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2.
Front Oncol ; 11: 758917, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34868972

RESUMO

Background: This study aimed to characterize the bacterial microbiota in the oral cavity (OC), throat, trachea, and distal alveoli of patients with primary malignant tracheal tumors (PMTT), including squamous cell carcinoma (SCC) and salivary gland carcinoma patients (SGC), for comparison with a matched non-malignant tracheal tumor (NMTT) group. Methods: Patients with pathological diagnosis of PMTT and NMTT were included in this study. Saliva, throat swab (TS), trachea protected specimen brush (PSB), and bronchoalveolar lavage fluid (BALF) samples were collected for 16S rRNA gene sequencing. The composition, diversity, and distribution of the microbiota were compared among biogeographic sampling sites and patient groups. The relationship between the genera-level taxon abundance and tracheal tumor types was also investigated to screen for candidate biomarkers. Findings: The most represented phyla in the four sites were Bacteroidetes, Firmicutes, Proteobacteria, and Fusobacteria. In SCC patients, the relative abundance of Bacteroidetes and Firmicutes gradually decreased with increasing depth into the respiratory tract, while the relative abundance of Proteobacteria gradually increased. Bacterial communities at the four biogeographic sites formed two distinct clusters, with OC and TS samples comprising one cluster and PSB and BALF samples comprising the other group. Principal coordinate analysis showed that trachea microbiota in SCC patients were distinct from that of SGC or NMTT patients. In the trachea, AUCs generated by Prevotella and Alloprevotella showed that the abundance of these genera could distinguish SCC patients from both NMTT and SGC patients. Interpretation: The structure of respiratory tract microbiota in PMTT patients is related to tumor type. Certain bacteria could potentially serve as markers of SCC, although verification with large-sample studies is necessary.

3.
Clin Transl Med ; 11(11): e563, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34841721

RESUMO

BACKGROUND: Our previous study shows that Adipose tissue-derived mesenchymal stem cells (ASCs) are a promising strategy for cell-based therapy against pulmonary infection with Pseudomonas aeruginosa (P. aeruginosa), but the underlying mechanisms remain unclear. METHODS: cDNA microarray assay was performed to explore the transcriptome of ASCs primed by P. aeruginosa. Small interfering RNA (siRNA) was constructed to select the receptor candidates for P. aeruginosa recognition and granulocyte-macrophage colony-stimulating factor (GM-CSF) production in ASCs. The soluble protein chimeras containing the extracellular domain of human CD69 fused to the Fc region of human immunoglobulin IgG1 were used as a probe to validate the recognition of P. aeruginosa. The association between CD69 and extracellular regulated protein kinases 1/2 (ERK1/2) was explored via co-immunoprecipitation, siRNA, and inhibitor. The murine models of P. aeruginosa pneumonia treated with WT-ASCs, GM-CSF-/- -ASCs Cd69-/- -ASCs or Erk1-/- -ASCs were used to determine the role of GM-CSF, CD69, and ERK1 in ASCs against P. aeruginosa infection. RESULTS: We showed that C-type lectin receptor CD69 mediated the protective effects of ASCs partly through GM-CSF. CD69 could specifically recognize P. aeruginosa and regulate GM-CSF secretion of ASCs. CD69 regulated the production of GM-CSF via ERK1 in ASCs after P. aeruginosa infection. Moreover, the Administration of ASCs with deficiency of CD69 or ERK1 completely blocked its protective effects in a murine model of P. aeruginosa pneumonia. CONCLUSIONS: CD69 recognizes P. aeruginosa and further facilitates ERK1 activation, which plays a crucial role in ASCs-based therapy against P. aeruginosa pneumonia. CD69 may be a novel target molecule to improve ASCs-based therapy against P. aeruginosa infection.

5.
Front Microbiol ; 12: 725483, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34790176

RESUMO

Glucocorticoids are commonly used for the treatment of asthma and chronic obstructive pulmonary disease (COPD). Inhaled corticosteroids are associated with a significantly increased risk of pneumonia. Syndecan-1 (SDC1) located in the cell membrane of airway epithelial cell is the crucial molecule mediating infections by P. aeruginosa (PA). In the present study, we found that SDC1 expression was upregulated and the adhesion of PA to human bronchial epithelial (HBE) cells increased to 125 and 138%, respectively, after stimulation by dexamethasone or budesonide. The HBE cells knocking down SDC1 showed lower affinity to PA compared with control. CCAAT-enhancer-binding protein ß (C/EBP ß) and its phosphorylated form participated in the regulation of glucocorticoid to SDC1 for interfering C/EBP ß or inhibiting phosphorylation of C/EBP ß by LiCl and BIO, which are inhibitors of glycogen synthase kinase 3ß (GSK-3ß), and could prevent glucocorticoids from upregulating SDC1 expression. One should be cautious in administering glucocorticoids in chronic lung disease because of their property of increasing the expression of SDC1 and PA binding to the airway epithelium.

6.
Pulm Circ ; 11(4): 0271678X20978861, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34603688

RESUMO

Cartilage oligomeric matrix protein (COMP) was a protective factor in the cardiovascular system. Previous studies showed that hypoxia led to decreased COMP in rat models of pulmonary hypertension. However, the expression pattern of COMP in the pulmonary hypertension population was unclear. A total of 35 patients newly diagnosed with pulmonary hypertension and 70 controls were enrolled in the study. Circulating COMP concentrations of serum samples were measured by enzyme-linked immunosorbent assay and were analyzed the association with multiple clinical variables. Serum COMP concentrations in the pulmonary hypertension group were significantly declined in comparison with age- and sex-matched normal controls, especially in the female subgroup. No significant difference of COMP concentrations was observed in the etiological classification, heart function classification, and risk stratification. Major hemodynamic parameters, six-minute walk distance, N-terminal pro brain natriuretic peptide, and short-term prognosis were not statistically associated with COMP. However, some echocardiography parameters, like tricuspid annular plane systolic excursion and mean right atrial pressure, were found the negative relation to COMP concentrations. In conclusion, serum COMP levels were decreased in the patients with pulmonary hypertension, which was in accordance with its known biological effects. Its association with long-term prognosis was worth further exploring.

7.
Genome Biol ; 22(1): 297, 2021 10 22.
Artigo em Inglês | MEDLINE | ID: mdl-34686207

RESUMO

BACKGROUND: Rhinoviruses (RVs) cause more than half of common colds and, in some cases, more severe diseases. Functional genomics analyses of RVs using siRNA or genome-wide CRISPR screen uncovered a limited set of host factors, few of which have proven clinical relevance. RESULTS: Herein, we systematically compare genome-wide CRISPR screen and surface protein-focused CRISPR screen, referred to as surfaceome CRISPR screen, for their efficiencies in identifying RV host factors. We find that surfaceome screen outperforms the genome-wide screen in the success rate of hit identification. Importantly, using the surfaceome screen, we identify olfactomedin-like 3 (OLFML3) as a novel host factor of RV serotypes A and B, including a clinical isolate. We find that OLFML3 is a RV-inducible suppressor of the innate immune response and that OLFML3 antagonizes type I interferon (IFN) signaling in a SOCS3-dependent manner. CONCLUSION: Our study suggests that RV-induced OLFML3 expression is an important mechanism for RV to hijack the immune system and underscores surfaceome CRISPR screen in identifying viral host factors.

8.
EBioMedicine ; 72: 103587, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34537448

RESUMO

BACKGROUND: Persistent cough and large amounts of purulent sputum affects many bronchiectasis patients. No studies have evaluated the efficacy and safety of bronchoscopic airway clearance therapy and bronchoalveolar lavage (B-ACT) for non-cystic fibrosis bronchiectasis patients with acute exacerbation. METHODS: A randomised controlled trial was conducted to explore the efficacy and safety of B-ACT among 189 bronchiectasis inpatients from February 1, 2018 to February 28, 2019. The primary outcome was the time to first acute exacerbation. Secondary outcomes included changes of health-related scores, length of hospital stay, hospitalization expenses and incidences of adverse events. FINDINGS: B-ACT therapy significantly prolonged the median days to first acute exacerbation when compared with control group (198 vs 168 days, HR 0·555 (0·322-0·958), p=0·012; effect size(r)= 0·94). Further analysis showed that B-ACT therapy was more beneficial for these patients with severe disease and greater symptoms. COPD Assessment Test (CAT) scores improved significantly on the third day (5·45 vs 4·85, 0·60 (0·09-1·11), p=0·023), and Leicester Cough Questionnaire (LCQ) scores improved obviously on the third and seventh days (1·53 vs 1·23, 0·30 (0·05-0·55), p=0·044; 1·66 vs 1·32, 0·34 (0·08-0·60), p=0·022; respectively) after B-ACT therapy. Adverse events associated with B-ACT were mostly transient and mild. Differences of the lengths of hospital stay and hospitalization expenses in both group was not significant. INTERPRETATION: B-ACT therapy significantly prolonged the time to first acute exacerbation after discharge, highlighting the importance of B-ACT therapy focused on symptom improvements in preventing exacerbation. FUNDING: National Natural Science Foundation of China. TRIAL REGISTRY: ClinicalTrials.gov; No.:NCT03643302; URL: www.clinicaltrials.gov.

9.
Cell Res ; 31(11): 1148-1162, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34561618

RESUMO

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.


Assuntos
Infecções Assintomáticas , COVID-19/imunologia , Portador Sadio/imunologia , Adulto , Linfócitos B/imunologia , COVID-19/patologia , Feminino , Humanos , Leucócitos Mononucleares/imunologia , Masculino , Células T Matadoras Naturais/imunologia , SARS-CoV-2/fisiologia , Linfócitos T/imunologia
10.
Front Cell Infect Microbiol ; 11: 723666, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34552886

RESUMO

Objective: Risk factors for the development of pneumonia among patients with diabetes mellitus are unclear. The aim of our study was to elucidate the potential risk factors and attempt to predict the probability of pneumonia based on the history of diabetes. Methods: We performed a population-based, prospective multicenter cohort study of 1,043 adult patients with diabetes in China during 2017-2019. Demographic information, comorbidities, or laboratory examinations were collected. Results: The study included 417 diabetic patients with pneumonia and 626 no-pneumonia-onset diabetic patients. The predictive risk factors were chosen on the basis of a multivariate logistic regression model to predict pneumonia among patients with diabetes including male sex [odds ratio (OR) = 1.72, 95% confidence interval (CI): 1.27-2.33, p < 0.001], age ≥ 75 years (OR = 2.31, 95% CI: 1.61-3.31, p < 0.001), body mass index < 25 (OR = 2.59, 95% CI: 1.92-3.50, p < 0.001), chronic obstructive pulmonary disease (OR = 6.58, 95% CI: 2.09-20.7, p = 0.001), hypertension (OR = 4.27, 95% CI: 3.12-5.85, p < 0.001), coronary heart disease (OR = 2.98, 95% CI: 1.61-5.52, p < 0.001), renal failure (OR = 1.82, 95% CI: 1.002-3.29, p = 0.049), cancer (OR = 3.57, 95% CI: 1.80-7.06, p < 0.001), use of insulin (OR = 2.28, 95% CI: 1.60-3.25, p < 0.001), and hemoglobin A1c ≥ 9% (OR = 2.70, 95% CI: 1.89-3.85, p < 0.001). A predictive nomogram was established. This model showed c-statistics of 0.811, and sensitivity and specificity were 0.717 and 0.780, respectively, under cut-off of 125 score. Conclusion: We designed a clinically predictive tool for assessing the risk of pneumonia among adult patients with diabetes. This tool stratifies patients into relevant risk categories and may provide a basis for individually tailored intervention for the purpose of early prevention.


Assuntos
Diabetes Mellitus , Pneumonia , Adulto , Idoso , Estudos de Coortes , Diabetes Mellitus/epidemiologia , Humanos , Masculino , Pneumonia/complicações , Pneumonia/epidemiologia , Prognóstico , Estudos Prospectivos , Estudos Retrospectivos , Fatores de Risco
11.
Sci Bull (Beijing) ; 66(22): 2312-2319, 2021 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-34336365

RESUMO

The presence of antiphospholipid antibodies was shown to be associated with thrombosis in coronavirus disease 2019 (COVID-19) patients. Recently, according to reports from several studies, the vaccine-induced immune thrombotic thrombocytopenia is mediated by anti-platelet factor 4 (PF4)-polyanion complex in adenovirus-vectored COVID-19 vaccine recipients. It is impendent to explore whether inactivated COVID-19 vaccine widely used in China influences prothrombotic autoantibody production and induces thrombosis. In this prospective study, we recruited 406 healthcare workers who received two doses, 21 days apart, of inactivated severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine (BBIBP-CorV, Sinopharm). Paired blood samples taken before vaccination and four weeks after the second vaccination were used in detecting prothrombotic autoantibodies, including anticardiolipin (aCL), anti-ß2 glycoprotein I (aß2GP1), anti-phosphatidylserine/prothrombin (aPS/PT), and anti-PF4-heparin. The seroconversion rate of SARS-CoV-2 specific antibodies was 95.81% (389/406) four weeks after vaccination. None of the subjects had spontaneous thrombosis or thrombocytopenia over a minimum follow-up period of eight weeks. There was no significant difference in the presence of all ten autoantibodies between samples collected before and after vaccination: for aCL, IgG (7 vs. 8, P = 0.76), IgM (41 vs. 44, P = 0.73), IgA (4 vs. 4, P = 1.00); anti-ß2GP1, IgG (7 vs. 6, P = 0.78), IgM (6 vs. 5, P = 0.76), IgA (3 vs. 5, P = 0.72); aPS/PT IgG (0 vs. 0, P = 1.00), IgM (6 vs. 5, P = 0.76); aPF4-heparin (2 vs. 7, P = 0.18), and antinuclear antibody (ANA) (18 vs. 21, P = 0.62). Notably, seven cases presented with anti-PF4-heparin antibodies (range: 1.18-1.79 U/mL) after vaccination, and none of them exhibited any sign of thrombotic disorder. In conclusion, inactivated SARS-CoV-2 vaccine does not influence the profile of antiphospholipid antibody and anti-PF4-heparin antibody nor increase the risk of thrombosis.

12.
J Extracell Vesicles ; 10(10): e12134, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34429860

RESUMO

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.

13.
Genome Med ; 13(1): 119, 2021 07 22.
Artigo em Inglês | MEDLINE | ID: mdl-34294113

RESUMO

BACKGROUND: Klebsiella pneumoniae, as a global priority pathogen, is well known for its capability of acquiring mobile genetic elements that carry resistance and/or virulence genes. Its virulence plasmid, previously deemed nonconjugative and restricted within hypervirulent K. pneumoniae (hvKP), has disseminated into classic K. pneumoniae (cKP), particularly carbapenem-resistant K. pneumoniae (CRKP), which poses alarming challenges to public health. However, the mechanism underlying its transfer from hvKP to CRKP is unclear. METHODS: A total of 28 sequence type (ST) 11 bloodstream infection-causing CRKP strains were collected from Ruijin Hospital in Shanghai, China, and used as recipients in conjugation assays. Transconjugants obtained from conjugation assays were confirmed by XbaI and S1 nuclease pulsed-field gel electrophoresis, PCR detection and/or whole-genome sequencing. The plasmid stability of the transconjugants was evaluated by serial culture. Genetically modified strains and constructed mimic virulence plasmids were employed to investigate the mechanisms underlying mobilization. The level of extracellular polysaccharides was measured by mucoviscosity assays and uronic acid quantification. An in silico analysis of 2608 plasmids derived from 814 completely sequenced K. pneumoniae strains available in GenBank was performed to investigate the distribution of putative helper plasmids and mobilizable virulence plasmids. RESULTS: A nonconjugative virulence plasmid was mobilized by the conjugative plasmid belonging to incompatibility group F (IncF) from the hvKP strain into ST11 CRKP strains under low extracellular polysaccharide-producing conditions or by employing intermediate E. coli strains. The virulence plasmid was mobilized via four modes: transfer alone, cotransfer with the conjugative IncF plasmid, hybrid plasmid formation due to two rounds of single-strand exchanges at specific 28-bp fusion sites or homologous recombination. According to the in silico analysis, 31.8% (242) of the putative helper plasmids and 98.8% (84/85) of the virulence plasmids carry the 28-bp fusion site. All virulence plasmids carry the origin of the transfer site. CONCLUSIONS: The nonconjugative virulence plasmid in ST11 CRKP strains is putatively mobilized from hvKP or E. coli intermediates with the help of conjugative IncF plasmids. Our findings emphasize the importance of raising public awareness of the rapid dissemination of virulence plasmids and the consistent emergence of hypervirulent carbapenem-resistant K. pneumoniae (hv-CRKP) strains.

14.
Microorganisms ; 9(6)2021 05 27.
Artigo em Inglês | MEDLINE | ID: mdl-34072189

RESUMO

Clinical evidence suggests that nebulized colistimethate sodium (CMS) has benefits for treating lower respiratory tract infections caused by multidrug-resistant Gram-negative bacteria (GNB). Colistin is positively charged, while CMS is negatively charged, and both have a high molecular mass and are hydrophilic. These physico-chemical characteristics impair crossing of the alveolo-capillary membrane but enable the disruption of the bacterial wall of GNB and the aggregation of the circulating lipopolysaccharide. Intravenous CMS is rapidly cleared by glomerular filtration and tubular excretion, and 20-25% is spontaneously hydrolyzed to colistin. Urine colistin is substantially reabsorbed by tubular cells and eliminated by biliary excretion. Colistin is a concentration-dependent antibiotic with post-antibiotic and inoculum effects. As CMS conversion to colistin is slower than its renal clearance, intravenous administration can lead to low plasma and lung colistin concentrations that risk treatment failure. Following nebulization of high doses, colistin (200,000 international units/24h) lung tissue concentrations are > five times minimum inhibitory concentration (MIC) of GNB in regions with multiple foci of bronchopneumonia and in the range of MIC breakpoints in regions with confluent pneumonia. Future research should include: (1) experimental studies using lung microdialysis to assess the PK/PD in the interstitial fluid of the lung following nebulization of high doses of colistin; (2) superiority multicenter randomized controlled trials comparing nebulized and intravenous CMS in patients with pandrug-resistant GNB ventilator-associated pneumonia and ventilator-associated tracheobronchitis; (3) non-inferiority multicenter randomized controlled trials comparing nebulized CMS to intravenous new cephalosporines/ß-lactamase inhibitors in patients with extensive drug-resistant GNB ventilator-associated pneumonia and ventilator-associated tracheobronchitis.

15.
Front Public Health ; 9: 646780, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34079783

RESUMO

Background: The COVID-19 pandemic is a significant health threat. Health care worker (HCWs) are at a significant risk of infection which may cause high levels of psychological distress. The aim of this study was to investigate the psychological impact of the COVID-19 on HCWs and factors which were associated with these stresses during the first outbreak in Shanghai. Methods: Between February 9 and 21, 2020, a total of 3,114 frontline HCWs from 26 hospitals in Shanghai completed an online survey. The questionnaire included questions on their sociodemographic characteristics, 15 stress-related questions, and General Health Questionnaire-12 (GHQ-12). Exploratory factor analysis was applied to the 15 stress-related questions which produced four distinct factors for evaluation. Multiple linear regression models were performed to explore the association of personal characteristics with each score of the four factors. Binary logistic analysis was used to explain the association of personal characteristics and these four factors with the GHQ-12. Results: There were 2,691 valid surveys received. The prevalence of emotional distress (defined as GHQ-12 ≥ 12) was noted in 47.7% (95%CI:45.7-49.6%) HCWs. Females (OR = 1.43, 95%CI:1.09-1.86) were more likely to have a psychological distress than males. However, HCWs who work in secondary hospitals (OR = 0.71, 95% CI:0.58-0.87) or had a no contact history (OR = 0.45, 95%CI: 0.35-0.58) were less likely to suffer psychological distress. HCWs who were nurses, married, and had a known contact history were highly likely to have anxiety. HCWs working at tertiary hospitals felt an elevated anxiety regarding the infection, a lack of knowledge, and less protected compared to those who worked at secondary hospitals. Conclusions: Our study shows that the frontline HCWs had a significant psychosocial distress during the COVID-19 outbreak in Shanghai. HCWs felt a lack of knowledge and had feelings of being not protected. It is necessary for hospitals and governments to provide additional trainings and psychological counseling to support the first-line HCWs.


Assuntos
COVID-19 , Pandemias , China/epidemiologia , Estudos Transversais , Surtos de Doenças , Feminino , Pessoal de Saúde , Humanos , Masculino , SARS-CoV-2
16.
Front Pharmacol ; 12: 638556, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33967773

RESUMO

Background: Coronavirus disease 2019 (COVID-19) pandemic is continuing to impact multiple countries worldwide and effective treatment options are still being developed. In this study, we investigate the potential of high-dose intravenous vitamin C (HDIVC) in the prevention of moderate COVID-19 disease aggravation. Methods: In this retrospective before-after case-matched clinical study, we compare the outcome and clinical courses of patients with moderate COVID-19 patients who were treated with an HDIVC protocol (intravenous injection of vitamin C, 100 mg/kg/day, 1 g/h, for 7 days from admission) during a one-month period (between March 18 and april 18, 2020, HDIVC group) with a control group treated without the HDIVC protocol during the preceding two months (January 18 to March 18, 2020). Patients in the two groups were matched in a 1:1 ratio according to age and gender. Results: The HDIVC and control groups each comprised 55 patients. For the primary outcomes, there was a significant difference in the number of patients that evolved from moderate to severe type between the two groups (HDIVC: 4/55 vs. control: 12/55, relative risk [RR] = 0.28 [0.08, 0.93], P = 0.03). Compared to the control group, there was a shorter duration of systemic inflammatory response syndrome (SIRS) (P = 0.0004) during the first week and lower SIRS occurrence (2/21 vs 10/22, P = 0.0086) on Day 7 (6-7 days after admission). In addition, HDIVC group had lower C-reactive protein levels (P = 0.005) and higher number of CD4+ T cells from Day 0 (on admission) to Day 7 (P = 0.04)." The levels of coagulation indicators, including activated partial thromboplastin time and D-dimer were also improved in the HDIVC compared to the control group on Day 7. Conclusion: HDIVC may be beneficial in limiting disease aggravation in the early stage of COVID-19 pneumonia, which may be related to its improvements on the inflammatory response, immune function and coagulation function. Further randomized controlled trials are required to augment these findings.

17.
Cell Prolif ; 54(6): e13046, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33960563

RESUMO

OBJECTIVES: Chronic obstructive pulmonary disease (COPD) is characterized by irreversible lung tissue damage including chronic bronchitis and emphysema, which could further develop into respiratory failure. Many studies have revealed a potential regenerative function of the distal airway stem/progenitor cells (DASCs) after lung injury. MATERIALS AND METHODS: Mouse and human DASCs were expanded, analysed, and engrafted into injured mouse lungs. Single-cell analyses were performed to reveal the differentiation path of the engrafted cells. Finally, human DASCs were transplanted into COPD mice induced by porcine pancreatic elastase (PPE) and lipopolysaccharide (LPS) administration. RESULTS: We showed that isolated mouse and human DASCs could be indefinitely expanded and were able to further differentiate into mature alveolar structures in vitro. Single-cell analysis indicated that the engrafted cells expressed typical cellular markers of type I alveolar cells as well as the specific secreted proteins. Interestingly, transplantation of human DASCs derived from COPD patients into the lungs of NOD-SCID mice with COPD injury repaired the tissue damage and improved the pulmonary function. CONCLUSIONS: The findings demonstrated that functional lung structure could be reconstituted by intrapulmonary transplantation of DASCs, suggesting a potential therapeutic role of DASCs transplantation in treatment for chronic obstructive pulmonary disease.


Assuntos
Pulmão/metabolismo , Doença Pulmonar Obstrutiva Crônica/terapia , Transplante de Células-Tronco , Células-Tronco/metabolismo , Animais , Feminino , Xenoenxertos , Humanos , Pulmão/patologia , Masculino , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Doença Pulmonar Obstrutiva Crônica/metabolismo , Doença Pulmonar Obstrutiva Crônica/patologia , Células-Tronco/patologia
18.
J Allergy Clin Immunol ; 148(6): 1545-1558, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33957164

RESUMO

BACKGROUND: Exosomes have emerged as a vital player in cell-cell communication; however, whether airway epithelial cell (AEC)-generated exosomes participate in asthma development remains unknown. OBJECTIVE: Our aims were to characterize the AEC-secreted exosomes and the potentially functional protein(s) that may contribute to the proinflammatory effects of AEC exosomes in the dendritic cell (DC)-dominant airway allergic models and to confirm their clinical significance in patients with asthma. METHODS: Mice were treated with exosomes derived from house dust mite (HDM)-stimulated AECs (HDM-AEC-EXOs) or monocyte-derived DCs primed by HDM and/or contactin-1 (CNTN1). The numbers of DCs in the lung were determined by flow cytometry. Proteomic analysis of purified HDM-AEC-EXOs was performed. CNTN1 small interfering RNA was designed to probe its role in airway allergy, and γ-secretase inhibitor was used to determine involvement of the Notch pathway. RESULTS: HDM-AEC-EXOs facilitate the recruitment, proliferation, migration, and activation of monocyte-derived DCs in cell culture and in mice. CNTN1 in exosomes is a critical player in asthma pathology. RNA interference-mediated silencing and pharmaceutical inhibitors characterize Notch2 receptor as necessary for relaying the CNTN1 signal to activate TH2 cell/TH17 cell immune response. Studies of patients with asthma also support existence of the CNTN1-Notch2 axis that has been observed in cell and mouse models. CONCLUSION: This study's findings reveal a novel role for CNTN1 in asthma pathogenesis mediated through exosome secretion, indicating a potential strategy for the treatment of allergic airway inflammation.

19.
ACS Biomater Sci Eng ; 7(5): 1817-1826, 2021 05 10.
Artigo em Inglês | MEDLINE | ID: mdl-33966375

RESUMO

Pseudomonas aeruginosa (PA) has emerged as a pressing challenge to pulmonary infection and lung damage. The LL37 peptide is an efficient antimicrobial agent against PA strains, but its application is limited because of fast clearance in vivo, biosafety concerns, and low bioavailability. Thus, an albumin-based nanodrug delivery system with reduction sensitivity was developed by forming intermolecular disulfide bonds to increase in vivo LL37 performance against PA. Cationic LL37 can be efficiently encapsulated via electrostatic interactions to exert improved antimicrobial effects. The LL37 peptide exhibits greater than 48 h of sustained released from LL37 peptide nanoparticles (LL37 PNP), and prolonged antimicrobial effects were noted as the incubation time increased. Levels of inflammatory cytokines secreted by peritoneal macrophages, including TNF-α and IL-6, were reduced significantly after LL37 PNP treatment following PA stimulation, indicating that LL37 PNP inhibits PA growth and exerts anti-inflammatory effects in vitro. In a murine model of acute PA lung infection, LL37 PNP significantly reduced TNF-α and IL-1ß expression and alleviated lung damage. The accelerated clearance of PA indicates that LL37 PNP could improve PA lung infection and the subsequent inflammation response more efficiently compared with free LL37 peptide. In conclusion, this excellent biocompatible LL37 delivery strategy may serve as an alternative approach for the application of new types of clinical treatment in future.


Assuntos
Nanopartículas , Pseudomonas aeruginosa , Albuminas , Animais , Peptídeos Catiônicos Antimicrobianos , Preparações de Ação Retardada , Pulmão , Camundongos
20.
BMC Infect Dis ; 21(1): 398, 2021 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-33926377

RESUMO

BACKGROUND: Secondary hemophagocytic lymphohistiocytosis (sHLH) is a life-threatening hyperinflammatory event and a fatal complication of viral infections. Whether sHLH may also be observed in patients with a cytokine storm induced by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is still uncertain. We aimed to determine the incidence of sHLH in severe COVID-19 patients and evaluate the underlying risk factors. METHOD: Four hundred fifteen severe COVID-19 adult patients were retrospectively assessed for hemophagocytosis score (HScore). A subset of 7 patients were unable to be conclusively scored due to insufficient patient data. RESULTS: In 408 patients, 41 (10.04%) had an HScore ≥169 and were characterized as "suspected sHLH positive". Compared with patients below a HScore threshold of 98, the suspected sHLH positive group had higher D-dimer, total bilirubin, alanine aminotransferase, aspartate aminotransferase, blood urea nitrogen, serum creatinine, triglycerides, ferritin, interleukin-6, C-reactive protein, procalcitonin, lactate dehydrogenase, creatine kinase isoenzyme, troponin, Sequential Organ Failure Assessment (SOFA) score, while leukocyte, hemoglobin, platelets, lymphocyte, fibrinogen, pre-albumin, albumin levels were significantly lower (all P < 0.05). Multivariable logistic regression revealed that high ferritin (>1922.58 ng/mL), low platelets (<101 × 109/L) and high triglycerides (>2.28 mmol/L) were independent risk factors for suspected sHLH in COVID-19 patients. Importantly, COVID-19 patients that were suspected sHLH positive had significantly more multi-organ failure. Additionally, a high HScore (>98) was an independent predictor for mortality in COVID-19. CONCLUSIONS: HScore should be measured as a prognostic biomarker in COVID-19 patients. In particular, it is important that HScore is assessed in patients with high ferritin, triglycerides and low platelets to improve the detection of suspected sHLH.


Assuntos
COVID-19/complicações , Linfo-Histiocitose Hemofagocítica/etiologia , Adulto , Idoso , Aspartato Aminotransferases/sangue , COVID-19/epidemiologia , COVID-19/terapia , China/epidemiologia , Comorbidade , Síndrome da Liberação de Citocina/complicações , Síndrome da Liberação de Citocina/virologia , Feminino , Ferritinas/sangue , Humanos , Incidência , Contagem de Linfócitos , Linfo-Histiocitose Hemofagocítica/epidemiologia , Linfo-Histiocitose Hemofagocítica/mortalidade , Masculino , Pessoa de Meia-Idade , Mortalidade , Estudos Retrospectivos , Fatores de Risco
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