endothelial cell line-5a and human CD46 mice were used for in vitro and in vivo experiments, respectively. RNA-seq was employed for correlative omics analysis. Viral infection and copy status were examined using transmission electron microscopy to observe virus particles, immunofluorescence to detect the viral protein Hexon, and qPCR to assess HAdV-7 fiber gene copies. Various methods, including ELISAs for VEGF and other injury markers, the CCK8 assay for cell viability, and flow cytometry for endothelium numbers, were employed to evaluate endothelial damage. Acute lung injury severity was evaluated by scoring pathological inflammation and measuring pulmonary vascular permeability. Autophagy activation was assessed by observing autophagosomes and validating marker proteins.ResultsGSEA analysis showed significant enrichment of gene sets related to endothelial functions (barrier, defense, and regeneration) and ALI in the HAdV-7-infected group. GO analysis indicated an enrichment of autophagy-related pathways linked to cell death. Subsequently, successful signs of HAdV-7 infection and replication were observed in the endothelium, including cytopathic effects, intracellular virions, and increased HAdV-7 fiber gene copies. Endothelial injury, including mitochondrial damage, decreased endothelium, and elevated levels of endothelial injury markers such as VEGF, sICAM-1, sVCAM-1, E-selectin, ESM1, MCP1, and IL1β were observed after HAdV-7 infection. Additionally, evidence of leaky lung blood vessels and ALI was observed, including progressive weight loss, elevated pulmonary vascular permeability, and severe lung consolidation. Furthermore, HAdV-7 infection induced autophagosome formation in the endothelium and triggered complete cell autophagy. Importantly, inhibiting autophagic flux reduced VEGF levels and other endothelial injury markers, decreased viral load, improved cell survival rate, alleviated pulmonary vessel leakage, and mitigated lung inflammation.ConclusionsHAdV-7 successfully infects pulmonary vascular endothelium and replicates effectively, causing injury to the endothelium, high VEGF expression and viral load in the serum, as well as ALI/ARDS. Autophagy inhibitors can alleviate endothelial injury, inhibit viral replication, relieve leakage from the vasculature, and reduce lung inflammation.

Analysis of outcomes of penetrating colonic injuries managed with or without fecal diversion

Traumatic colorectal injuries can be managed by either fecal diversion or primary repair / resection and anastomosis. We aimed to study differences in outcomes in adult patients managed with or without fecal diversion at time of initial operation. The National Trauma Databank (NTDB) was used to identify adult patients (ages 18–64 years) with penetrating colonic injuries for the years 2013–2015. We included patients with Injury Severity Score (ISS) of 9–24 excluding patients with concomitant extra-abdominal Abbreviated Injury Scale (AIS) score of 3 or more. Subjects arriving without signs of life, expiring in ER or with missing data were excluded. Data was collected for age, gender, vital signs on presentation, discharge disposition and length of stay (LOS). Patients were divided into two groups based on whether or not fecal diversion was performed within 1 day of presentation. Primary outcome assessed was in-hospital mortality and unplanned return to OR. Secondary outcomes were acute kidney injury (AKI), acute respiratory distress syndrome (ARDS), deep vein thrombosis (DVT), pulmonary embolism (PE), pneumonia, organ surgical site infection (SSI), deep SSI, severe sepsis and unplanned intubation. Statistical analysis was conducted using SPSS for windows. P-value < 0.05 was considered statistically significant. Of 2,598,467 patients, 5344 (0.21%) sustained a penetrating colonic injury. 2339 (43.8%) patients met criteria for age, ISS, AIS, signs of life and ED outcome. 173 patients underwent fecal diversion within 24 h of presentation (Group 1) while 708 did not (Group 2). Patients with missing data were excluded leaving 162 patients in Group 1 and 657 patients in Group 2. Groups 1 and 2 were noted to be similar in terms of ISS (median of 10 in both), age (median of 31 vs 29 years), percentage of male patients (85.2% vs 87.8%; p = 0.44), mean systolic blood pressure (127 mmHg vs 126 mmHg; p = 0.54), mean pulse rate (95.4 vs 94.5; p = 0.60) and mean respiratory rate (20.4 vs 20.1; p = 0.56) respectively. Median LOS was 10 days in both groups. No statistically significant differences were found between groups 1 and 2 in the primary outcomes of in-hospital mortality (2.4% vs 3.5%; OR: 1.43; 95% confidence interval (CI): 0.49–4.20) or unplanned return to OR (4.3% vs 7.8%; OR: 1.86; 95% CI: 0.83–4.19). No statistically significant differences were noted between groups 1 and 2 in the secondary outcomes of AKI (3.7% vs 3.8%; OR: 1.03; 95% CI 0.41–2.55), ARDS (1.2% VS 1.7%; OR: 1.36; 95% CI 0.30–6.21), DVT (1.9% vs 4.0%; OR: 2.18; 95% CI 0.65–7.31), PE (1.9% vs 2.0%; OR: 1.07; 95% CI 0.30–3.80), pneumonia (4.9% vs 5.3%; OR: 1.08; 95% CI 0.49–2.38), organ SSI (3.7% vs 7.0%; OR: 1.96; 95% CI: 0.82–4.67), deep SSI (3.7% vs 4.4%; OR: 1.20, 95% CI 0.49–2.94), severe sepsis (3.7% vs 3.3%; OR: 0.90; 95% CI: 0.36–2.26) or unplanned intubation (1.9% vs 1.7%; OR: 0.90; 95% CI 0.25–3.27). Adult patients with penetrating colonic injuries with ISS 9–24 in the absence of serious extra-abdominal injury who undergo surgery within 24 h of presentation do not seem to derive a statistically significant benefit from fecal diversion in terms of post-operative complications and mortality. In more severely injured patients fecal diversion may continue to provide a benefit.

Human liver stem cells and derived extracellular vesicles protect from sepsis-induced acute lung injury and restore bone marrow myelopoiesis in a murine model of sepsis

BackgroundSepsis is a condition with high mortality and morbidity, characterized by deregulation of the immune response against the pathogen. Current treatment strategies rely mainly on antibiotics and supportive care. However, there is growing interest in exploring cell-based therapies as complementary approaches. Human liver stem cells (HLSCs) are pluripotent cells of mesenchymal origin, showing some advantages compared to mesenchymal stem cells in terms of immunomodulatory properties. HSLC-derived extracellular vesicles (EVs) exhibited a superior efficacy profile compared to cells due to their potential to get through biological barriers and possibly to avoid tumorigenicity and showed to be effective in vivo and ex vivo models of liver and kidney disease. The potential of HLSCs and their EVs in recovering damage to distal organs due to sepsis other than the kidney remains unknown. This study aimed to investigate the therapeutic potential of the intravenous administration of HSLCs or HSLCs-derived EVs in a murine model of sepsis.ResultsSepsis was induced by caecal ligation and puncture (CLP) on C57/BL6 mice. After CLP, mice were assigned to receive either normal saline, HLSCs or their EVs and compared to a sham group which underwent only laparotomy. Survival, persistence of bacteraemia, lung function evaluation, histology and bone marrow analysis were performed. Administration of HLSCs or HLSC-EVs resulted in improved bacterial clearance and lung function in terms of lung elastance and oedema. Naïve murine hematopoietic progenitors in bone marrow were enhanced after treatment as well. Administration of HLSCs and HLSC-EVs after CLP to significantly improved survival.ConclusionsTreatment with HLSCs or HLSC-derived EVs was effective in improving acute lung injury, dysmyelopoiesis and ultimately survival in this experimental murine model of lethal sepsis.

Esophageal Manometry in Pediatric Acute Respiratory Distress Syndrome: Necessity or Simply a Neighbor of the Pulmonary Artery Catheter?

Esophageal Manometry in Pediatric Acute Respiratory Distress Syndrome: Necessity or Simply a Neighbor of the Pulmonary Artery Catheter?

NOD3 Reduces Sepsis-Induced Acute Lung Injury by Regulating the Activation of NLRP3 Inflammasome and the Polarization of Alveolar Macrophages.

The pathogenesis of sepsis-induced Acute lung injury (ALI) progresses rapidly, and no effective treatment drugs are known, resulting in a high mortality rate. NLR family pyrin domain containing 3 (NLRP3) inflammasome activation plays an important role in the pathological progression of ALI, and often coincide with the inflammatory activation and polarization of macrophages. NLR family CARD domain-containing protein 3 (NOD3) was reported protecting against sepsis-induced pulmonary pathological injury and inhibiting the inflammatory response in lung tissue. NOD3 can also inhibit NLRP3 inflammasome activation by competitively inhibiting the binding of pro-caspase-1 to apoptosis-related ASC or reducing NLRP3/cryopyrin-induced ASC speckle formation. In this study, we aimed to explore whether NOD3 decrease sepsis-induced lung injury by interfering with NLRP3 inflammasome activation and regulating alveolar macrophages (AMs) polarization. To investigate whether NOD3 reduce sepsis-induced ALI by inhibiting the activation of NLRP3 inflammasome to regulate the polarization of AMs. Sepsis-induced WT (C57BL/6) and NLRC3-/--C57BL/6 mice ALI models were established by intraperitoneal injection of lipopolysaccharide (LPS). In vitro experiments, AMs and bone marrow-derived macrophages (BMDMs) were isolated from WT and NLRC3-/- mice. Using in vivo and in vitro experiments, we found that NOD3 knockout promoted the sepsis-induced inflammatory response in lung tissue. In addition, NOD3 knockout promoted the activation of the TRAF6-NF-κB signaling pathway and the NLRP3 inflammasome in AMs, enhanced the M1-type polarization of AMs and decreased the M2-type polarization of AMs in sepsis-induced lung injury model mice. NOD3 interfered with NLRP3 inflammasome activation by inhibiting NLRP3 inflammasome assembly or negatively regulating the TRAF6-NF-κB signaling pathway, and regulating the polarization of AMs, thereby alleviating sepsis-induced lung injury.

Pharmacological Activities of Warm Alkaline Hydrogen Peroxide Solution and Therapeutic Potential in Medicine: Physical-Chemical Reprofiling as a Promising Lead for Drug Discovery

Abstract: The traditional use of antiseptics, chemotherapeutic, expectorant, mucolytic drugs, and oxygen gas by artificial ventilation does not effectively eliminate hypoxemia in sputum, mucus, pus, and blood asphyxia in COVID-19. The emergency conversion of sputum, mucus, pus, and blood into oxygenated foam inside the airways utilizing the enzyme catalase and warm alkaline hydrogen solutions (WAHPSs) is proposed as a promising area for new therapeutic development.. The possibility of physical-chemical repurposing of hydrogen peroxide from an antiseptic in pyolytics, mucolytics, hemolytics, and oxygen-producing antihypoxants by con-verting a cold, acidic non-carbonated drug into an oxygen-saturated WAHPS and its intrap-ulmonary injection is pointed out as a way to solve this problem. The possibility of medically enriching blood oxygen in hypoxemia by catalase cleavage of hydrogen peroxide when WAHPSs are administered orally as energy drinks or directly into the blood as injections is pointed out. The fact is that virtually all human tissues are rich in catalase, which immediately breaks down hydrogen peroxide into water and oxygen gas. Inhalation and/or intrapulmonary injections of WAHPSs have been shown to provide intra-airway interaction with catalase in sputum, mucus, pus and/or blood and releases oxygen gas, which foams the biological masses, is absorbed into the blood and eliminates hypoxemia. Thus, the physical-chemical repurposing of known drugs can be considered a promising direction for the discovery of new drugs. Value of the data: 1) Why are these data useful? These studies indicate that the enzyme catalase, which is present in many tissues of animals and humans in both normal and disease, can be employed to enrich the tissues with oxygen and eradicate hypoxia when hydrogen peroxide solution is injected into them.. 2) Who can benefit from these data? Mountaineers, divers, submarine sailors, miners, astronauts, traumatologists, resuscitators, car-diologists, transplantologists, pulmonologists, obstetricians and gynecologists, emergency phy-sicians, EMERCOM personnel, and medical workers, providing emergency medical care in cases of smoke in rooms, lack of oxygen in the inhaled air, drowning, bronchial asthma attack, acute respiratory distress syndrome, and asphyxia can use the data presented in this article. 3) How can these data be used/reused for further insights or development of experi-ments? These data can be used to develop new antihypoxants, to improve methods of increasing the organism's endurance to hypoxia, methods of organ and tissue preservation, methods of ische-mia treatment, methods of emergency medical care in urgent conditions, methods of ARDS treatment and standards of medical care.

Determination of positive end-expiratory pressure in COVID-19-related acute respiratory distress syndrome

BACKGROUND The impact of high positive end-expiratory pressure (PEEP) ventilation and the optimization of PEEP titration in COVID-19-induced acute respiratory distress syndrome (ARDS) continues to be a subject of debate. In this systematic review, we investigated the effects of varying PEEP settings on patients with severe ARDS primarily resulting from COVID-19 (C-ARDS). OBJECTIVES Does higher or lower PEEP improve the outcomes in COVID-19 ARDS? Does individually titrated PEEP lead to better outcomes compared with PEEP set by standardised (low and high ARDS network PEEP tables) approaches? Does the individually set PEEP (best PEEP) differ from PEEP set according to the standardised approaches (low and high ARDS network PEEP tables)? DESIGN Systematic review of observational studies without metaanalysis. DATA SOURCES We performed an extensive systematic literature search in Cochrane COVID-19 Study Register (CCSR), PubMed, Embase.com, Web of Science Core Collection, World Health Organization COVID-19 Global literature on coronavirus disease, World Health Organization International Clinical Trials Registry Platform (ICTRP), medRxiv, Cochrane Central Register of Controlled Trials until 24/01/2024. ELIGIBILITY CRITERIA Ventilated adult patients (≧18 years) with C-ARDS. RESULTS We screened 16 026 records, evaluated 119 full texts, and included 12 studies (n = 1431 patients) in our final data synthesis, none of them being a randomised controlled trial. The heterogeneity of study procedures and populations did not allow conduction of a meta-analysis. The results of those studies that compared lower and higher PEEP strategies in C-ARDS were ambiguous pointing out either positive effects on oxygenation with high levels of PEEP, or negative changes in lung mechanics. CONCLUSION The available evidence does not provide sufficient guidance for recommendations on optimal PEEP settings in C-ARDS. In general, well designed platform studies are needed to answer the questions raised in this review and, in particular, to investigate the use of individualised PEEP titration techniques and the inclusion of patients with different ARDS entities, severities and disease stages. TITLE REGISTRATION Our systematic review protocol was registered with the international prospective register of systematic reviews (PROSPERO 2021: CRD42021260303).

Zang Siwei Qingfei Mixture Alleviates Inflammatory Response to Attenuate Acute Lung Injury by the ACE2/NF-κB Signaling Pathway in Mice.

Acute lung injury (ALI) is a serious lung disease characterized by acute and severe inflammation. Upregulation of ACE2 and inhibition of the NF-κB signaling pathway attenuate LPS-induced ALI. To explore whether Zang Siwei Qingfei Mixture inhibits the development of ALI through the ACE2/NF-κB signaling pathway. Alveolar type II epithelial cells (AEC II) were identified by immunofluorescence staining and flow cytometry. C57BL/6J mice were treated with LPS to establish an ALI model. Cell viability was assessed using CCK8 assays. The levels of ACE, ACE2, p-p38/p38, p- ERK1/2/ERK1/2, p-JNK/JNK, p-IκBα/IκB-α, p-NF-κBp65 were analyzed by Western blotting. ELISA was applied to detect the levels of TNF-a, IL-6, AGT, and Ang1-7. HE staining was used to observe lung injury. The mRNA expression of ACE, ACE2, and Mas was measured by RT-qPCR. AEC II cells were successfully isolated. Treatment with the Zang Siwei Qingfei Mixture resulted in a decrease in ACE, p-p38/p38, p-ERK1/2/ERK1/2, p-JNK/JNK, p-IκBα/IκB-α, p-NF-κBp65 levels, while increasing ACE2 levels. Zang Siwei Qingfei mixture also led to a reduction in TNF-α, IL6, and AGT levels, while increasing Ang1-7 level. Histological analysis showed that Zang Siwei Qingfei Mixture treatment improved the alveolar structure of ALI mice and reduced inflammatory infiltration. The pretreatment with MLN-4760, an ACE2 inhibitor, resulted in opposite effects compared to Zang Siwei Qingfei Mixture treatment. Zang Siwei Qingfei mixture attenuates ALI by regulating the ACE2/NF-κB signaling pathway in mice. This study provides a theoretical foundation for the development of improved ALI treatments.

ROS responsive nanozyme loaded with STING silencing for the treatment of sepsis-induced acute lung injury

Acute lung injury (ALI) is a common complication of sepsis and a leading cause of mortality in septic patients. Studies indicate that STING may play a crucial role in the pathogenesis of sepsis-induced ALI by interacting with the PARP-1/NLRP3 pathway. Therefore, targeting STING inhibition has potential as a novel therapeutic strategy for ALI. However, effective inhibition remains challenging due to the widespread expression of STING across various tissues. In this study, we developed a nanozyme-based drug delivery system, DSPE-TK-mPEG-MnO2@siSTING (abbreviated as DTmM@siSTING), using DSPE-TK-mPEG-MnO2 as the carrier, and characterized it via scanning electron microscopy, dynamic light scattering, nanoparticle size analysis, and gel electrophoresis. To evaluate the therapeutic effects of DTmM@siSTING, an in vitro ALI cell model and an in vivo ALI mouse model were established, assessing the nanozyme's impact on ROS levels, inflammatory responses, and the PARP-1/NLRP3 pathway in sepsis-induced ALI. Results demonstrated that DTmM@siSTING exhibited good physiological stability. In vitro, DTmM@siSTING significantly reduced ROS levels, myeloperoxidase activity, and expression of inflammatory cytokines, while also inhibiting PARP-1/NLRP3 pathway activation. In vivo experiments further revealed that DTmM@siSTING effectively delivered siSTING to the lungs, mitigating sepsis-induced ALI and associated inflammatory responses. Additionally, DTmM@siSTING displayed excellent biocompatibility. In summary, our findings suggest that DTmM@siSTING significantly enhances the therapeutic efficacy of siSTING, alleviating ALI by inhibiting ROS production, inflammatory responses, and activation of the PARP-1/NLRP3 pathway. This novel approach presents a promising therapeutic avenue for sepsis-induced ALI.

Association Between Baseline Driving Pressure and Mortality in Very Old Patients with Acute Respiratory Distress Syndrome.

Rationale: Because of the effects of aging on the respiratory system, it is conceivable that the association between driving pressure and mortality depends on age. Objectives: We endeavored to evaluate whether the association between driving pressure and mortality of patients with acute respiratory distress syndrome (ARDS) varies across the adult lifespan, hypothesizing that it is stronger in older, including very old (⩾80 yr), patients. Methods: We performed a secondary analysis of individual patient-level data from seven ARDS Network and PETAL Network randomized controlled trials ("ARDSNet cohort"). We tested our hypothesis in a second, independent, national cohort ("Hellenic cohort"). We performed both binary logistic and Cox regression analyses including the interaction term between age (as a continuous variable) and driving pressure at baseline (i.e., the day of trial enrollment) as the predictor and 90-day mortality as the dependent variable. Measurements and Main Results: On the basis of data from 4,567 patients with ARDS included in the ARDSNet cohort, we found that the effect of driving pressure on mortality depended on age (P = 0.01 for the interaction between age as a continuous variable and driving pressure). The difference in driving pressure between survivors and nonsurvivors significantly changed across the adult lifespan (P < 0.01). In both cohorts, a driving pressure threshold of 11 cm H2O was associated with mortality in very old patients. Conclusions: Data from randomized controlled trials with strict inclusion criteria suggest that the effect of driving pressure on the mortality of patients with ARDS may depend on age. These results may advocate for a personalized age-dependent mechanical ventilation approach.

The polysaccharide from purple sweet potato (Ipomoea batatas (L.) Lam) alleviates lipopolysaccharide-induced acute lung injury in mice via the VIP/cAMP/PKA/AQPs signaling pathway

BackgroundThe polysaccharide (PSP) from purple sweet potato has great potential for regulating apoptosis, but its regulatory role in acute lung injury (ALI) is unknown. MethodsThe objective of this study was to investigate the protective effect of PSP on lipopolysaccharide (LPS)-induced ALI in mice and lung epithelial A549 cells and its mechanism. Moreover, subacute toxicity evaluation of PSP was carried out on ICR mice. ResultsThe results showed that compared with the ALI group, PSP significantly reduced the total protein content, wet-to-dry (W/D) ratio, the number of neutrophils, lymphocytes, and monocytes. Moreover, PSP was able to reduce cell apoptosis, the levels of macrophage inflammatory protein-2 (MIP-2), intercellular adhesion molecule-1 (ICAM-1), tumor necrosis factor-α (TNF-α), malondialdehyde (MDA) and myeloperoxidase (MPO) and increase the level of superoxide (SOD). In addition, PSP could up-regulate the levels of VIP, cAMP, p-PKA/PKA and AQP1 in mice and A549 cells. And PSP exhibited no apparent adverse effects on the mice. ConclusionsPSP had a protective effect on LPS-induced ALI in mice and lung epithelial A549 cells, which may be related to the inflammatory response and via VIP/cAMP/PKA/AQPs signaling pathway. Thus, PSP may be a promising pharmacologic agent for ALI therapy.

Aspiration after Anesthesia: Chemical versus Bacterial, Differential Diagnosis, Management, and Prevention.

Aspiration following anesthesia is a major patient issue and a difficulty for anesthesiologists. Aspiration syndromes are more common than anticipated, and the condition is frequently undetected. Clinical signs are often dictated by the characteristics of aspiration, such as the infectivity of the material, its volume, and the severity of the underlying clinical condition. Pulmonary aspiration can cause an acute or persistent inflammatory response in the lungs and upper airways that can be complicated by tracheobronchitis, aspiration pneumonia, aspiration pneumonitis, acute respiratory distress syndrome, and subsequent bacterial infection due to particle, acid, and bacteria-related processes. Aspiration during anesthesia, while relatively rare, poses significant risks for patient morbidity and mortality. Chemical and bacterial aspiration provide distinct diagnostic and management issues. Preventive strategies such as a complete preoperative risk assessment, adherence to fasting rules, proper patient positioning, and the use of protective airway devices are critical in reducing aspiration risk. In addition, drugs such as proton pump inhibitors can help lower stomach acidity and volume. Innovations in monitoring techniques, better training, and awareness activities are critical to enhancing aspiration event management. Given the importance of this entity, this narrative review sought to make an updated overview of the management of aspiration after anesthesia: chemical versus bacterial, differential diagnosis, management, and prevention.

A retrospective analysis on the effectiveness of cytokine hemadsorption in patients with severe coronavirus disease 2019

Background: An increase in systemic inflammation due to hyperimmune activation leads to severe coronavirus disease 2019 (COVID-19) disease, acute respiratory distress syndrome, multiple organ failure, and ultimately death. Extracorporeal blood purification using hemadsorption to reduce excessive inflammatory cytokine was suggested as an effective treatment for patients with severe COVID-19. We investigated the effectiveness of intermittent cytokine hemadsorption with a HA330 cartridge in patients with severe COVID-19. Methods: We gathered data from severe COVID-19 patients who underwent hemadsorption using Jafron® (HA330) between October and December 2021. We assessed pre- and post-hemadsorption inflammatory cytokine levels, treatment complications, and mortality. Statistical significance was set at P &lt; 0.05. Results: Of the total 40 patients, 13 (32.5%) were males with a mean age of 63.6 years. In patients who survived (n = 23), a 2-fold decrease in interleukin-6 (IL-6, P = 0.0433), a 3-fold decrease in procalcitonin (P = 0.0163), a 2.5-fold decrease in C-reactive protein (CRP, P = 0.0080), a 2.5-fold increase in D-dimer (P = 0.0337), and a 1.3-fold increase in white blood cell (WBC) (P = 0.0102) were observed before and after cytokine hemadsorption. In patients who died (n = 17), a 2-fold increase in WBC (P = 0.0022) was observed with no significant changes in other parameters. Except for a few cases of platelet transfusion, catheter occlusion, hypotension, and hematoma, no other complications were observed. A low rate of mortality (33.3%) was observed in patients who received 3 sessions of hemadsorption. Conclusion: Intermittent hemadsorption reduced inflammatory factors and improved outcomes of patients with severe COVID-19. Cytokine hemadsorption can be an effective therapeutic option for establishing inflammatory equilibrium. Our study was a non-comparator and single-center observational study. Larger studies like RCTs are warranted.

The role of the interplay between macrophage glycolytic reprogramming and NLRP3 inflammasome activation in acute lung injury/acute respiratory distress syndrome.

Acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) is a severe respiratory condition associated with elevated morbidity and mortality. Understanding their complex pathophysiological mechanisms is crucial for developing new preventive and therapeutic strategies. Recent studies highlight the significant role of inflammation involved in ALI/ARDS, particularly the hyperactivation of the NOD-like receptor thermal protein domain-associated protein 3 (NLRP3) inflammasome in macrophages. This activation drives pulmonary inflammation by releasing inflammatory signalling molecules and is linkedto metabolic reprogramming, marked by increased glycolysis and reduced oxidative phosphorylation. However, the relationship between NLRP3 inflammasome activation and macrophage glycolytic reprogramming in ALI/ARDS, as well as the molecular mechanisms regulating these processes, remain elusive. This review provides a detailed description of the interactions and potential mechanisms linking NLRP3 inflammasome activation with macrophage glycolytic reprogramming, proposing that glycolytic reprogramming may represent a promising therapeutic target for mitigating inflammatory responses in ALI/ARDS. KEY POINTS: NLRP3 inflammasome activation is pivotal in mediating the excessive inflammatory response in ALI/ARDS. Glycolytic reprogramming regulates NLRP3 inflammasome activation. Therapeutic potential of targeting glycolytic reprogramming to inhibit NLRP3 inflammasome activation in ALI/ARDS.

Substituted 4H-3,1-benzoxazine-4-one Derivatives as Inhibitors of Cathepsin G.

Cathepsin G (CatG) is a cationic serine protease with a wide substrate specificity. CatG has been reported to play a role in several pathologies, including rheumatoid arthritis, ischemic reperfusion injury, acute respiratory distress syndrome, and cystic fibrosis, among others. We aim to develop a new class of CatG inhibitors and evaluate their potency and selectivity against a series of serine proteases. We exploited chemical synthesis as well as chromogenic substrate hydrolysis assays to construct and evaluate the new inhibitors. In this communication, we report on a new class of CatG inhibitors of 4H-3,1-benzoxazin- 4-one derivatives. We constructed a small library of seven substituted 4H-3,1-benzoxazin-4-one derivatives and identified their inhibition potential against CatG. Five molecules were identified as CatG inhibitors with values of 0.84-5.5 μM. Inhibitor 2 was the most potent, with an IC50 of 0.84 ± 0.11 μM and significant selectivity over representative serine proteases of thrombin, factor XIa, factor XIIa, and kallikrein. Thus, we propose this inhibitor as a lead molecule to guide subsequent efforts to develop clinically relevant potent and selective CatG inhibitors for use as anti-inflammatory agents.