S1PR3 inhibition protects against LPS-induced ARDS by inhibiting NF-κB and improving mitochondrial oxidative phosphorylation.

BACKGROUND: Inflammation and endothelial barrier dysfunction are the major pathophysiological changes in acute respiratory distress syndrome (ARDS). Sphingosine-1-phosphate receptor 3 (S1PR3), a G protein-coupled receptor, has been found to mediate inflammation and endothelial cell (EC) integrity. However, the function of S1PR3 in ARDS has not been fully elucidated. METHODS: We used a murine lipopolysaccharide (LPS)-induced ARDS model and an LPS- stimulated ECs model to investigate the role of S1PR3 in anti-inflammatory effects and endothelial barrier protection during ARDS. RESULTS: We found that S1PR3 expression was increased in the lung tissues of mice with LPS-induced ARDS. TY-52156, a selective S1PR3 inhibitor, effectively attenuated LPS-induced inflammation by suppressing the expression of proinflammatory cytokines and restored the endothelial barrier by repairing adherens junctions and reducing vascular leakage. S1PR3 inhibition was achieved by an adeno-associated virus in vivo and a small interfering RNA in vitro. Both the in vivo and in vitro studies demonstrated that pharmacological or genetic inhibition of S1PR3 protected against ARDS by inhibiting the NF-κB pathway and improving mitochondrial oxidative phosphorylation. CONCLUSIONS: S1PR3 inhibition protects against LPS-induced ARDS via suppression of pulmonary inflammation and promotion of the endothelial barrier by inhibiting NF-κB and improving mitochondrial oxidative phosphorylation, indicating that S1PR3 is a potential therapeutic target for ARDS.

Machine learning reveals sex differences in clinical features of acute exacerbation of chronic obstructive pulmonary disease: A multicenter cross-sectional study.

Introduction: Intrinsically, chronic obstructive pulmonary disease (COPD) is a highly heterogonous disease. Several sex differences in COPD, such as risk factors and prevalence, were identified. However, sex differences in clinical features of acute exacerbation chronic obstructive pulmonary disease (AECOPD) were not well explored. Machine learning showed a promising role in medical practice, including diagnosis prediction and classification. Then, sex differences in clinical manifestations of AECOPD were explored by machine learning approaches in this study. Methods: In this cross-sectional study, 278 male patients and 81 female patients hospitalized with AECOPD were included. Baseline characteristics, clinical symptoms, and laboratory parameters were analyzed. The K-prototype algorithm was used to explore the degree of sex differences. Binary logistic regression, random forest, and XGBoost models were performed to identify sex-associated clinical manifestations in AECOPD. Nomogram and its associated curves were established to visualize and validate binary logistic regression. Results: The predictive accuracy of sex was 83.930% using the k-prototype algorithm. Binary logistic regression revealed that eight variables were independently associated with sex in AECOPD, which was visualized by using a nomogram. The AUC of the ROC curve was 0.945. The DCA curve showed that the nomogram had more clinical benefits, with thresholds from 0.02 to 0.99. The top 15 sex-associated important variables were identified by random forest and XGBoost, respectively. Subsequently, seven clinical features, including smoking, biomass fuel exposure, GOLD stages, PaO2, serum potassium, serum calcium, and blood urea nitrogen (BUN), were concurrently identified by three models. However, CAD was not identified by machine learning models. Conclusions: Overall, our results support that the clinical features differ markedly by sex in AECOPD. Male patients presented worse lung function and oxygenation, less biomass fuel exposure, more smoking, renal dysfunction, and hyperkalemia than female patients with AECOPD. Furthermore, our results also suggest that machine learning is a promising and powerful tool in clinical decision-making.

Comparison of Clinical Characteristics and Predictors of Mortality between Direct and Indirect ARDS.

Background and Objectives: Acute Respiratory Distress Syndrome (ARDS) is a heterogeneous syndrome that encompasses lung injury from a direct pulmonary or indirect systemic insult. Studies have shown that direct and indirect ARDS differ in their pathophysiologic process. In this study, we aimed to compare the different clinical characteristics and predictors of 28-day mortality between direct and indirect ARDS. Materials and Methods: The data of 1291 ARDS patients from September 2012 to December 2021 at the Second Affiliated Hospital of Chongqing Medical University were reviewed. We enrolled 451 ARDS patients in our study through inclusion and exclusion criteria. According to the risk factors, each patient was divided into direct (n = 239) or indirect (n = 212) ARDS groups. The primary outcome was 28-day mortality. Results: The patients with direct ARDS were more likely to be older (p < 0.001) and male (p = 0.009) and have more comorbidity (p < 0.05) and higher 28-day mortality (p < 0.001) than those with indirect ARDS. Age and multiple organ dysfunction syndrome (MODS) were predictors of 28-day mortality in the direct ARDS group, while age, MODS, creatinine, prothrombin time (PT), and oxygenation index (OI) were independent predictors of 28-day mortality in the indirect ARDS group. Creatinine, PT, and OI have interactions with ARDS types (all p < 0.01). Conclusions: The patients with direct ARDS were more likely to be older and male and have worse conditions and prognoses than those with indirect ARDS. Creatinine, PT, and OI were predictors of 28-day mortality only in the indirect ARDS group. The differences between direct and indirect ARDS suggest the need for different management strategies of ARDS.

No sex differences in the incidence, risk factors and clinical impact of acute kidney injury in critically ill patients with sepsis.

Background: Sex-stratified medicine is an important aspect of precision medicine. We aimed to compare the incidence and risk factors of acute kidney injury (AKI) for critically ill men and women with sepsis. Furthermore, the short-term mortality was compared between men and women with sepsis associated acute kidney injury (SA-AKI). Method: This was a retrospective study based on the Medical Information Mart for Intensive Care IV database. We used the multivariable logistic regression analysis to evaluate the independent effect of sex on the incidence of SA-AKI. We further applied three machine learning methods (decision tree, random forest and extreme gradient boosting) to screen for the risk factors associated with SA-AKI in the total, men and women groups. We finally compared the intensive care unit (ICU) and hospital mortality between men and women with SA-AKI using propensity score matching. Results: A total of 6463 patients were included in our study, including 3673 men and 2790 women. The incidence of SA-AKI was 83.8% for men and 82.1% for women. After adjustment for confounders, no significant association was observed between sex and the incidence of SA-AKI (odds ratio (OR), 1.137; 95% confidence interval (CI), 0.949-1.361; p=0.163). The machine learning results revealed that body mass index, Oxford Acute Severity of Illness Score, diuretic, Acute Physiology Score III and age were the most important risk factors of SA-AKI, irrespective of sex. After propensity score matching, men had similar ICU and hospital mortality to women. Conclusions: The incidence and associated risk factors of SA-AKI are similar between men and women, and men and women with SA-AKI experience comparable rates of ICU and hospital mortality. Therefore, sex-related effects may play a minor role in developing SA-AKI. Our study helps to contribute to the knowledge gap between sex and SA-AKI.

Case Report: The Experience of Managing a Moderate ARDS Caused by SARS-CoV-2 Omicron BA.2 Variant in Chongqing, China: Can We Do Better?

Background: The severe coronavirus disease 2019 (COVID-19) pandemic is still raging worldwide, and the Omicron BA.2 variant has become the new circulating epidemic strain. However, our understanding of the Omicron BA.2 variant is still scarce. This report aims to present a case of a moderate acute respiratory distress syndrome (ARDS) caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) Omicron BA.2 variant and to discuss some management strategies that may benefit this type of case. Case Presentation: A 78-year-old man, who had four negative nucleic acid tests and a fifth positive, was admitted to our hospital. This patient was generally good upon admission and tested negative for anti-SARS-CoV-2 antibodies even after receiving two doses of the COVID-19 vaccine. On the 7th day of hospitalization, he developed a moderate ARDS. Improved inflammatory index and decreased oxygen index were primarily found in this patient, and a series of treatments, including anti-inflammation and oxygen therapies, were used. Then this patient's condition improved soon and reached two negative results of nucleic acid tests on the 18th day of hospitalization. Conclusion: At-home COVID-19 rapid antigen test could be complementary to existing detection methods, and the third booster dose of COVID-19 vaccine may be advocated in the face of the omicron BA.2 variant. Anti-inflammatory and oxygen therapies are still essential treatments for ARDS patients infected with SARS-CoV-2 Omicron BA.2 variant.

Adipose-Derived Circulating Exosomes Promote Protection of the Pulmonary Endothelial Barrier by Inhibiting EndMT and Oxidative Stress through Down-Regulation of the TGF-ß Pathway: A Potential Explanation for the Obesity Paradox in ARDS.

The "obesity paradox in acute respiratory distress syndrome" (ARDS) refers to the phenomenon in which obesity is associated with higher morbidity but lower mortality in patients with ARDS. Endothelial-to-mesenchymal transition (EndMT) represents a key link in the interaction between endothelial disruption and mesenchymal fibrosis under inflammatory and oxidative conditions, which represent the intersectional pathophysiology of ARDS. Adipose tissue is considered to constitute the major source of circulating exosomal microRNAs (miRNAs), which act as genetic forms of adipokines for cell-cell crosstalk. We aimed to demonstrate the regulation and mechanism of adipose-derived exosomes in the obesity paradox in ARDS. High-fat-induced obese mice and lean control mice were subjected to ARDS insult to investigate the effects of obesity on ARDS and microarray analysis was performed to screen for differences in circulating miRNAs. In addition, mice and pulmonary endothelial cells were administered with adipose-derived exosomal miR-122-5p to investigate the underlying molecular mechanisms. We found high-fat diet-induced obesity protected against ARDS in mice by reinforcing endothelial barrier and attenuating fibroproliferation. Circulating exosomes produced in the obese state mediated these protective effects by inhibiting EndMT and oxidative stress. Mechanistically, adipose-derived exosomal miR-122-5p promoted the integrity and function of pulmonary endothelial barrier and alleviated fibrogenesis by suppressing EndMT and oxidative stress through down-regulation of the transforming growth factor ß1 (TGF-ß1)/TGF-ß receptor 1 (TGF-ßR1)/Smad2 pathway in vivo and in vitro. In conclusion, adipose-derived circulating exosomal miR-122-5p protects against ARDS by reinforcing pulmonary endothelial barrier through inhibition of EndMT and oxidative stress via down-regulation of the TGF-ß pathway, which propose a potential explanation for the obesity paradox in ARDS and indicate promising prospects for adipose-derived exosomes in cell-free therapies for ARDS.

Central Venous Pressure Measurement Is Associated With Improved Outcomes in Patients With or at Risk for Acute Respiratory Distress Syndrome: An Analysis of the Medical Information Mart for Intensive Care IV Database.

Background: Central venous pressure (CVP) monitoring is widely used in the intensive care unit (ICU). However, the formal utility of CVP measurement to altering patient outcomes among ICU patients with or at risk for acute respiratory distress syndrome (ARDS) has never been investigated. Our study aimed to explore the association of CVP measurement with 28-day mortality specifically in that population. Methods: This study was based on the Medical Information Mart for Intensive Care IV (MIMIC-IV) database. Patients were divided into CVP and no CVP groups according to whether they had CVP measurement within 24 h of admission to the ICU. The primary outcome was 28-day mortality. Multivariate regression was used to elucidate the association between CVP measurement and 28-day mortality, and propensity score matching (PSM) and propensity score-based overlap weighting (OW) were employed to verify the stability of our results. Results: A total of 10,198 patients with or at risk for ARDS were included in our study, of which 4,647 patients (45.6%) belonged to the CVP group. Multivariate logistic regression showed that the early measurement of CVP was independently associated with lower 28-day mortality (OR: 0.49; 95% CI: 0.42-0.57; p < 0.001). This association remained robust after PSM and OW (both p < 0.001). Patients in the CVP group had shorter ICU stay, lower in-hospital mortality, more fluid on day 1 and higher clearance of blood lactate than those in the no CVP group. Conclusion: Early CVP measurement is associated with an improvement in 28-day mortality among a general population of critically ill patients with or at risk for ARDS.

Predictive Value of the Baseline and Early Changes in Blood Eosinophils for Short-Term Mortality in Patients with Acute Respiratory Distress Syndrome.

Background: Eosinophils play an essential role in the pathogenesis of acute respiratory distress syndrome (ARDS). We aimed to assess the association between the baseline blood eosinophils, eosinophil changes during the first week in the intensive care unit (ICU) and short-term patient outcomes. Methods: All patients meeting the Berlin definition of ARDS from the Medical Information Mart for Intensive Care IV database were retrospectively analyzed. We used logistic regression, Kaplan-Meier survival and random forest analysis to determine the association between the baseline eosinophils and short-term mortality. Then the trends in eosinophils over time were compared between the survivors and non-survivors using a generalized additive mixed model (GAMM), which is a common approach used for analysis of repeated measurement data. Area under the receiver-operating characteristic curve (AUC) was used to evaluate the predictive value. Results: A total of 1685 patients were included, and the 30-day mortality was 25.1%. Kaplan-Meier analysis showed that patients with high baseline eosinophils (>0.3%) had lower 30-day mortality (p < 0.001). Random forest model selected the baseline eosinophils as an important factor associated with 30-day mortality. Multivariable logistic regression analysis identified high baseline eosinophils as an independent factor for 30-day mortality (OR 0.743, 95% CI 0.568-0.970). The GAMM result showed that the levels of eosinophils were increased in both survival and non-survival groups, and the between-group differences increased over time, with an average of 0.154 daily after adjusting for confounders. The AUC of changes in eosinophils within the first week was significantly higher than that of baseline eosinophils. Conclusion: There is a negative association between the baseline eosinophils and short-term mortality in ARDS patients, and the differences in eosinophils increased over time between the survivors and non-survivors. Higher increase in eosinophils is associated with decreased short-term mortality, and dynamic monitoring of eosinophils could better predict the survival of ARDS patients.

Protective effects of adipose-derived biogenic nanoparticles on the pulmonary microvascular endothelial barrier in mice with ventilator-induced lung injury via the TRPV4/ROCK1 signalling pathway.

PURPOSE: The "obesity paradox" phenomenon occurs in critically ill patients who receive mechanical ventilation. Our previous studies found that the adipose-derived exosomes secreted by obese mice have a protective effect on the pulmonary microvascular endothelial barrier. However, the extraction of exosomes is cumbersome, their yield is low, and their storage is difficult. After further research, we discovered a new type of adipose-derived bioactive material called: lipoaspirate nanoparticles (Lipo-NPs). METHODS: Lipo-NPs were extracted and identified using a tangential flow filtration system. The Lipo-NPs were used as an intervention in ventilator-induced lung injury (VILI) models in vivo and in vitro to investigate whether they have a protective effect on lung tissue damage (haematoxylin and eosin staining), lung barrier function (lung wet/dry [W/D] weight ratio, protein concentration in bronchoalveolar lavage fluid (BALF), and Vascular endothelial (VE)-expression), as well as their related mechanisms. RESULTS: In both in vivo and in vitro studies, Lipo-NPs can attenuate lung injury, reduce lung W/D ratio and protein concentration in BALF, and augment the expression of the adhesion link-protein VE-cadherin, thus playing a protective role in lung barrier function. This protective effect involves the activation of the transient receptor potential vanilloid 4 (TRPV4)/Rho-associated kinase1 (ROCK1) signalling pathway. We further verified the role of this signalling pathway via activation and inhibition of TRPV4 and ROCK1. Moreover, phosphorylation of myosin light chain 2 (MLC2) regulates F-actin and is a target of the ROCK pathway. CONCLUSION: Lipo-NPs can enhance the expression of VE-cadherin by inhibiting the TRPV4/ROCK1/pMLC2 signalling pathway in the mechanical ventilation model, thereby exerting a protective effect on the VILI pulmonary microvascular endothelial barrier.

A trauma-related survival predictive model of acute respiratory distress syndrome.

PURPOSE: The purpose of this study was to construct and validate a simple model for the prediction of survival in patients with trauma-related ARDS. METHODS: This is a single-center, retrospective cohort study using MIMIC-III Clinical Database. RESULTS: 842 patients were included in this study. 175 (20.8%) died in-hospital, whereas 215 (25.5%) died within 90 days. The deceased group had higher Acute Physiology Score (APS III), Sequential Organ Failure Assessment (SOFA), and Simplified Acute Physiology Score II (SAPS II). In multivariate logistic regression model, independent risk factors for mortality in ARDS patients included age ([odds ratio] OR, 1.035; 95% confidence interval [CI], 1.020-1.049), body mass index (OR, 0.957; 95% CI, 0.926-0.989), red blood cell distribution width (OR, 1.283; 95% CI, 1.141-1.443), hematocrit (OR, 1.055; 95% CI, 1.017-1.095), lactate (OR, 1.226; 95% CI, 1.127-1.334), blood urea nitrogen (OR, 1.025; 95% CI, 1.007-1.044), acute kidney failure (OR, 1.875; 95% CI, 1.188-2.959), sepsis (OR, 1.917; 95% CI, 1.165-3.153), type of admission (emergency vs. elective [OR, 2.822; 95% CI, 1.647-4.837], and urgent vs. elective [OR, 5.156; 95% CI, 1.896-14.027]). The area under the curve (AUC) of the model was 0.826, which was superior than the SAPS II (0.776), APS III (0.718), and SOFA (0.692). In the cross-validation model, the accuracy of the test set was 0.823, the precision was 0.643, and the AUC was 0.813. CONCLUSIONS: We established a prediction model using data commonly used in the clinic, which has high accuracy and precision and is worthy of use in clinical practice.

High Blood Eosinophil and YKL-40 Levels, as Well as Low CXCL9 Levels, are Associated with Increased Readmission in Patients with Acute Exacerbation of Chronic Obstructive Pulmonary Disease.

BACKGROUND: Readmission after hospital discharge is common among patients with acute exacerbation of chronic obstructive pulmonary disease (AECOPD). Predictive biomarkers of readmission would facilitate stratification strategies and individualized prognosis. Therefore, this study aimed to investigate the utility of type 2 biomarkers (eosinophils, periostin, and YKL-40) and a type 1 biomarker (CXCL9) in predicting readmission events in patients with AECOPD. METHODS: This is a prospective observational study design. Blood levels of eosinophils, periostin, YKL-40, and CXCL9 were measured at admission. The clinical outcomes were 12-month COPD-related readmission, time to COPD-related readmission, and number of 12-month COPD-related readmissions. These outcomes were analyzed using logistic and Cox regression models and Spearman's rank test. RESULTS: A total of 123 patients were included, of whom 51 had experienced at least one readmission for AECOPD. High levels of eosinophils (≥200 cells/µL or 2% of the total white blood cell count, adjusted odds ratio [aOR] =3.138, P=0.009) and YKL-40 (≥14.5 ng/mL, aOR =2.840, P=0.015), as well as low CXCL9 levels (≤30.1 ng/mL, aOR =2.551, P=0.028), were associated with an increased COPD-related readmission. The highest relative readmission rate was observed in patients with both high eosinophil and YKL-40 levels. Moreover, high eosinophil and YKL-40 levels were associated with a shorter time to first COPD-related readmission and an increased number of 12-month COPD-related readmissions. CONCLUSION: High blood eosinophil and YKL-40 levels, as well as low CXCL9 levels, have predictive utility for the 12-month COPD-related readmission rate. Using eosinophils and YKL-40 together allows more precise identification of patients at high risk of COPD-related readmission.

Clinical Differences between Eosinophilic and Noneosinophilic Acute Exacerbation of Chronic Obstructive Pulmonary Disease: A Multicenter Cross-Sectional Study.

METHODS: A total of 643 AECOPD patients were enrolled in this multicenter cross-sectional study. Finally, 455 were included, 214 in the normal-eosinophil AECOPD (NEOS-AECOPD) group, 63 in the mild increased-eosinophil AECOPD (MEOS-AECOPD) group, and 138 in the severe increased-eosinophil AECOPD (SEOS-AECOPD) group. Demographic data, underlying diseases, symptoms, and laboratory findings were collected. Multiple logistic regression analysis was performed to identify the independent factors associated with blood eosinophils (EOS). Correlations between blood EOS and its associated independent factors were evaluated. RESULTS: The significant differences in 19 factors, including underlying diseases, clinical symptoms, and laboratory parameters, were identified by univariate analysis. Subsequently, multiple logistic regression analysis revealed that lymphocyte%, neutrophil% (NS%), procalcitonin (PCT), and anion gap (AG) were independently associated with blood EOS in AECOPD. Both blood EOS counts and EOS% were significantly correlated with lymphocyte%, NS%, PCT, and AG. CONCLUSIONS: Collectively, blood EOS was independently associated with lymphocyte%, NS%, PCT, and AG in AECOPD patients. Lymphocyte% was lower, and NS%, PCT, and AG were higher in eosinophilic AECOPD. Our results indicate that viral-dominant infections are the probable major etiologies of eosinophilic AECOPD. Noneosinophilic AECOPD is more likely associated with bacterial-dominant infections. The systemic inflammation in noneosinophilic AECOPD was more severe.

Diagnostic value of peripheral hematologic markers for coronavirus disease 2019 (COVID-19): A multicenter, cross-sectional study.

BACKGROUND: To determine the diagnostic value of hematologic markers for coronavirus disease 2019 (COVID-19) and explore their relationship with disease severity. METHODS: Subjects included 190 COVID-19 patients, 190 healthy subjects, and 105 influenza pneumonia (IP) patients. COVID-19 patients were divided into the ARDS and non-ARDS groups. Routine blood examination, biochemistry indicator, days in hospital, body temperature, pneumonia severity index (PSI), CURB-65, and MuLBSTA were recorded. Correlations between variables were assessed using Spearman's correlation analysis. Receiver operating characteristic (ROC) curves were used to study the accuracy of the various diagnostic tests. RESULTS: Compared with healthy subjects, COVID-19 patients had lower white blood cell (WBC), lymphocyte, platelet, and hemoglobin levels; higher percentages of neutrophils and monocytes; lower percentages of lymphocytes and higher neutrophil-to-lymphocyte ratio (NLR), monocyte-to-lymphocyte ratio (MLR), and platelet-to-lymphocyte ratio (PLR) values (P < .05). COVID-19 patients had higher WBC and neutrophil levels and lower percentages of lymphocytes compared to IP (P < .05). ROC curve analysis revealed that MLR had a high diagnostic value in differentiating COVID-19 patients from healthy subjects, but not from IP patients. NLR showed significant positive correlations with PSI, CURB-65, and MuLBSTA. Lymphocyte count was lower in the ARDS group and yielded a higher diagnostic value than the other variables. CONCLUSIONS: Monocyte-to-lymphocyte ratio showed an acceptable efficiency to separate COVID-19 patients from healthy subjects, but failed to rule out IP patients. NLR may be a reliable marker to evaluate the disease severity of COVID-19. Lymphocyte count may be useful to establish the early diagnosis of ARDS in the COVID-19 patients.