Dynasore Alleviates LPS-Induced Acute Lung Injury by Inhibiting NLRP3 Inflammasome-Mediated Pyroptosis.

Background: Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are clinically severe respiratory disorders without available pharmacological therapies. Dynasore is a cell-permeable molecule that inhibits GTPase activity and exerts protective effects in several disease models. However, whether dynasore can alleviate lipopolysaccharide (LPS)-induced ALI is unknown. This study investigated the effect of dynasore on macrophage activation and explored its potential mechanisms in LPS-induced ALI in vitro and in vivo. Methods: Bone marrow-derived macrophages (BMDMs) were activated classically with LPS or subjected to NLRP3 inflammasome activation with LPS+ATP. A mouse ALI model was established by the intratracheal instillation (i.t.) of LPS. The expression of PYD domains-containing protein 3 (NLRP3), caspase-1, and gasdermin D (GSDMD) protein was detected by Western blots. Inflammatory mediators were analyzed in the cell supernatant, in serum and bronchoalveolar lavage fluid (BALF) by enzyme-linked immunosorbent assays. Morphological changes in lung tissues were evaluated by hematoxylin and eosin staining. F4/80, Caspase-1 and GSDMD distribution in lung tissue was detected by immunofluorescence. Results: Dynasore downregulated nuclear factor (NF)-κB signaling and reduced proinflammatory cytokine production in vitro and inhibited the production and release of interleukin (IL)-1ß, NLRP3 inflammasome activation, and macrophage pyroptosis through the Drp1/ROS/NLRP3 axis. Dynasore significantly reduced lung injury scores and proinflammatory cytokine levels in both BALF and serum in vivo, including IL-1ß and IL-6. Dynasore also downregulated the co-expression of F4/80, caspase-1 and GSDMD in lung tissue. Conclusion: Collectively, these findings demonstrated that dynasore could alleviate LPS-induced ALI by regulating macrophage pyroptosis, which might provide a new therapeutic strategy for ALI/ARDS.

Mitochondrial pyruvate carrier-mediated metabolism is dispensable for the classical activation of macrophages.

Glycolysis is essential for the classical activation of macrophages (M1), but how glycolytic pathway metabolites engage in this process remains to be elucidated. Glycolysis leads to production of pyruvate, which can be transported into the mitochondria by the mitochondrial pyruvate carrier (MPC) followed by utilization in the tricarboxylic acid cycle. Based on studies that used the MPC inhibitor UK5099, the mitochondrial route has been considered to be of significance for M1 activation. Using genetic approaches, here we show that the MPC is dispensable for metabolic reprogramming and activation of M1 macrophages. In addition, MPC depletion in myeloid cells has no impact on inflammatory responses and macrophage polarization toward the M1 phenotype in a mouse model of endotoxemia. While UK5099 reaches maximal MPC inhibitory capacity at approximately 2-5 µM, higher concentrations are required to inhibit inflammatory cytokine production in M1 and this is independent of MPC expression. Taken together, MPC-mediated metabolism is dispensable for the classical activation of macrophages and UK5099 inhibits inflammatory responses in M1 macrophages due to effects other than MPC inhibition.

Multi-channel AgNWs-doped interdigitated organic electrochemical transistors enable sputum-based device towards noninvasive and portable diagnosis of lung cancer.

Biochemical monitoring of bodily fluidics such as sweat, urine, and tears have been extensively developed, but reliable biochemical analysis of sputum biospecimens remains limited and challenging due to the low abundance of biomarkers in intrinsically viscous sputum. We reported a portable multi-channel sputum-based interdigitated organic electrochemical transistors (SiOECTs) device for noninvasive sputum diagnosis. We tailored the AgNWs-doped organic electrochemical transistors, integrating with multiplexed aptamer-antigen assays, to realize the signal amplification and simultaneous detection of biomarkers in raw sputum biospecimens from lung cancer patients. Clinical validation studies demonstrated favorable correlation coefficients between the sputum and serum biospecimens. By utilizing our portable multi-channel iOECTs devices, lung cancer patients were differentiated from health control with an optimum area under the curve (AUC) of 0.931, sensitivity of 87.0%, and specificity of 86.5%. Our miniaturized and portable device could even realize the continuous in-home tracking of the biomarkers change for lung cancer patients after radiotherapy/chemotherapy. It is envisaged that the SiOECTs will shed light on noninvasive diagnostics platforms for sputum-related diseases.

Extracorporeal Membrane Oxygenation for COVID-19: Case Report of Nine Patients.

Covid-19, Coronavirus disease 2019; ARDS, Acute respiratory distress syndrome; ECMO, Extracorporeal Membrane Oxygenation; WHO, World Health Organization; ICUs, Intensive care units. Acute respiratory distress syndrome (ARDS) is a fatal comorbidity of critically ill patients with COVID-19, who often end up on respiratory support. However, the safety and effectiveness of Extracorporeal Membrane Oxygenation (ECMO) in the treatment of COVID-19 remains to be elucidated at present. Here, we report on nine patients who received ECMO due to severe SARS-CoV-2 infection in Wuhan, China. Our initial experiences suggest that carefully selecting patients, as well as management by a well-trained team, are critical to implementing ECMO in patients with COVID-19. More randomized controlled trials with larger sample sizes are needed to evaluate the usefulness of ECMO in patients with COVID-19.

Identifying critically ill patients at risk of death from coronavirus disease.

BACKGROUND: A pandemic of coronavirus disease (COVID-19) has been declared by the World Health Organization (WHO) and caring for critically ill patients is expected to be at the core of battling this disease. However, little is known regarding an early detection of patients at high risk of fatality. METHODS: This retrospective cohort study recruited consecutive adult patients admitted between February 8 and February 29, 2020, to the three intensive care units (ICUs) in a designated hospital for treating COVID-19 in Wuhan. The detailed clinical information and laboratory results for each patient were obtained. The primary outcome was in-hospital mortality. Potential predictors were analyzed for possible association with outcomes, and the predictive performance of indicators was assessed from the receiver operating characteristic (ROC) curve. RESULTS: A total of 121 critically ill patients were included in the study, and 28.9% (35/121) of them died in the hospital. The non-survivors were older and more likely to develop acute organ dysfunction, and had higher Sequential Organ Failure Assessment (SOFA) and quick SOFA (qSOFA) scores. Among the laboratory variables on admission, we identified 12 useful biomarkers for the prediction of in-hospital mortality, as suggested by area under the curve (AUC) above 0.80. The AUCs for three markers neutrophil-to-lymphocyte ratio (NLR), thyroid hormones free triiodothyronine (FT3), and ferritin were 0.857, 0.863, and 0.827, respectively. The combination of two easily accessed variables NLR and ferritin had comparable AUC with SOFA score for the prediction of in-hospital mortality (0.901 vs. 0.955, P=0.085). CONCLUSIONS: Acute organ dysfunction combined with older age is associated with fatal outcomes in COVID-19 patients. Circulating biomarkers could be used as powerful predictors for the in-hospital mortality.

Epidemiology and Outcomes of Acute Kidney Injury in COVID-19 Patients with Acute Respiratory Distress Syndrome: A Multicenter Retrospective Study.

BACKGROUND: Acute kidney injury (AKI) is associated with increased mortality in patients with acute respiratory distress syndrome (ARDS). However, the epidemiological features and outcomes of AKI among COVID-19 patients with ARDS are unknown. METHODS: We retrospectively recruited consecutive adult COVID-19 patients who were diagnosed with ARDS according to Berlin definition from 13 designated intensive care units in the city of Wuhan, China. Potential risk factors of AKI as well as the relation between AKI and in-hospital mortality were investigated. RESULTS: A total of 275 COVID-19 patients with ARDS were included in the study, and 49.5% of them developed AKI during their hospital stay. In comparison with patients without AKI, patients who developed AKI were older, tended to have chronic kidney disease, had higher Sepsis-Related Organ Failure Assessment score on day 1, and were more likely to receive invasive ventilation and develop acute organ dysfunction. Multivariate analysis showed that age, history of chronic kidney disease, neutrophil-to-lymphocyte ratio, and albumin level were independently associated with the occurrence of AKI. Importantly, increasing AKI severity was associated with increased in-hospital mortality when adjusted for other potential variables: odds ratio of stage 1 = 5.374 (95% CI: 2.147-13.452; p < 0.001), stage 2 = 6.216 (95% CI: 2.011-19.210; p = 0.002), and stage 3 = 34.033 (95% CI: 9.723-119.129; p < 0.001). CONCLUSION: In this multicenter retrospective study, we found that nearly half of COVID-19 patients with ARDS experienced AKI during their hospital stay. The coexistence of AKI significantly increased the mortality of these patients.

Association between chest CT features and clinical course of Coronavirus Disease 2019.

PURPOSE: This retrospective study aims to illustrate the radiographic characteristics of Coronavirus Disease 2019 and the correlation with the clinical course. METHODS: 195 hospitalized patients confirmed as Coronavirus Disease 2019 at First Hospital of Changsha, Hunan Province from December 31, 2019 to February 20, 2020 were enrolled. Chest computed tomography scan, clinical data and laboratory tests results were collected accordingly. Variable characteristics were recorded, radiographic evolution and outcome were analyzed along with the time course. Representative laboratory tests results were analyzed based on the image findings. RESULTS: Majority of the patients showed bilateral (73.8%), multiple lobes involvements (75.9%), peripheral distribution (83.1%), ground-glass opacification (41.0%), increased vascular margins (63.1%), long axis parallelism (55.9%), patchy ground-glass opacities beneath the pleura (51.3%) and consolidation (45.6%). According to the repeated radiology analysis, patients of improving/stable group tended to have younger age compared with worsening group (45.3 ± 15.0 VS. 59.3 ± 13.5, P = 0.001). Based on the laboratory test results, patients with positive image findings shared elder age, 46.0 (35.0-60.0)VS.31.0 (12.0-37.0) P < 0.001, and higher chance developing fever(P < 0.05); higher level of lymphocytes, C-reactive protein, erythrocyte sedimentation rate and lactate dehydrogenase; lower level of white blood cells, neutrophil and albumin(P < 0.001). CONCLUSIONS: There are several specific image changes along with the disease progression may be helpful in early recognition and differential diagnosis of Coronavirus Disease 2019. Comprehensive assessments of both imaging feature and laboratory test results may offer an intact knowledge of Coronavirus Disease 2019.