Molybdenum Nanodots for Acute Lung Injury Therapy.

Acute respiratory disease syndrome (ARDS) is a common critical disease with high morbidity and mortality rates, yet specific and effective treatments for it are currently lacking. ARDS was especially apparent and rampant during the COVID-19 pandemic. Excess reactive oxygen species (ROS) production and an uncontrolled inflammatory response play a critical role in the disease progression of ARDS. Herein, we developed molybdenum nanodots (MNDs) as a functional nanomaterial with ultrasmall size, good biocompatibility, and excellent ROS scavenging ability for the treatment of acute lung injury (ALI). MNDs, which were administered intratracheally, significantly ameliorated lung oxidative stress, inflammatory response, protein permeability, and histological severity in ALI mice without inducing any safety issues. Importantly, transcriptomics analysis indicated that MNDs protected lung tissues by inhibiting the activation of the Nod-like receptor protein 3 (NLRP3)-dependent pyroptotic pathway. This work presents a promising therapeutic agent for patients suffering from ARDS.

Distinct immune signatures discriminate between asymptomatic and presymptomatic SARS-CoV-2pos subjects.

Increasing numbers of SARS-CoV-2-positive (SARS-CoV-2pos) subjects are detected at silent SARS-CoV-2 infection stage (SSIS). Yet, SSIS represents a poorly examined time-window wherein unknown immunity patterns may contribute to the fate determination towards persistently asymptomatic or overt disease. Here, we retrieved blood samples from 19 asymptomatic and 12 presymptomatic SARS-CoV-2pos subjects, 47 age/gender-matched patients with mild or moderate COVID-19 and 27 normal subjects, and interrogated them with combined assays of 44-plex CyTOF, RNA-seq and Olink. Notably, both asymptomatic and presymptomatic subjects exhibited numerous readily detectable immunological alterations, while certain parameters including more severely decreased frequencies of CD107alow classical monocytes, intermediate monocytes, non-classical monocytes and CD62Lhi CD8+ Tnaïve cells, reduced plasma STC1 level but an increased frequency of CD4+ NKT cells combined to distinguish the latter. Intercorrelation analyses revealed a particular presymptomatic immunotype mainly manifesting as monocytic overactivation and differentiation blockage, a likely lymphocyte exhaustion and immunosuppression, yielding mechanistic insights into SSIS fate determination, which could potentially improve SARS-CoV-2 management.

Preclinical efficacy and clinical safety of clinical-grade nebulized allogenic adipose mesenchymal stromal cells-derived extracellular vesicles.

Mesenchymal stromal cell-derived extracellular vesicles (MSC-EVs) turn out to be a promising source of cell-free therapy. Here, we investigated the biodistribution and effect of nebulized human adipose-derived MSC-EVs (haMSC-EVs) in the preclinical lung injury model and explored the safety of nebulized haMSC-EVs in healthy volunteers. DiR-labelled haMSC-EVs were used to explore the distribution of nebulized haMSC-EVs in the murine model. Pseudomonas aeruginosa-induced murine lung injury model was established, and survival rate, as well as WBC counts, histology, IL-6, TNF-α and IL-10 levels in bronchoalveolar lavage fluid (BALF) were measured to explore the optimal therapeutic dose of haMSC-EVs through the nebulized route. Twenty-four healthy volunteers were involved and received the haMSC-EVs once, ranging from 2 × 108 particles to 16 × 108 particles (MEXVT study, NCT04313647). Nebulizing haMSC-EVs improved survival rate to 80% at 96 h in P. aeruginosa-induced murine lung injury model by decreasing lung inflammation and histological severity. All volunteers tolerated the haMSC-EVs nebulization well, and no serious adverse events were observed from starting nebulization to the 7th day after nebulization. These findings suggest that nebulized haMSC-EVs could be a promising therapeutic strategy, offering preliminary evidence to promote the future clinical applications of nebulized haMSC-EVs in lung injury diseases.

Role of miR-466 in mesenchymal stromal cell derived extracellular vesicles treating inoculation pneumonia caused by multidrug-resistant Pseudomonas aeruginosa.

RATIONALE: The effects of mesenchymal stromal cells (MSCs) and MSC-derived extracellular vesicles (MSC EVs) on multidrug-resistant pseudomonas aeruginosa (MDR-PA)-induced pneumonia remain unclear. MATERIALS AND METHODS: MicroRNA array and RT-PCR were used to select the major microRNA in MSC EVs. Human peripheral blood monocytes were obtained and isolated from qualified patients. The crosstalk between MSCs/MSC EVs and macrophages in vitro was studied. MDR-PA pneumonia models were further established in C57BL/6 mice and MSC EVs or miR-466 overexpressing MSC EVs were intratracheally instilled. RESULTS: MiR-466 was highly expressed in MSC EVs. MSCs and miR-466 promoted macrophage polarization toward Type 2 phenotype through TIRAP-MyD88-NFκB axis. Moreover, cocultured macrophages with miR-466 overexpressing MSCs significantly increased the phagocytosis of macrophages. MSC EVs significantly reduced mortality and decreased influx of BALF neutrophils, proinflammatory factor levels, protein, and bacterial load in murine MDR-PA pneumonia. Administration of miR-466 overexpressing MSC EVs further alleviated the inflammatory severity. CONCLUSIONS: MSC-derived EVs containing high levels of miR-466 may partly participate in host immune responses to MDR-PA. Both MSCs and MSC EVs have therapeutic effects in treating MDR-PA-induced pneumonia.

The mNCP-SPI Score Predicting Risk of Severe COVID-19 among Mild-Pneumonia Patients on Admission.

PURPOSE: To predict the risk of developing severe pneumonia among mild novel coronavirus pneumonia (mNCP) patients on admission. METHODS: A retrospective cohort study was conducted at three hospitals in Shanghai and Wuhan from January 2020 to February 2020. Real-time polymerasechain-reaction assays were used to detect COVID-19. A total of 529 patients diagnosed with NCP were recruited from three hospitals and classified by four severity types during hospitalization following the standards of the Chinese Diagnosis and Treatment of Pneumonia Caused by New Coronavirus Infection (eighth version). Patients were excluded if admitted by ICU on admission (n=92, on a general ward while meeting the condition of severe or critical type on admission (n=25), or there was insufficient clinical information (n=64). In sum, 348 patients with mNCP were finally included, and 68 developed severe pneumonia. RESULTS: mNCP severity prognostic index values were calculated based on multivariate logistic regression: history of diabetes (OR 2.064, 95% CI 1.010-4.683; p=0.043), time from symptom onset to admission ≥7 days (OR 1.945, 95% CI 1.054-3.587; p=0.033), lymphocyte count ≤0.8 (OR 1.816, 95% CI 1.008-3.274; p=0.047), myoglobin ≥90 mg/L (OR 2.496, 95% CI 1.235-5.047; p=0.011), and D-dimer ≥0.5 mg/L (OR 2.740, 95% CI 1.395-5.380; p=0.003). This model showed a c-statistics of 0.747, with sensitivity and specificity 0.764 and 0.644, respectively, under cutoff of 165. CONCLUSION: We designed a clinical predictive tool for risk of severe pneumonia among mNCP patients to provided guidance for medicines. Further studies are required for external validation.

Troponin I, a risk factor indicating more severe pneumonia among patients with novel coronavirus infected pneumonia.

BACKGROUND: In December 2019, a novel communicable disease, novel coronavirus infected pneumonia (NCIP) caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) broke out. We aimed to analyze the characteristics and severity of patients with myocardial damage in NCIP. METHODS: We enrolled 215 adult patients with NCIP from January 2020 to February 2020. Outcomes were followed up until March 1st, 2020. RESULTS: 28.37% of the total patients showed increased level of TnI (> 0.040 ng/ml). Patients were older and had more cardiovascular complications in increased TnI group. Higher CRP, NT-proBNP, lower immune CD3, CD4 and CD8 cell account and more involved lobes detected by CT scan in the lung were observed in increased TnI group. Patients with elevated TnI had higher CURB-65 scores and were more likely given glucocorticoid therapy and mechanical ventilation than patients in normal TnI group. CONCLUSIONS: Markers of cardiomyocyte injury were elevated not least in elderly males with pre-existing cardiovascular disease. Patients with elevated TnI presented more severe situation, leading to multiple organ dysfunctions, which appeared as a pivotal feature of patients with NCIP that requires attention by clinicians in order to provide necessary treatment as soon as possible and improve patients' outcomes.

COVID-19 with Different Severities: A Multicenter Study of Clinical Features.

Rationale: The coronavirus disease (COVID-19) pandemic is now a global health concern.Objectives: We compared the clinical characteristics, laboratory examinations, computed tomography images, and treatments of patients with COVID-19 from three different cities in China.Methods: A total of 476 patients were recruited from January 1, 2020, to February 15, 2020, at three hospitals in Wuhan, Shanghai, and Anhui. The patients were divided into four groups according to age and into three groups (moderate, severe, and critical) according to the fifth edition of the Guidelines on the Diagnosis and Treatment of COVID-19 issued by the National Health Commission of China.Measurements and Main Results: The incidence of comorbidities was higher in the severe (46.3%) and critical (67.1%) groups than in the moderate group (37.8%). More patients were taking angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers in the moderate group than in the severe and critical groups. More patients had multiple lung lobe involvement and pleural effusion in the critical group than in the moderate group. More patients received antiviral agents within the first 4 days in the moderate group than in the severe group, and more patients received antibiotics and corticosteroids in the critical and severe groups. Patients >75 years old had a significantly lower survival rate than younger patients.Conclusions: Multiple organ dysfunction and impaired immune function were the typical characteristics of patients with severe or critical illness. There was a significant difference in the use of angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers among patients with different severities of disease. Involvement of multiple lung lobes and pleural effusion were associated with the severity of COVID-19. Advanced age (≥75 yr) was a risk factor for mortality.