ABSTRACT
Objective: To investigate the pathogen distribution and clinical characteristics of acute community-acquired lower respiratory tract infections (CALRTIs). Methods: This was a retrospective study. The clinical data of 218 patients with CALRTIs admitted to Baoding No.1 Central Hospital from December 2021 to December 2022 were retrospectively collected and were divided into two groups according to the results of polymerase chain reaction(PCR) testing using a nasopharyngeal swab: streptococcus pneumoniae positive group(observation group) and non-streptococcus pneumoniae positive group(control group). Clinical symptoms, blood gas analysis indicators were compared between the two groups. Results: Haemophilus influenzae and Staphylococcus aureus, as well as virus and atypical pathogen infection, were the predominant pathogenic bacteria in both groups. No statistically significant differences were observed in the positive rates of sputum smear, sputum culture, respiratory virus detection and atypical pathogen detection between the two groups(P>0.05). However, the control group had a higher detection rate of gram-positive bacteria, gram-negative bacteria and Legionella pneumophila in sputum smears than the observation group, with a statistically significant difference(P<0.05). One death occurred in each group, with no significant difference in mortality and six in each group left the hospital or were transferred due to deterioration, with no significant difference in improved discharge rates. Conclusion: Acute community-acquired lower respiratory tract infections(CALRTIs) take bacteria, viruses and atypical pathogens as its leading pathogenic bacteria. In the treatment of patients with acute CALRTIs, early pathogenic examination should be performed to assist in guiding antibiotic therapy for rapid control, early recovery and ameliorated clinical outcomes.
ABSTRACT
Chronic obstructive pulmonary disease (COPD) and asthma are the most common chronic respiratory diseases. In middle-aged and elderly patients, it is difficult to distinguish between COPD and asthma based on clinical symptoms and pulmonary function examinations in clinical practice. Thus, an accurate and reliable inspection method is required. In this study, we aimed to identify breath biomarkers and evaluate the accuracy of breathomics-based methods for discriminating between COPD and asthma. In this multi-center cross-sectional study, exhaled breath samples were collected from 89 patients with COPD and 73 with asthma and detected on a high-pressure photon ionization time-of-flight mass spectrometry (HPPI-TOFMS) platform from 20 October 2022, to 20 May 2023, in four hospitals. Data analysis was performed from 15 June 2023 to 16 August 2023. The sensitivity, specificity, and accuracy were calculated to assess the overall performance of the volatile organic component (VOC)-based COPD and asthma discrimination models. Potential VOC markers related to COPD and asthma were also analyzed. The age of all participants ranged from to 18-86 years, and 54 (33.3%) were men. The age [median (minimum, maximum)] of COPD and asthma participants were 66.0 (46.0, 86.0), and 44.0 (17.0, 80.0). The male and female ratio of COPD and asthma participants were 14/75 and 40/33, respectively. Based on breathomics feature selection, ten VOCs were identified as COPD and asthma discrimination biomarkers via breath testing. The joint panel of these ten VOCs achieved an area under the curve of 0.843, sensitivity of 75.9%, specificity of 87.5%, and accuracy of 80.0% in COPD and asthma discrimination. Furthermore, the VOCs detected in the breath samples were closely related to the clinical characteristics of COPD and asthma. The VOC-based COPD and asthma discrimination model showed good accuracy, providing a new strategy for clinical diagnosis. Breathomics-based methods may play an important role in the diagnosis of COPD and asthma.
Subject(s)
Asthma , Biomarkers , Breath Tests , Exhalation , Pulmonary Disease, Chronic Obstructive , Volatile Organic Compounds , Humans , Pulmonary Disease, Chronic Obstructive/diagnosis , Pulmonary Disease, Chronic Obstructive/metabolism , Breath Tests/methods , Asthma/diagnosis , Asthma/metabolism , Male , Female , Middle Aged , Aged , Cross-Sectional Studies , Adult , Biomarkers/analysis , Aged, 80 and over , Volatile Organic Compounds/analysis , Young Adult , Diagnosis, Differential , Adolescent , Sensitivity and SpecificityABSTRACT
BACKGROUND: Extensive deposition of extracellular matrix (ECM) in idiopathic pulmonary fibrosis (IPF) is due to hyperactivation and proliferation of pulmonary fibroblasts. However, the exact mechanism is not clear. OBJECTIVE: This study focused on the role of CTBP1 in lung fibroblast function, elaborated its regulation mechanism, and analyzed the relationship between CTBP1 and ZEB1. Meanwhile, the antipulmonary fibrosis effect and its molecular mechanism of Toosendanin were studied. METHODS: Human IPF fibroblast cell lines (LL-97A and LL-29) and normal fibroblast cell lines (LL-24) were cultured in vitro. The cells were stimulated with FCS, PDGF-BB, IGF-1, and TGF-ß1, respectively. BrdU detected cell proliferation. The mRNA expression of CTBP1 and ZEB1 was detected by QRT-PCR. Western blotting was used to detect the expression of COL1A1, COL3A1, LN, FN, and α-SMA proteins. An animal model of pulmonary fibrosis was established to analyze the effects of CTBP1 silencing on pulmonary fibrosis and lung function in mice. RESULTS: CTBP1 was up-regulated in IPF lung fibroblasts. Silencing CTBP1 inhibits growth factor-driven proliferation and activation of lung fibroblasts. Overexpression of CTBP1 promotes growth factor-driven proliferation and activation of lung fibroblasts. Silencing CTBP1 reduced the degree of pulmonary fibrosis in mice with pulmonary fibrosis. Western blot, CO-IP, and BrdU assays confirmed that CTBP1 interacts with ZEB1 and promotes the activation of lung fibroblasts. Toosendanin can inhibit the ZEB1/CTBP1protein interaction and further inhibit the progression of pulmonary fibrosis. CONCLUSION: CTBP1 can promote the activation and proliferation of lung fibroblasts through ZEB1. CTBP1 promotes lung fibroblast activation through ZEB1, thereby increasing excessive deposition of ECM and aggravating IPF. Toosendanin may be a potential treatment for pulmonary fibrosis. The results of this study provide a new basis for clarifying the molecular mechanism of pulmonary fibrosis and developing new therapeutic targets.
Subject(s)
Idiopathic Pulmonary Fibrosis , Humans , Mice , Animals , Bromodeoxyuridine/metabolism , Bromodeoxyuridine/pharmacology , Idiopathic Pulmonary Fibrosis/genetics , Lung , Fibroblasts/metabolism , Transforming Growth Factor beta1/metabolism , Transcription Factors/genetics , Transcription Factors/metabolism , Intercellular Signaling Peptides and Proteins/metabolism , Zinc Finger E-box-Binding Homeobox 1/genetics , Zinc Finger E-box-Binding Homeobox 1/metabolismABSTRACT
Autophagy mediates PM2.5-related lung injury (LI) and is tightly linked to inflammation and apoptosis processes. IL-37 has been demonstrated to regulate autophagy. This research aimed to examine the involvement of IL-37 in the progression of PM2.5-related LI and assess whether autophagy serves as a mediator for its effects.To create a model of PM2.5-related LI, this research employed a nose-only PM2.5 exposure system and utilized both human IL-37 transgenic mice and wild-type mice. The hIL-37tg mice demonstrated remarkable reductions in pulmonary inflammation and pathological LI compared to the WT mice. Additionally, they exhibited activation of the AKT/mTOR signaling pathway, which served to regulate the levels of autophagy and apoptosis.Furthermore, in vitro experiments revealed a dose-dependent upregulation of autophagy and apoptotic proteins following exposure to PM2.5 DMSO extraction. Simultaneously, p-AKT and p-mTOR expression was found to decrease. However, pretreatment with IL-37 demonstrated a remarkable reduction in the levels of autophagy and apoptotic proteins, along with an elevation of p-AKT and p-mTOR. Interestingly, pretreatment with rapamycin, an autophagy inducer, weakened the therapeutic impact of IL-37. Conversely, the therapeutic impact of IL-37 was enhanced when treated with 3-MA, a potent autophagy inhibitor. Moreover, the inhibitory effect of IL-37 on autophagy was successfully reversed by administering AKT inhibitor MK2206. The findings suggest that IL-37 can inhibit both the inflammatory response and autophagy, leading to the alleviation of PM2.5-related LI. At the molecular level, IL-37 may exert its anti autophagy and anti apoptosis effects by activating the AKT/mTOR signaling pathway.
Subject(s)
Lung Injury , Particulate Matter , Proto-Oncogene Proteins c-akt , Animals , Humans , Mice , Autophagy/drug effects , Interleukins/pharmacology , Lung Injury/chemically induced , Lung Injury/drug therapy , Particulate Matter/toxicity , Proto-Oncogene Proteins c-akt/metabolism , Signal Transduction , TOR Serine-Threonine Kinases/genetics , TOR Serine-Threonine Kinases/metabolismABSTRACT
BACKGROUND: The associations between short- and long-term exposure to ambient fine particulate matter with an aerodynamic diameter ≤ 2.5 µm (PM2.5) and allergic symptoms in middle-aged and elderly populations remain unclear, particularly in China, where most cities have severe air pollution. METHODS: Participants (n = 10,142; age = 40-75 years) were recruited from ten regions in China from 2018 to 2021 for the Predictive Value of Inflammatory Biomarkers and Forced Expiratory Volume in 1 s (FEV1) for Chronic Obstructive Pulmonary Disease (PIFCOPD) study. Short-term (lag0 and lag0-7 day) and long-term (1-, 3- and 5-year) PM2.5 concentrations at residences were extracted from the air pollutant database known as Tracking Air Pollution (TAP) in China. Multivariate logistic regression models were used to estimate associations for short- and long-term PM2.5 exposure concentrations and long-term exposure models were additionally adjusted for short-term deviations. RESULTS: A 10 µg/m3 increase in PM2.5 on the day the allergic symptoms questionnaire was administered (lag0 day) was associated with higher odds of allergic nasal (1.09, 95% CI 1.05, 1.12) and eye symptoms (1.08, 95% CI 1.05, 1.11), worsening dyspnea caused by allergens (1.06, 95% CI 1.02, 1.10), and ≥ 2 allergic symptoms (1.07, 95% CI 1.03, 1.11), which was similar in the lag0-7 day concentrations. A 10 µg/m3 increase in the 1-year average PM2.5 concentration was associated with an increase of 23% for allergic nasal symptoms, 22% for eye symptoms, 20% for worsening dyspnea caused by allergens, and 21% for ≥ 2 allergic symptoms, similar to the 3- and 5-year average PM2.5 concentrations. These associations between long-term PM2.5 concentration and allergic symptoms were generally unchanged after adjustment for short-term deviations. CONCLUSIONS: Short- and long-term exposure to ambient PM2.5 was associated with an increased risk of allergic nasal and eye symptoms, worsening dyspnea caused by allergens, and ≥ 2 allergic symptoms. TRIAL REGISTRATION: Clinical trial ID: NCT03532893 (29 Mar 2018).
Subject(s)
Air Pollutants , Air Pollution , Middle Aged , Humans , Aged , Adult , Particulate Matter/adverse effects , Particulate Matter/analysis , Air Pollutants/adverse effects , Air Pollutants/analysis , Air Pollution/adverse effects , Air Pollution/analysis , China/epidemiology , Dyspnea , Allergens , Environmental Exposure/adverse effects , Environmental Exposure/analysisABSTRACT
Air pollution consisting of fine particulate matter (PM2.5) can induce or aggravate pulmonary inflammatory injury. Irisin has been shown to inhibit inflammation and help to protect against acute kidney, lung or brain injury. However, the role of irisin in lung inflammation after exposure to PM2.5 remains unclear. The aim of this study was to investigate the effect and molecular mechanism of irisin supplementation on in vitro and in vivo models of PM2.5-induced acute lung injuryï¼ALI). C57BL/6 mice and alveolar macrophage cell line (MH-S) were treated with PM2.5. Histopathological examination and FNDC5/ irisin immunofluorescence staining was performed on lung tissue sections. MH-S cell viability was determined by CCK-8 assay. The levels of Nod2, NF-κB p65 and NLRP3 were detected by qRT-PCR and western blotting. The levels of cytokines (IL-1ß, IL-18 and TNF-α) were detected by ELISA. PM2.5 exposure induced increased secretion of pro-inflammatory factors and activation of Nod2, NF-κB p65 and NLRP3 as well as endogenous levels of irisin. In vivo and in vitro inflammation was alleviated by irisin supplementation. Irisin significantly decreased IL-1ß, IL-18, and TNF-α production at both mRNA and protein level. Expression levels of Nod2, NF-κB p65, and NLRP3 were all significantly affected by irisin. In vivo the degree of pulmonary injury and inflammatory infiltration was weakened after irisin administration. In vitro, irisin could inhibit the activation of the NLRP3 inflammasome for a sustained period of 24 h, and its inhibitory ability was gradually enhanced. In conclusion, our findings indicate that irisin can modulate the inflammatory injury of lung tissue caused by PM2.5 through the Nod2/NF-κB signaling pathway, suggesting that irisin can be a candidate for the therapeutic or preventive intervention in acute lung inflammation.
Subject(s)
Acute Lung Injury , Pneumonia , Mice , Animals , NF-kappa B/metabolism , Particulate Matter/adverse effects , Interleukin-18 , Fibronectins/adverse effects , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , Tumor Necrosis Factor-alpha/metabolism , Mice, Inbred C57BL , Signal Transduction , Inflammation/metabolismABSTRACT
Background: PM2.5 exposure is one of the major inducements of various respiratory diseases and related mortality. Meanwhile, irisin, a metabolism and thermogenesis-related hormone, is found to be protective against acute lung injury induced by LPS, which indicates its therapeutic function in lung injury. However, the function and underlying mechanism of irisin in PM2.5-induced acute lung injury (ALI) are still unclear. This study is aimed to discover the potential mechanisms of irisin in PM2.5-induced acute lung injury. Methods: Atg5 deficient mice and cells were established to clarify the relationship between irisin and autophagy in PM2.5-induced ALI. We also used Ad-mCherry-GFP-LC3B as a monitor of autophagy flux to claim the effects of irisin on autophagy. Western blotting and qPCR were used to reveal the molecular mechanism. Results: As a result, PM2.5 exposure induced lung injury whereas mitigated by irisin. Moreover, PM2.5 hampered autophagy flux, characterized by accumulation of p62, and autophagosomes, as well as blocked autolysosomes. Irisin improved the disturbed autophagy flux, which was abrogated by deficiency of Atg5. Additionally, we demonstrated that irisin activated AMPK and inhibited mTOR, which indicated the enhanced autophagy. Moreover, blockage of AMPK by compound C terminated irisin's induction of autophagy in cultured MH-S cells. Conclusion: Our findings reveal that irisin performs protective effects against PM2.5-induced ALI by activating autophagy through AMPK/mTOR signaling pathway.
ABSTRACT
Particulate matter 2.5 (PM2.5)-induced pulmonary inflammation is an important issue worldwide. NLRP3 inflammasome activation has been found to be involved in pulmonary inflammation development. However, whether PM2.5 induces pulmonary inflammation by activating the NLRP3 inflammasome has not yet been fully elucidated. This study researched whether PM2.5 induces the NLRP3 inflammasomes activation to trigger pulmonary inflammation.Mice and MH-S cells were exposed to PM2.5, BOX5, and Rapamycin. Hematoxylin and eosin staining was performed on the lung tissues of mice. M1 macrophage marker CD80 expression in the lung tissues of mice and LC3B expression in MH-S cells was detected by immunofluorescence. IL-1ß level in the lavage fluid and MH-S cells were detected by enzyme-linked immunosorbent assay. Protein expression was detected by Western blot. Autophagy assay in MH-S cells was performed by LC3B-GFP punctae experiment.PM2.5 exposure induced the lung injury of mice and increased NLRP3, P62, Wnt5a, LC3BII/I, and CD80 expression and IL-1ß release in the lung tissues. PM2.5 treatment increased NLRP3, pro-caspase-1, cleaved caspase-1, Pro-IL-1ß, Pro-IL-18, P62, LC3BII/I, and Wnt5a expression, IL-1ß release, and LC3B-GFP punctae in MH-S cells. However, BOX5 treatment counteracted this effect of PM2.5 on lung tissues of mice and MH-S cells. Rapamycin reversed the effect of BOX5 on PM2.5-induced lung tissues of mice and MH-S cells.PM2.5 activated the NLRP3 inflammasome and IL-1ß release in MH-S cells by facilitating the autophagy via activating Wnt5a. The findings of this study provided a new clue for the treatment of pulmonary inflammation caused by PM2.5.
Subject(s)
Inflammasomes , Pneumonia , Humans , Inflammasomes/metabolism , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , Particulate Matter/toxicity , Interleukin-1beta/metabolism , Caspase 1/metabolism , Pneumonia/chemically induced , Pneumonia/metabolism , Autophagy , Sirolimus/adverse effects , Wnt-5a ProteinABSTRACT
Background: Asymptomatic patients are unneglected sources in propagating transmission chain due to their high viral loads. However, treatments available based on symptoms seem not applicable to asymptomatic patients. In this study, the authors want to estimate the effectiveness of Lianhua Qingwen (LH) capsule on asymptomatic coronavirus disease 2019 (COVID-19) patients. Methods: A randomized controlled trial (RCT) was performed to explore the effectiveness and safety of LH capsule in treating asymptomatic COVID-19 patients. Patients were randomized to control group (isolated observation) and treatment group (LH, 4 capsules, thrice daily) for 14 days. The primary endpoints were the rate and time of nucleic acid turning negative during the isolation observation. Results: A total of 120 participants were included in the full analysis set (60 each in the control and treatment groups). Data showed that the rate of nucleic acid turning negative during the isolation observation in the treatment group was higher than that in the control group (rate difference: 21.66%, 95% confidence interval [CI]: 4.34 to 37.27, p = 0.0142). Patients in the treatment group have a shorter time of nucleic acid turning negative (7.5 vs. 14.5 days, p = 0.018). Moreover, the rate of clinical symptoms appearance in the treatment group was lower compared with that in the control group (rate difference: -31.67, 95% CI: -46.83 to -13.82, p = 0.0005). The proportion of confirmed mild and common cases in the treatment group was also lower (35.00% vs. 66.67%, p = 0.0005). No serious adverse events were documented. Conclusions: In this study, the authors illustrated that LH capsule is beneficial to asymptomatic COVID-19 patients. Considering the lack of interventions for treating asymptomatic COVID-19 patients at this stage, LH capsule could be considered as a choice. Chinese Clinical Trial Registry: ChiCTR2100042066.
Subject(s)
COVID-19 Drug Treatment , Drugs, Chinese Herbal , Nucleic Acids , Humans , Drugs, Chinese Herbal/adverse effectsABSTRACT
OBJECTIVE: To explore the roles of macrophages' miR-217-5p in the process of PM2.5 induced acute lung injury. METHODS: GEO database and KEGG pathway enrichment analysis as well as GSEA were used to predicted the miRNA and associated target signals. And then mice and RAW246.7 macrophages treated with PM2.5 to imitate PM2.5 induced acute lung injury environment and then transfected with miR-217-5p NC or miR-217-5p mimic. The levels of inflammatory factors TNF-α and anti-inflammatory factor IL-10 of mice serum were tested by ELISA. And the pathological changes and ROS level of mouse lung tissues were stained by HE and DHE staining. The proteins expression of phosphorylated-STAT1, total-STAT1, TNF-α, IFN-γ as well as p47, gp91, NOX4 in mice or RAW264.7 cells were tested by western blot or immunofluorescence of RAW264.7 cell slides. RESULTS: The results of bioinformatics analysis indicated the miR-217 as well as STAT1 were involved PM2.5 associated lung injury. After exposure to PM2.5, the decreased levels of serum TNF-α but not IL-10, consistent with reduced macrophages' accumulation as well as decreased ROS levels in lung tissues in miR-217-5p mimic group vs miR-217-5p NC group mice, and moreover, the protein expression levels of phosphorylated--STAT1, total-STAT1, TNF-α, IFN-γ, p47, gp91 and NOX4 in mouse lung tissues and RTAW246.7 macrophages cells were all significantly reduced with miR-217-5p mimic administration. The above phenomena were reversed by specific STAT1-inhibitor HY-N8107. CONCLUSIONS: miR-217-5p suppressed the activated STAT1-signal induced inflammation and oxidative stress trigged by PM2.5 in macrophages and resulted in the decreased lung injure caused by PM2.5.
Subject(s)
Acute Lung Injury , MicroRNAs , Acute Lung Injury/metabolism , Animals , Inflammation/metabolism , Lung/metabolism , Macrophages/metabolism , Mice , MicroRNAs/genetics , MicroRNAs/metabolism , Oxidative Stress , Reactive Oxygen Species/metabolism , STAT1 Transcription Factor/genetics , STAT1 Transcription Factor/metabolism , Smog , Tumor Necrosis Factor-alpha/metabolismABSTRACT
OBJECTIVES: Cuffed endotracheal intubation and stent implantation were employed to simulate two types of benign airway stenosis and further to analysis the different features between them from trachecscopic characteristics, gross anatomy to histopathological changes. In addition, our study explored the therapeutic effect of mitomycin C at different concentrations on granulation tissue caused by stent implantation in order to provide a new therapeutic strategy for clinical treatment of benign airway stenosis. METHODS: Twelve beagle dogs were randomly divided into four groups, with three dogs in each group. Group A: Three beagle dogs were intubated through oral trachea after general anesthesia and cuff pressure maintained at 200 mmHg for 24 h. Group B, Group C and Group D: endotracheal coated self-expanding metal stents were placed after general anesthesia under the guidance of bronchoscope. On the Day7 after stent implantation, Group B, as control group, was injected phosphate buffer solution of 1 ml into granulation tissue at the end of stent; Group C was injected mitomycin C of 1 ml at 0.4 mg/ml and Group D was injected mitomycin C of 1 ml at 0.8 mg/ml into granulation tissue at the end of metal airway stent respectively, the same method as Group B. Bronchoscopy was used to observe tracheal lumen on the seventh day, fourteenth day and twenty-first day after modeling and pathological changes were examined on twenty-first day. RESULTS: Two models of benign airway stenosis can be established by cuffed endotracheal intubation and stent implantation. There was tracheal rupture in the trachea cartiage ring in the cuffed endotracheal intubation group, but was't in stent implantation group. Histopathological characteristics were different between cuffed endotracheal intubation and stent implantation groups. In stent placement groups, we found that the stenosis degree of mitomycin C at 0.4 mg/ml was approximately 19%-32%, mitomycin C at 0.8 mg/ml was approximately 16%-21% and the control group was approximately 36%-47%. CONCLUSION: The two models of canine benign tracheal stenosis induced by cuffed endotracheal intubation and stent implantation are relatively simple, reliable and reproducible and have different characteristics. Mitomycin C could inhibit proliferation of granulation tissue and attenuate the degree of airway stenosis caused by stent implantation.
Subject(s)
Trachea , Tracheal Stenosis , Animals , Dogs , Constriction, Pathologic/complications , Intubation, Intratracheal/adverse effects , Intubation, Intratracheal/methods , Mitomycin/pharmacology , Mitomycin/therapeutic use , Rupture/complications , Rupture/drug therapy , Rupture/pathology , Stents/adverse effects , Trachea/pathology , Tracheal Stenosis/etiology , Tracheal Stenosis/therapyABSTRACT
BACKGROUND: Lianhua Qingke (LH) tablets is an effective traditional Chinese medicine against various viral infections, especially in relieving coughing. However, its effects on COVID-19 are unknown. METHODS: To examine the therapeutic effectiveness of LH tablets in COVID-19 patients with mild and common types, a randomized, multicenter, controlled study was carried out. COVID-19 cases were randomized to undergo routine treatment with or without LH tablets (4 tablets, three times a day) for 14 days. The primary endpoints were the rate of achieving clinical symptom resolution and the corresponding time. RESULTS: There were 144 participants in the full analysis set (72 each in the LH and control groups). The LH group participants had elevated symptom alleviation rate at 14 days compared with control cases (FAS: 98.61% vs. 84.72%, p = 0.0026). In comparison with control group participants, the LH group participants had reduced median time to clinical symptom alleviation (median: 4 vs. 7 days, p < 0.0001). Higher resolution rates of coughing (98.44% vs. 84.51%, p = 0.0045) and expectoration (100% vs. 82.35%, p = 0.0268) were observed in the LH group. Times to recovery of fever (median: 2 vs. 3 days, p = 0.0007), coughing (median: 4 vs. 7 days, p < 0.0001), and expectoration (median: 3 vs. 6 days, p < 0.0001) were also notably shorter in the LH group. Moreover, the LH group had elevated improvement rates in chest computed tomography signs (FAS: 86.11% vs. 72.22%, p = 0.0402) and clinical cure at day 28 (FAS: 83.33% vs. 68.06%, p = 0.0326). However, no differences were found in the laboratory test and viral assay. Serious adverse events were not detected. CONCLUSION: These preliminary findings indicate LH tablets may be effective in symptomatic COVID-19, especially in relieving coughing. This trial was registered in Chinese Clinical Trial Registry (ChiCTR2100042069).
ABSTRACT
BACKGROUND: Omalizumab has > 15 years of real-world evidence of effectiveness in Caucasian patients. In August 2017, it was approved as an add-on therapy for the management of moderate-to-severe asthma in China. OBJECTIVE: To compare the efficacy and safety of omalizumab in Chinese and Caucasian patients. METHODS: This analysis included clinical trial data from a Chinese study (NCT01202903) and four studies with predominantly Caucasian patients (008, 009, EXTRA and INNOVATE). The following outcomes were analyzed: change from baseline in morning peak expiratory flow (mPEF), percentage predicted forced expiratory volume in one second (FEV1), patient-reported outcomes (PROs), asthma exacerbation and safety. Further, a population pharmacokinetic/pharmacodynamic (PK/PD) was also assessed. RESULTS: In the Chinese study, omalizumab significantly improved the mPEF from baseline vs placebo at Weeks > 4-8 through > 16-20; however, the change in mPEF did not reach statistical significance at Week 24. A similar trend towards improvement in mPEF was observed in the studies with Caucasians (INNOVATE, 008 and 009). In all studies, omalizumab showed greater improvement in %predicted FEV1, AQLQ score, and GETE score vs placebo. In addition, asthma symptom scores and seasonal exacerbations were lower, especially during winter, in the Chinese study, and was comparable to studies in Caucasians. PK/PD analyses showed that steady-state PK of omalizumab; free or total immunoglobulin E levels were similar in all studies. CONCLUSIONS: The clinical efficacy and safety of omalizumab was comparable among Chinese and Caucasian patients with moderate-to-severe asthma supporting therapeutic effectiveness, irrespective of race, ethnicity and geographical factors.
Subject(s)
Anti-Asthmatic Agents , Asthma , Anti-Asthmatic Agents/adverse effects , Antibodies, Monoclonal, Humanized/therapeutic use , Asthma/drug therapy , Humans , Omalizumab/adverse effects , Randomized Controlled Trials as Topic , Treatment OutcomeABSTRACT
The aim of this study was to investigate the efficacy and underlying mechanism of high concentration of hydrogen on lipopolysaccharide (LPS)-induced acute lung injury (ALI). We have established a corresponding mouse model and examined the function of hydrogen inhalation on lung pathology and pulmonary edema induced by LPS, as well as contents of IL-1ß, TNF-α and IL-8. The pulmonary microvascular permeability and 66.7 % hydrogen on the expression of sirt1 and its downstream signaling molecules were tested. Results showed that 66.7 % hydrogen alleviated lung pathological changes and pulmonary edema caused by LPS, and reduced the degree of ALI by inhibiting pro-inflammatory cytokine release and oxidative stress response, thereby decreasing the expression of molecules related to intercellular adhesion. sirt1 contributed to the repair of LPS-induced ALI by hydrogen through the regulation of NF-κB and catalase expression. In conclusion, 66.7 % hydrogen protected against LPS-induced ALI by suppressing inflammatory response and oxidative stress mediated by NF-κB and catalase in a sirt1-dependent manner.
Subject(s)
Acute Lung Injury/drug therapy , Endothelial Cells/drug effects , Hydrogen/pharmacology , Inflammation/drug therapy , Lung/drug effects , Oxidative Stress/drug effects , Sirtuin 1/drug effects , Acute Lung Injury/chemically induced , Administration, Inhalation , Animals , Disease Models, Animal , Inflammation/chemically induced , Lipopolysaccharides/pharmacology , Lung/blood supply , Male , Mice , MicrovesselsABSTRACT
We have shown in the past studies that fine particulate matter (PM2.5) exposure increases airway hyperresponsiveness and leads to lung inflammation damage. Interleukin (IL)-37 plays a inhibitory role in inflammation activation and maintenance. However, the function of IL-37 in the above processes keep unclear. We aim to explore the role of IL-37 in PM2.5-induced airway hyperresponsiveness in this study. A nose-only PM2.5 online concentration, enrichment and exposure instrument was also applied to generate mice model of airway hyperresponsiveness. A transgenic mice strain using a CMV promoter to express human IL-37b (hIL-37tg) was obtained. PM2.5 exposure was shown to increase airway resistance, followed by lung inflammation and IL-1ß, TNFα, and IL-6 release, which was inhibited by IL-37tg mice and mice administrated recombinant human IL-37 intranasally (i.n). Moreover, expression of the proliferation-related protein PCNA and migration-related proteins MMP-2, MMP-9, and Vimentin was reduced in lung tissues of IL-37tg mice and mice given recombinant human IL-37 i.n. Abnormal cell contraction, proliferation, and migration of human airway smooth muscle cells (hASMCs) incubated with PM2.5 were also decreased by IL-37 treatment. In addition, IL-37 intervention of hASMCs before PM2.5 incubation decreased cytoplasmic calcium level and expression of PCNA, MMP-2, MMP-9 and Vimentin. Finally, knockdown of the IL-37 receptor IL-1R8 gene eliminated the protective effects of IL-37 in the above responses. We conclude that IL-37 inhibits inflammation activation and disease severity of airway hyperreactivity by PM2.5 induction.
Subject(s)
Particulate Matter , Respiratory Hypersensitivity , Animals , Humans , Inflammation/chemically induced , Interleukin-1 , Lung , Mice , Particulate Matter/toxicity , Respiratory Hypersensitivity/chemically induced , Severity of Illness IndexABSTRACT
Epidemiological research has identified that exposure to fine particulate matter (PM2.5) can increase airway hyperresponsiveness (AHR) which is considered a typical characteristic of asthma. Although the effect of PM2.5 on AHR has been elucidated to a certain degree, its exact mechanism remains unclear. Bromodomain-containing protein 4 (BRD4) is recognized as a member of the bromodomain and extraterminal (BET) family, with the ability to maintain higher-order chromatin configuration and regulate gene expression programs. The primary objective of our study was to examine the role of BRD4 in AHR triggered by PM2.5, and to elucidate its possible molecular mechanism. A mouse model with AHR was established using a nose-only PM2.5 exposure system. We observed that PM2.5 enhanced AHR in the experimental group compared to the control group, and this alteration was accompanied by increased lung inflammation and BRD4 expression in bronchi-lung tissue. However, the BRD4 inhibitor (ZL0420) could alleviate the aforementioned alterations in the mouse model with PM2.5 exposure. To explore the exact molecular mechanism, we further examined the role of BRD4 in human airway smooth muscle cells (hASMCs) after exposure to PM2.5 DMSO extracts. We found that PM2.5 DMSO extracts, which promoted the contraction and migration of hASMCs, was accompanied by an increase in the levels of BRD4, kallikrein 14 (KLK14), bradykinin 2 receptor (B2R), matrix metalloproteinases2(MMP-2), matrix metalloproteinases9(MMP-9), vimentin and bradykinin (BK) secretion, while ZL0420 and BRD4 gene silencing could reverse this response. In summary, these results demonstrate that BRD4 is an important player in AHR triggered by PM2.5, and BRD4 inhibition can ameliorate AHR induced by PM2.5. In addition, PM2.5 DMSO extracts can promote the contraction and migration of hASMCs by increasing BRD4 expression.
Subject(s)
Cell Cycle Proteins/metabolism , Particulate Matter/toxicity , Respiratory Hypersensitivity/chemically induced , Transcription Factors/metabolism , Animals , Disease Models, Animal , Humans , Lung/drug effects , Mice , Myocytes, Smooth Muscle/drug effects , Myocytes, Smooth Muscle/pathology , Pneumonia/chemically induced , Respiratory Hypersensitivity/physiopathologyABSTRACT
BACKGROUND: Novel coronavirus disease 2019 (COVID-19) poses a huge threat to the global public health. This study aimed to identify predictive indicators of severe COVID-19. METHODS: We retrospectively collected clinical data on hospital admission of all patients with severe COVID-19 and a control cohort (1:1) of gender- and hospital-matched patients with mild disease from 13 designated hospitals in the Hebei Province between 22 January and 15 April 2020. RESULTS: A total of 104 patients (52 with severe COVID-19 and 52 with mild disease) were included. Only age, fever, duration from symptom onset to confirmation, respiratory rate, percutaneous oxygen saturation (SpO2 ) and neutrophilic percentage were independent predictors of severe COVID-19. Age and neutrophilic percentage performed best in predicting severe COVID-19, followed by SpO2 . 'Age + neutrophilic percentage' (the sum of age and neutrophilic percentage) (area under the curve [AUC] 0.900, 95% confidence interval [CI] 0.825-0.950, P < .001) and 'age and neutrophilic percentage' (the prediction probability of age and neutrophilic percentage for severe type obtained by logistic regression analysis) (AUC 0.899, 95% CI 0.824-0.949, P < .001) had excellent predictive performance for severe type. The optimal cut-off for 'age + neutrophilic percentage' was >119.1 (sensitivity, 86.5%; specificity, 84.6%; Youden index, 0.712). CONCLUSION: The combination of age and neutrophil percentage could effectively predict severe COVID-19. The sum of age and neutrophil percentage was recommended for clinical application because of its excellent predictive value and practicability. TRAIL REGISTRATION: China Clinical Trial Registry, number ChiCTR2000030226. Registered 26 February 2020-Retrospectively registered, http://www.chictr.org.cn/showproj.aspx?proj=49855.
Subject(s)
COVID-19 , China/epidemiology , Humans , Neutrophils , Prognosis , Retrospective Studies , SARS-CoV-2ABSTRACT
Airway hyperresponsiveness (AHR) is characterized by excessive bronchoconstriction in response to nonspecific stimuli, thereby leading to airway stenosis and increased airway resistance. AHR is recognized as a key characteristic of asthma and is associated with significant morbidity. At present, many studies on the molecular mechanisms of AHR have mainly focused on the imbalance in Th1/Th2 cell function and the abnormal contraction of airway smooth muscle cells. However, the specific mechanisms of AHR remain unclear and need to be systematically elaborated. In addition, the effect of air pollution on the respiratory system has become a worldwide concern. To date, numerous studies have indicated that certain concentrations of fine particulate matter (PM2.5) can increase airway responsiveness and induce acute exacerbation of asthma. Of note, the concentration of PM2.5 does correlate with the degree of AHR. Numerous studies exploring the toxicity of PM2.5 have mainly focused on the inflammatory response, oxidative stress, genotoxicity, apoptosis, autophagy, and so on. However, there have been few reviews systematically elaborating the molecular mechanisms by which PM2.5 induces AHR. The present review separately sheds light on the underlying molecular mechanisms of AHR and PM2.5-induced AHR.
Subject(s)
Air Pollution , Asthma , Respiratory Hypersensitivity , Air Pollution/adverse effects , Humans , Lung , Particulate Matter/toxicityABSTRACT
Chronic obstructive pulmonary disease (COPD) is a chronic and devastating condition characterized by poor airflow and breath. Smoking and other environmental factors-caused inflammations triggered excessive autophagy of normal lung epithelial cells, eventually leading to impaired lung functions. Previous studies showed that ghrelin exhibited beneficial effects on patients with COPD. However, the mechanisms underlying this impact remained largely unknown. In this study, in vitro and in vivo models of COPD-associated inflammation were established, and we found that inflammation and autophagy were abonormally activated through nuclear factor kappa b (NF-κB) and activator protein-1 (AP-1) signaling pathways. Interestingly, ghrelin could inhibit the excessive inflammation pathways and autophagy induced by particle matter and/or cigarette extract in bronchial epithelial cells. Furthermore, NF-κB and AP-1 signaling were both inhibited while lung functions were significantly improved. Taken together, identification of downstream signaling of ghrelin in inflammation provided a new avenue in the treatment of COPD.
Subject(s)
Autophagy/drug effects , Ghrelin/pharmacology , Pulmonary Disease, Chronic Obstructive , Animals , Cell Line , Disease Models, Animal , Humans , Inflammation/drug therapy , Inflammation/metabolism , Inflammation/pathology , Mice , NF-kappa B/metabolism , Pulmonary Disease, Chronic Obstructive/drug therapy , Pulmonary Disease, Chronic Obstructive/metabolism , Pulmonary Disease, Chronic Obstructive/pathology , Transcription Factor AP-1/metabolismABSTRACT
Myricetin belongs to the flavonoid family which is derived from plant source. It is well-known for the anti-inflammatory and anti-oxidative properties yet the clinical use of myricetin awaits further discovery. Acute lung injury (ALI) is commonly caused by sepsis which leads to enormous burden with high morbidity and mortality. In this study, a murine sepsis model was constructed by cecal ligation and puncture (CLP). The indicated dose of myricetin (100 mg/kg) was further administrated intragastrically. The survival rate test indicated that myricetin significantly improved the vitality of CLP-operated mice. The pathological changes in morphology, biomarkers of inflammatory response, oxidative stress response, and mitochondrial damage were further detected. Myricetin showed significant inhibitory effects on these changes in CLP-induced mice. Furthermore, expression levels of transcription factor Nrf2 and heme oxygenase-1 (HO-1) along with DNA binding activity of Nrf2 were analyzed by western blot and EMSA, indicating that myricetin positively regulates the Nrf2/HO-1 pathway in CLP-induced sepsis mice. Murine sepsis models with knockdown of Nrf2 and control were further established and suggested that myricetin might exert protective effects on sepsis lung injury in dependent with Nrf2. Our study provides novel mechanisms for the protective effect of myricetin in sepsis-associated acute lung injury.