Heterogeneity of immune cells and their communications unveiled by transcriptome profiling in acute inflammatory lung injury.

Background: Acute Respiratory Distress Syndrome (ARDS) or its earlier stage Acute lung injury (ALI), is a worldwide health concern that jeopardizes human well-being. Currently, the treatment strategies to mitigate the incidence and mortality of ARDS are severely restricted. This limitation can be attributed, at least in part, to the substantial variations in immunity observed in individuals with this syndrome. Methods: Bulk and single cell RNA sequencing from ALI mice and single cell RNA sequencing from ARDS patients were analyzed. We utilized the Seurat program package in R and cellmarker 2.0 to cluster and annotate the data. The differential, enrichment, protein interaction, and cell-cell communication analysis were conducted. Results: The mice with ALI caused by pulmonary and extrapulmonary factors demonstrated differential expression including Clec4e, Retnlg, S100a9, Coro1a, and Lars2. We have determined that inflammatory factors have a greater significance in extrapulmonary ALI, while multiple pathways collaborate in the development of pulmonary ALI. Clustering analysis revealed significant heterogeneity in the relative abundance of immune cells in different ALI models. The autocrine action of neutrophils plays a crucial role in pulmonary ALI. Additionally, there was a significant increase in signaling intensity between B cells and M1 macrophages, NKT cells and M1 macrophages in extrapulmonary ALI. The CXCL, CSF3 and MIF, TGFß signaling pathways play a vital role in pulmonary and extrapulmonary ALI, respectively. Moreover, the analysis of human single-cell revealed DCs signaling to monocytes and neutrophils in COVID-19-associated ARDS is stronger compared to sepsis-related ARDS. In sepsis-related ARDS, CD8+ T and Th cells exhibit more prominent signaling to B-cell nucleated DCs. Meanwhile, both MIF and CXCL signaling pathways are specific to sepsis-related ARDS. Conclusion: This study has identified specific gene signatures and signaling pathways in animal models and human samples that facilitate the interaction between immune cells, which could be targeted therapeutically in ARDS patients of various etiologies.

The impact of delayed tracheostomy on critically ill patients receiving mechanical ventilation: a retrospective cohort study in a chinese tertiary hospital.

OBJECTIVES: The timing of tracheostomy for critically ill patients on mechanical ventilation (MV) is a topic of controversy. Our objective was to determine the most suitable timing for tracheostomy in patients undergoing MV. DESIGN: Retrospective cohort study. SETTING AND PARTICIPANTS: One thousand eight hundred eighty-four hospitalisations received tracheostomy from January 2011 to December 2020 in a Chinese tertiary hospital. METHODS: Tracheostomy timing was divided into three groups: early tracheostomy (ET), intermediate tracheostomy (IMT), and late tracheostomy (LT), based on the duration from tracheal intubation to tracheostomy. We established two criteria to classify the timing of tracheostomy for data analysis: Criteria I (ET ≤ 5 days, 5 days < IMT ≤ 10 days, LT > 10 days) and Criteria II (ET ≤ 7 days, 7 days < IMT ≤ 14 days, LT > 14 days). Parameters such as length of ICU stay, length of hospital stay, and duration of MV were used to evaluate outcomes. Additionally, the outcomes were categorized as good prognosis, poor prognosis, and death based on the manner of hospital discharge. Student's t-test, analysis of variance (ANOVA), Mann-Whitney U test, Kruskal-Wallis test, Chi-square test, and Fisher's exact test were employed as appropriate to assess differences in demographic data and individual characteristics among the ET, IMT, and LT groups. Univariate Cox regression model and multivariable Cox proportional hazards regression model were utilized to determine whether delaying tracheostomy would increase the risk of death. RESULTS: In both of two criterion, patients with delayed tracheostomies had longer hospital stays (p < 0.001), ICU stays (p < 0.001), total time receiving MV (p < 0.001), time receiving MV before tracheostomy (p < 0.001), time receiving MV after tracheostomy (p < 0.001), and sedation durations. Similar results were also found in sub-population diagnosed as trauma, neurogenic or digestive disorders. Multinomial Logistic regression identified LT was independently associated with poor prognosis, whereas ET conferred no clinical benefits compared with IMT. CONCLUSIONS: In a mixed ICU population, delayed tracheostomy prolonged ICU and hospital stays, sedation durations, and time receiving MV. Multinomial logistic regression analysis identified delayed tracheostomies as independently correlated with worse outcomes. TRIAL REGISTRATION: ChiCTR2100043905. Registered 05 March 2021. http://www.chictr.org.cn/listbycreater.aspx.

NETs Promote Inflammatory Injury by Activating cGAS-STING Pathway in Acute Lung Injury.

Acute respiratory distress syndrome (ARDS) threatens the survival of critically ill patients, the mechanisms of which are still unclear. Neutrophil extracellular traps (NETs) released by activated neutrophils play a critical role in inflammatory injury. We investigated the role of NETs and the underlying mechanism involved in acute lung injury (ALI). We found a higher expression of NETs and cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) in the airways, which was reduced by Deoxyribonuclease I (DNase I) in ALI. The administration of the STING inhibitor H-151 also significantly relieved inflammatory lung injury, but failed to affect the high expression of NETs in ALI. We isolated murine neutrophils from bone marrow and acquired human neutrophils by inducing HL-60 to differentiate. After the PMA interventions, exogenous NETs were obtained from such extracted neutrophils. Exogenous NETs intervention in vitro and in vivo resulted in airway injury, and such inflammatory lung injury was reversed upon degrading NETs with or inhibiting cGAS-STING with H-151 as well as siRNA STING. In conclusion, cGAS-STING participates in regulating NETs-mediated inflammatory pulmonary injury, which is expected to be a new therapeutic target for ARDS/ALI.

Neutrophil extracellular traps and their implications in airway inflammatory diseases.

Neutrophil extracellular traps (NETs) are essential for immune defense and have been increasingly recognized for their role in infection and inflammation. In the context of airway inflammatory diseases, there is growing evidence suggesting the involvement and significance of NETs. This review aims to provide an overview of the formation mechanisms and components of NETs and their impact on various airway inflammatory diseases, including acute lung injury/ARDS, asthma, chronic obstructive pulmonary disease (COPD) and cystic fibrosis. By understanding the role of NETs in airway inflammation, we can gain valuable insights into the underlying pathogenesis of these diseases and identify potential targets for future therapeutic strategies that either target NETs formation or modulate their harmful effects. Further research is warranted to elucidate the complex interactions between NETs and airway inflammation and to develop targeted therapies that can effectively mitigate their detrimental effects while preserving their beneficial functions in host defense.

The effect of renin-angiotensin-aldosterone system inhibitors in patients with hypertension and COVID-19: A meta-analysis of randomized controlled trials and propensity score-matched studies.

Background: High-quality evidence for whether the use of renin-angiotensin-aldosterone system (RAAS) inhibitors worsens clinical outcomes for patients with coronavirus disease 2019 (COVID-19) is lacking. The present study aimed to evaluate the effect of RAAS inhibitors on disease severity and mortality in patients with hypertension and COVID-19 using randomized controlled trials (RCTs) and propensity score-matched (PSM) studies. Methods: A literature search was conducted with PubMed, Embase, and Scopus databases from 31 December 2019 to 10 January 2022. We included RCTs and PSM studies comparing the risk of severe illness or mortality in patients with hypertension and COVID-19 treated or not treated with RAAS inhibitors. Individual trial data were combined to estimate the pooled odds ratio (OR) with a random-effects model. Results: A total of 17 studies (4 RCTs and 13 PSM studies) were included in the meta-analysis. The use of RAAS inhibitors was not associated with an increased risk of severe illness (OR=1.00, 95% confidence interval [CI]: 0.88-1.14, I2=28%) or mortality (OR=0.96, 95% CI: 0.83-1.11, I2=16%) for patients with hypertension and COVID-19. Furthermore, there was no significant difference in the severity of COVID-19 when patients continued or discontinued treatment with RAAS inhibitors (OR=1.01, 95% CI: 0.78-1.29, I2=0%). Conclusions: This study suggests that there was no association between treatment with RAAS inhibitors and worsened COVID-19 disease outcomes. Our findings support the current guidelines that RAAS inhibitors should be continued in the setting of the COVID-19 pandemic. However, the benefit of RAAS inhibitor medications for COVID-19 patients should be further validated with more RCTs.

Microbiology and Outcomes of Institutionalized Patients With Stroke-Associated Pneumonia: An Observational Cohort Study.

Background: The attributable mortality and microbial etiology of stroke-associated pneumonia (SAP) vary among different studies and were inconsistent. Purpose: To determine the microbiology and outcomes of SAP in the lower respiratory tract (LRT) for patients with invasive mechanical ventilation (MV). Methods: In this observational study, included patients were divided into SAP and non-SAP based on a comprehensive analysis of symptom, imaging, and laboratory results. Baseline characteristics, clinical characteristics, microbiology, and outcomes were recorded and evaluated. Results: Of 200 patients, 42.5% developed SAP after the onset of stroke, and they had a lower proportion of non-smokers (p = 0.002), lower GCS score (p < 0.001), higher serum CRP (p < 0.001) at ICU admission, and a higher proportion of males (p < 0.001) and hypertension (p = 0.039) than patients with non-SAP. Gram-negative aerobic bacilli were the predominant organisms isolated (78.8%), followed by Gram-positive aerobic cocci (29.4%). The main pathogens included K. pneumoniae, S. aureus, H. influenzae, A. baumannii, P. aeruginosa, E. aerogenes, Serratia marcescens, and Burkholderia cepacia. SAP prolonged length of MV (p < 0.001), duration of ICU stay (p < 0.001) and hospital stay (p = 0.027), shortened MV-free days by 28 (p < 0.001), and caused elevated vasopressor application (p = 0.001) and 60-day mortality (p = 0.001). Logistic regression analysis suggested that patients with coma (p < 0.001) have a higher risk of developing SAP. Conclusion: The microbiology of SAP is similar to early phase of HAP and VAP. SAP prolongs the duration of MV and length of ICU and hospital stays, but also markedly increases 60-day mortality.

National Early Warning Score Does Not Accurately Predict Mortality for Patients With Infection Outside the Intensive Care Unit: A Systematic Review and Meta-Analysis.

Background: The prognostic value of the national early warning score (NEWS) in patients with infections remains controversial. We aimed to evaluate the prognostic accuracy of NEWS for prediction of in-hospital mortality in patients with infections outside the intensive care unit (ICU). Methods: We searched PubMed, Embase, and Scopus for related articles from January 2012 to April 2021. Sensitivity, specificity, and likelihood ratios were pooled by using the bivariate random-effects model. Overall prognostic performance was summarized by using the area under the curve (AUC). We performed subgroup analyses to assess the prognostic accuracy of NEWS in selected populations. Results: A total of 21 studies with 107,008 participants were included. The pooled sensitivity and specificity of NEWS were 0.71 and 0.60. The pooled AUC of NEWS was 0.70, which was similar to quick sequential organ failure assessment (qSOFA, AUC: 0.70) and better than systemic inflammatory response syndrome (SIRS, AUC: 0.60). However, the sensitivity (0.55) and AUC (0.63) of NEWS were poor in elder patients. The NEWS of 5 was more sensitive, which was a better threshold for activating urgent assessment and treatment. Conclusions: The NEWS had good diagnostic accuracy for early prediction of mortality in patients with infections outside the ICU, and the sensitivity and specificity were more moderate when compared with qSOFA and SIRS. Insufficient sensitivity and poor performance in the elder population may have limitations as an early warning score for adverse outcomes. NEWS should be used for continuous monitoring rather than a single time point predictive tool.

The Prognostic Accuracy of National Early Warning Score 2 on Predicting Clinical Deterioration for Patients With COVID-19: A Systematic Review and Meta-Analysis.

Background: During the coronavirus disease 2019 (COVID-19) pandemic, the National Early Warning Score 2 (NEWS2) is recommended for the risk stratification of COVID-19 patients, but little is known about its ability to detect severe cases. Therefore, our purpose is to assess the prognostic accuracy of NEWS2 on predicting clinical deterioration for patients with COVID-19. Methods: We searched PubMed, Embase, Scopus, and the Cochrane Library from December 2019 to March 2021. Clinical deterioration was defined as the need for intensive respiratory support, admission to the intensive care unit, or in-hospital death. Sensitivity, specificity, and likelihood ratios were pooled by using the bivariate random-effects model. Overall prognostic performance was summarized by using the area under the curve (AUC). We performed subgroup analyses to assess the prognostic accuracy of NEWS2 in different conditions. Results: Eighteen studies with 6,922 participants were included. The NEWS2 of five or more was commonly used for predicting clinical deterioration. The pooled sensitivity, specificity, and AUC were 0.82, 0.67, and 0.82, respectively. Benefitting from adding a new SpO2 scoring scale for patients with hypercapnic respiratory failure, the NEWS2 showed better sensitivity (0.82 vs. 0.75) and discrimination (0.82 vs. 0.76) than the original NEWS. In addition, the NEWS2 was a sensitive method (sensitivity: 0.88) for predicting short-term deterioration within 72 h. Conclusions: The NEWS2 had moderate sensitivity and specificity in predicting the deterioration of patients with COVID-19. Our results support the use of NEWS2 monitoring as a sensitive method to initially assess COVID-19 patients at hospital admission, although it has a relatively high false-trigger rate. Our findings indicated that the development of enhanced or modified NEWS may be necessary.

IL-17-Mediated Inflammation Promotes Cigarette Smoke-Induced Genomic Instability.

(1) Background: Chronic inflammation has been regarded as a risk factor for the onset and progression of human cancer, but the critical molecular mechanisms underlying this pathological process have yet to be elucidated. (2) Methods: In this study, we investigated whether interleukin (IL)-17-mediated inflammation was involved in cigarette smoke-induced genomic instability. (3) Results: Higher levels of both IL-17 and the DNA damage response (DDR) were found in the lung tissues of smokers than in those of non-smokers. Similarly, elevated levels of IL-17 and the DDR were observed in mice after cigarette smoke exposure, and a positive correlation was observed between IL-17 expression and the DDR. In line with these observations, the DDR in the mouse lung was diminished in IL-17 KO when exposed to cigarette smoke. Besides this, the treatment of human bronchial epithelium cells with IL-17 led to increased levels of the DDR and chromosome breakage. (4) Conclusions: These results suggest that cigarette smoke induces genomic instability at least partially through IL-17-mediated inflammation, implying that IL-17 could play an important role in the development of lung cancer.

Do probiotics help prevent ventilator-associated pneumonia in critically ill patients? A systematic review with meta-analysis.

BACKGROUND: Probiotic treatments might contribute to the prevention of ventilator-associated pneumonia (VAP). Due to its unclear clinical effects, here we intend to assess the preventive effect and safety of probiotics on intensive care unit (ICU) patients. METHODS: Eligible randomised controlled trials were selected in databases until 30 September 2019. The characteristics of the studies were extracted, including study design, definition of VAP, probiotics intervention, category of included patients, incidence of VAP, mortality, duration of mechanical ventilation (MV) and ICU stay. Heterogeneity was evaluated by Chi-squared and I2 tests. RESULTS: 15 studies involving 2039 patients were identified for analysis. The pooled analysis suggests significant reduction on VAP (risk ratio, 0.68; 95% Cl, 0.60 to 0.77; p<0.00001) in a fixed-effects model. Subgroup analyses performed on the category of clinical and microbiological criteria both support the above conclusion; however, there were no significant differences in duration of MV or length of ICU stay in a random-effects model. Also, no significant differences in total mortality, overall mortality, 28-day mortality or 90-day mortality were found in the fixed-effects model. CONCLUSIONS: The probiotics helped to prevent VAP without impacting the duration of MV, length of ICU stay or mortality.

Clinical characteristics, risk factors and outcomes of mixed Candida albicans/bacterial bloodstream infections.

PURPOSE: The purpose of this study was to explore the clinical features, risk factors, and outcomes of mixed Candida albicans/bacterial bloodstream infections (mixed-CA/B-BSIs) compared with monomicrobial Candida albicans bloodstream infection (mono-CA-BSI) in adult patients in China. METHODS: All hospitalized adults with Candida albicans bloodstream infection (CA-BSI) were recruited for this retrospective observational study from January 1, 2013, to December 31, 2018. RESULTS: Of the 117 patients with CA-BSI, 24 patients (20.5%) had mixed-CA/B-BSIs. The most common copathogens were coagulase-negative Staphylococcus (CNS) (24.0%), followed by Klebsiella pneumoniae (20.0%) and Staphylococcus aureus (16.0%). In the multivariable analysis, a prior ICU stay > 2 days (adjusted odds ratio [OR], 7.445; 95% confidence interval [CI], 1.152-48.132) was an independent risk factor for mixed-CA/B-BSIs. Compared with patients with mono-CA-BSI, patients with mixed-CA/B-BSIs had a prolonged length of mechanical ventilation [17.5 (4.5, 34.8) vs. 3.0 (0.0, 24.5), p = 0.019] and prolonged length of ICU stay [22.0 (14.3, 42.2) vs. 8.0 (0.0, 31.5), p = 0.010]; however, mortality was not significantly different. CONCLUSIONS: There was a high rate of mixed-CA/B-BSIs cases among CA-BSI cases, and CNS was the predominant coexisting species. A prior ICU stay > 2 days was an independent risk factor for mixed -CA/B-BSIs. Although there was no difference in mortality, the outcomes of patients with mixed -CA/B-BSIs, including prolonged length of mechanical ventilation and prolonged length of ICU stay, were worse than those with mono-CA-BSI; this deserves further attention from clinicians.

The Potential Intermediate Hosts for SARS-CoV-2.

The coronavirus disease 19 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has become a global pandemic since the first report in Wuhan. COVID-19 is a zoonotic disease and the natural reservoir of SARS-CoV-2 seems to be bats. However, the intermediate host explaining the transmission and evolvement is still unclear. In addition to the wildlife which has access to contact with bats in the natural ecological environment and then infects humans in wildlife market, domestic animals are also able to establish themselves as the intermediate host after infected by SARS-CoV-2. Although recent studies related to SARS-CoV-2 have made a lot of progress, many critical issues are still unaddressed. Here, we reviewed findings regarding the investigations of the intermediate host, which may inspire future investigators and provide them with plenty of information. The results demonstrate the critical role of the intermediate host in the transmission chain of SARS-CoV-2, and the efficient intervention on this basis may be useful to prevent further deterioration of COVID-19.

Neurogenic pulmonary edema following acute stroke: The progress and perspective.

Neurogenic pulmonary edema (NPE) following acute stroke is an acute respiratory distress syndrome (ARDS) with clinical characteristics that include acute onset, apparent pulmonary interstitial fluid infiltration and rapid resolution. The pathological process of NPE centers on sympathetic stimulation and fulminant release of catecholamines, which cause contraction of resistance vessels. Elevated systemic resistance forces fluid into pulmonary circulation, while pulmonary circulation overload induces pulmonary capillary pressure that elevates, and in turn damages the alveolar capillary barrier. Damage to the alveolar capillary barrier leads to pulmonary ventilation disorder, blood perfusion disorder and oxygenation disorder. Eventually, NPE will cause post-stroke patients' prognosis to further deteriorate. At present, we lack specific biological diagnostic indicators and a meticulously unified diagnostic criterion, and this results in a situation in which many patients are not recognized quickly and/or diagnosed accurately. There are no drugs that are effective against NPE. Therefore, understanding how to diagnose NPE early by identifying the risk factors and how to apply appropriate treatment to avoid a deteriorating prognosis are important scientific goals. We will elaborate the progress of NPE after acute stroke in terms of its pathophysiological mechanisms, etiology, epidemiology, clinical diagnosis and early prediction, comprehensive treatment strategies, and novel drug development. We also propose our own thinking and prospects regarding NPE.

[Progress of neutrophil extracellular traps in airway inflammation of acute lung injury/acute respiratory distress syndrome: Review].

Acute lung injury (ALI) or acute respiratory distress syndrome (ARDS) is defined as pulmonary diffuse inflammatory injury characterized by acute onset and progressive exacerbation, which is caused by various factors and leads to respiratory insufficiency or respiratory failure eventually. In response to a variety of stimulis, activated neutrophils can release many components including genomic DNA, histones, myeloperoxidase, neutrophil elastase, citrullinated histones, and cathepsins to the inflammatory environment. All the above substances constitute a fibrous meshwork that is named neutrophil extracellular traps (NETs). The overproduction of the NETs is involved in the inflammatory injury in lung tissues. We reviewed the basic features of NETs and its generation mechanism as well as regulatory role in lung inflammation. Besides, we analyzed the components and celluar singal pathway involed in the formation of NETs in order to find appropriate therapeutic targets, which would shed light on developing potential drugs and designing new strategies.

Clinical Characteristics And Risk Factors In Mixed-Enterococcal Bloodstream Infections.

PURPOSE: Although the enterococcal bloodstream infections (EBSI) are often observed in clinic, the mixed-EBSI are few reported. The aim of this study was to investigate the clinical characteristics and risk factors of mixed-EBSI in comparison with monomicrobial EBSI (mono-EBSI). METHODS: A single-center retrospective observational study was performed between Jan 1, 2013 and Dec 31, 2018 in a tertiary hospital. All patients with EBSI were enrolled, and their data were collected by reviewing electronic medical records. RESULTS: A total of 451 patients with EBSI were enrolled including 157 cases (34.8%) with mixed-EBSI. The most common co-pathogens were Coagulase-negative Staphylococcus (26.86%), followed by Acinetobacter baumannii (23.43%) and Klebsiella pneumoniae (8.57%). In multivariable analysis, burn injury (adjusted odds ratio [aOR], 7.39; 95% confidence interval [CI], 2.69-20.28), and length of prior hospital stay (aOR, 1.01; 95% CI, 1.00-1.02) were associated with mixed-EBSI. Patients with mixed-EBSI developed with more proportion of septic shock (19% vs. 31.8%, p=0.002), prolonged length of intensive care unit (ICU) stay [9(0,25) vs. 15(2.5,36), p<0.001] and hospital stay [29(16,49) vs. 33(18.5,63), p=0.031]. The mortality was not significantly different between mixed-EBSI and mono-EBSI (p=0.219). CONCLUSION: A high rate of mixed-EBSI is among EBSI, and Acinetobacter baumannii is the second predominant co-existed species, except for Coagulase-negative Staphylococcus. Burn injury and length of prior hospital stay are independent risk factors for mixed-EBSI. Although the mortality is not different, patients with mixed-EBSI might have poor outcomes in comparison with mono-EBSI, which merits more attention by physicians in the future.

The efficacy and safety of azithromycin in asthma: A systematic review.

Azithromycin is a potential therapeutic choice for asthma control, which is a heterogeneous airway inflammatory disease. Because of variable findings, we intend to evaluate the therapeutic effect and safety of azithromycin in asthma. Databases, including PubMed, EMBASE, Cochrane, and CNKI until 31 December 2017, were searched to identify available randomised controlled trials regarding azithromycin treatment for asthma. We identified seven studies involving 1520 cases that met our criteria. The mean difference for lung function (FEV1 , FVC, PEF), symptom assessment (ACQ, AQLQ), airway inflammation, and risk ratios for adverse events were extracted. Chi-square and I2 tests were applied to evaluate the heterogeneity among the studies towards each index with a random effect model or a fixed effect model. Pooled analysis shows that azithromycin administration results in no significant improvement in FEV1 (MD: 0.09, 95% CI -0.10 to 0.29, P = 0.36), PEF (MD: 11.76; 95% CI, -2.86 to 26.38, P = 0.11), total airway inflammatory cells (MD: -0.29; 95% CI, -1.38 to 0.80, P =  0.60), ACQ (MD: 0.05; 95% CI, -0.08 to 0.19, P = 0.44), and AQLQ (MD: 0.12; 95% CI, -0.02 to 0.26, P =  0.10). Moreover, no significant difference was detected in adverse events (Risk ratio 0.99; 95% CI, 0.82-1.19, P = 0.90). These findings demonstrate no beneficial clinical outcome of azithromycin in asthma control, and we propose that further prospective cohorts are warranted.

Nanoformulated ABT-199 to effectively target Bcl-2 at mitochondrial membrane alleviates airway inflammation by inducing apoptosis.

Elimination of airway inflammatory cells is essential for asthma control. As Bcl-2 protein is highly expressed on the mitochondrial outer membrane in inflammatory cells, we chose a Bcl-2 inhibitor, ABT-199, which can inhibit airway inflammation and airway hyperresponsiveness by inducing inflammatory cell apoptosis. Herein, we synthesized a pH-sensitive nanoformulated Bcl-2 inhibitor (Nf-ABT-199) that could specifically deliver ABT-199 to the mitochondria of bronchial inflammatory cells. The proof-of-concept study of an inflammatory cell mitochondria-targeted therapy using Nf-ABT-199 was validated in a mouse model of allergic asthma. Nf-ABT-199 was proven to significantly alleviate airway inflammation by effectively inducing eosinophil apoptosis and inhibiting both inflammatory cell infiltration and mucus hypersecretion. In addition, the nanocarrier or Nf-ABT-199 showed no obvious influence on cell viability, airway epithelial barrier and liver function, implying excellent biocompatibility and with non-toxic effect. The nanoformulated Bcl-2 inhibitor Nf-ABT-199 accumulates in the mitochondria of inflammatory cells and efficiently alleviates allergic asthma.

Endothelial cell-specific anticoagulation reduces inflammation in a mouse model of acute lung injury.

Tissue factor (TF)-dependent coagulation contributes to lung inflammation and the pathogenesis of acute lung injury (ALI). In this study, we explored the roles of targeted endothelial anticoagulation in ALI using two strains of transgenic mice expressing either a membrane-tethered human tissue factor pathway inhibitor (hTFPI) or hirudin fusion protein on CD31+ cells, including vascular endothelial cells (ECs). ALI was induced by intratracheal injection of LPS, and after 24 h the expression of TF and protease-activated receptors (PARs) on EC in lungs were assessed, alongside the extent of inflammation and injury. The expression of TF and PARs on the EC in lungs was upregulated after ALI. In the two strains of transgenic mice, expression of either of hTFPI or hirudin by EC was associated with significant reduction of inflammation, as assessed by the extent of leukocyte infiltration or the levels of proinflammatory cytokines, and promoted survival after LPS-induced ALI. The beneficial outcomes were associated with inhibition of the expression of chemokine CCL2 in lung tissues. The protection observed in the CD31-TFPI-transgenic strain was abolished by injection of an anti-hTFPI antibody, but not by prior engraftment of the transgenic strains with WT bone marrow, confirming that the changes observed were a specific transgenic expression of anticoagulants by EC. These results demonstrate that the inflammation in ALI is TF and thrombin dependent, and that expression of anticoagulants by EC significantly inhibits the development of ALI via repression of leukocyte infiltration, most likely via inhibition of chemokine gradients. These data enhance our understanding of the pathology of ALI and suggest a novel therapeutic strategy for treatment.