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Development and multimodal characterization of an elastase-induced emphysema mouse disease model for the COPD frequent bacterial exacerbator phenotype.

ABSTRACT: Chronic obstructive pulmonary disease (COPD) patients undergo infectious exacerbations whose frequency identifies a clinically meaningful phenotype. Mouse models have been mostly used to separately study both COPD and the infectious processes, but a reliable model of the COPD frequent exacerbator phenotype is still lacking. Accordingly, we first established a model of single bacterial exacerbation by nontypeable Haemophilus influenzae (NTHi) infection on mice with emphysema-like lesions. We characterized this single exacerbation model combining both noninvasive in vivo imaging and ex vivo techniques, obtaining longitudinal information about bacterial load and the extent of the developing lesions and host responses. Bacterial load disappeared 48 hours post-infection (hpi). However, lung recovery, measured using tests of pulmonary function and the disappearance of lung inflammation as revealed by micro-computed X-ray tomography, was delayed until 3 weeks post-infection (wpi). Then, to emulate the frequent exacerbator phenotype, we performed two recurrent episodes of NTHi infection on the emphysematous murine lung. Consistent with the amplified infectious insult, bacterial load reduction was now observed 96 hpi, and lung function recovery and disappearance of lesions on anatomical lung images did not happen until 12 wpi. Finally, as a proof of principle of the use of the model, we showed that azithromycin successfully cleared the recurrent infection, confirming this macrolide utility to ameliorate infectious exacerbation. In conclusion, we present a mouse model of recurrent bacterial infection of the emphysematous lung, aimed to facilitate investigating the COPD frequent exacerbator phenotype by providing complementary, dynamic information of both infectious and inflammatory processes.

SUBMITTER: Rodriguez-Arce I

PROVIDER: S-EPMC8276669 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundThe lung microbiome is an inflammatory stimulus whose role in COPD pathogenesis is incompletely understood. We hypothesised that the frequent exacerbator phenotype is associated with decreased α-diversity and increased lung inflammation. Our objective was to assess correlations between the frequent exacerbator phenotype, the microbiome and inflammation longitudinally during exacerbation-free periods.MethodsWe conducted a case-control longitudinal observational study of the frequent exacerbator phenotype and characteristics of the airway microbiome. 81 subjects (41 frequent and 40 infrequent exacerbators) provided nasal, oral and sputum microbiome samples at two visits over 2-4 months. Exacerbation phenotype, relevant clinical factors and sputum cytokine values were associated with microbiome findings.ResultsThe frequent exacerbator phenotype was associated with lower sputum microbiome α-diversity (p=0.0031). This decrease in α-diversity among frequent exacerbators was enhanced when the sputum bacterial culture was positive (p<0.001). Older age was associated with decreased sputum microbiome α-diversity (p=0.0030). Between-visit β-diversity was increased among frequent exacerbators and those who experienced a COPD exacerbation between visits (p=0.025 and p=0.014, respectively). Sputum cytokine values did not differ based on exacerbation phenotype or other clinical characteristics. Interleukin (IL)-17A was negatively associated with α-diversity, while IL-6 and IL-8 were positively associated with α-diversity (p=0.012, p=0.012 and p=0.0496, respectively). IL-22, IL-17A and IL-5 levels were positively associated with Moraxella abundance (p=0.027, p=0.0014 and p=0.0020, respectively).ConclusionsEven during exacerbation-free intervals, the COPD frequent exacerbator phenotype is associated with decreased sputum microbiome α-diversity and increased β-diversity. Decreased sputum microbiome α-diversity and Moraxella abundance are associated with lung inflammation.

Project description:Introduction:Exacerbations of COPD (ECOPDs) are important events in the course of COPD, accelerating the rate of decline in lung function and increasing the mortality risk. A growing body of evidence suggests the significance of the "frequent exacerbator" phenotype. This phenotype seems to be associated with a more severe airflow limitation, symptoms, health-related quality of life impairment, and higher mortality. However, there is no described biomarker that would help to identify this group of patients. Patients and methods:Patients with COPD in "D" GOLD category were monitored for 3 years according to events of ECOPD. Serum samples were collected from the patients. Circulating level of plasma soluble receptor for advanced glycation end-products (sRAGE) was measured using commercially available high sensitivity kits. The receiver operating characteristic (ROC) curve analysis was used to assess the usefulness of sRAGE to identify frequent exacerbator phenotype. Log-rank test was used in the analysis of time to the subsequent exacerbation. Pearson (R) or Spearman's rank (R S) correlation coefficients were used for correlation analysis. Results:Nineteen patients were enrolled. The area under the ROC curve (AUROC) for sRAGE for the identification of frequent exacerbator phenotype was 0.81. Analysis identified the cutoff point as 850.407 pg/mL, characterized by a sensitivity of 0.80 (95% CI: 0.28-1.0) and specificity of 0.93 (95% CI: 0.66-1.0). Additionally, in the group with sRAGE ?850.407 pg/mL, we observed significantly shorter time to the subsequent exacerbation: median of 32 vs 105.5 days (P=0.03). Correlation analysis revealed significant negative correlation between sRAGE and the number of exacerbations requiring hospitalization during the whole time of follow-up (R S=-0.53; P=0.02) and significant positive correlation with FEV1 expressed as the percentage of reference value (R=0.6; P=0.006). Conclusion:sRAGE seems to be useful in the identification of frequent exacerbator phenotype. This parameter may also be used in the prediction of time to ECOPD. Our findings should be confirmed in a sufficiently powered larger sample.

Project description:Chronic obstructive pulmonary disease (COPD) exacerbations accelerate loss of lung function and increased mortality. The complex nature of COPD presents challenges in accurately predicting and understanding frequent exacerbations. The present study aimed to assess the metabolic characteristics of the frequent exacerbation of COPD (COPD‑FE) phenotype, identify potential metabolic biomarkers associated with COPD‑FE risk and evaluate the underlying pathogenic mechanisms. An internal cohort of 30 stable patients with COPD was recruited. A widely targeted metabolomics approach was used to detect and compare serum metabolite expression profiles between patients with COPD‑FE and patients with non‑frequent exacerbation of COPD (COPD‑NE). Bioinformatics analysis was used for pathway enrichment analysis of the identified metabolites. Spearman's correlation analysis assessed the associations between metabolites and clinical indicators, while receiver operating characteristic (ROC) analysis evaluated the ability of metabolites to distinguish between two groups. An external cohort of 20 patients with COPD validated findings from the internal cohort. Out of the 484 detected metabolites, 25 exhibited significant differences between COPD‑FE and COPD‑NE. Metabolomic analysis revealed differences in lipid, energy, amino acid and immunity pathways. Spearman's correlation analysis demonstrated associations between metabolites and clinical indicators of acute exacerbation risk. ROC analysis demonstrated that the area under the curve (AUC) values for D‑fructose 1,6‑bisphosphate (AUC=0.871), arginine (AUC=0.836), L‑2‑hydroxyglutarate (L‑2HG; AUC=0.849), diacylglycerol (DG) (16:0/20:5) (AUC=0.827), DG (16:0/20:4) (AUC=0.818) and carnitine‑C18:2 (AUC=0.804) were >0.8, highlighting their discriminative capacity between the two groups. External validation results demonstrated that DG (16:0/20:5), DG (16:0/20:4), carnitine‑C18:2 and L‑2HG were significantly different between patients with COPD‑FE and those with COPD‑NE. In conclusion, the present study offers insights into early identification, mechanistic understanding and personalized management of the COPD‑FE phenotype.

Project description:Exacerbation frequency is central in treatment strategies for chronic obstructive pulmonary disease. However, whether chronic obstructive pulmonary disease patients from the general population with frequent exacerbations continue to have frequent exacerbations over an extended period of time is currently unknown. In this study, we aimed to investigate the stability of the frequent exacerbator in a population-based setting. To this end, we conducted a nationwide register-based descriptive study with a 10-year follow-up period of chronic obstructive pulmonary disease patients with at least one medically treated exacerbation in 2003. Each subsequent year, we divided the population into frequent, infrequent and non-exacerbators and quantified the flow between categories. Further, we estimated the percentage of frequent exacerbators at baseline who stayed in this category each year during a 5-year follow-up. We identified 19,752 patients with chronic obstructive pulmonary disease and an exacerbation in 2003. Thirty percent were frequent exacerbators. Overall, the majority of exacerbators in 2003 were non-exacerbators in the following years (60% in 2004 increasing to 68% in 2012). Approximately half of frequent exacerbators in one year experienced a decrease in exacerbation frequency and had either zero or one exacerbation in the subsequent year. This pattern was stable throughout follow-up. During a 5-year follow-up period, a substantial proportion (42%) of frequent exacerbators in 2003 had no additional years as frequent exacerbators, while the minority (6%) remained in this category each year. In conclusion, the rate of exacerbations shows considerable variation over time among chronic obstructive pulmonary disease patients in the general population. This might hold implications for chronic obstructive pulmonary disease treatment guidelines and their practical application.Chronic obstructive lung diseaseVARIATIONS IN DISEASE PROGRESSION: Patients with chronic obstructive pulmonary disease (COPD) who suffer from frequent exacerbations do not necessarily persist with such severity over time. Exacerbations in COPD are defined by worsening respiratory symptoms that result in changes to treatment, hospitalization and, at worst, death. However, clarity is needed on whether frequent exacerbations is a stable feature of some patients' disease. Mette Reilev at the University of Southern Denmark and co-workers followed, over 10 years, 19,752 COPD patients living in Denmark who suffered at least one exacerbation in 2003. By 2004, 60% of patients were classed as infrequent or non-exacerbators, rising to 68% by 2012. Very few patients remained "frequent exacerbators", suggesting the rate of exacerbations changes considerably over time. This could hold implications for COPD treatment and challenge assumptions made about disease progression.

Project description:Many experimental models have been proposed to study the pathophysiological features of emphysema, as well as to search for new therapeutic approaches for acute or chronically injured lung parenchyma. We aimed to characterize an emphysema model induced by multiple instillations of elastase by tracking changes in inflammation, remodeling, and cardiac function after each instillation. Forty-eight C57BL/6 mice were randomly assigned across two groups. Emphysema (ELA) animals received 1, 2, 3, or 4 intratracheal instillations of pancreatic porcine elastase (PPE, 0.2 IU) with a 1-week interval between them. Controls (C) received saline following the same protocol. Before and after implementation of the protocol, animals underwent echocardiographic analysis. After the first instillation of PPE, the percentage of mononuclear cells in the lung parenchyma increased compared to C (p = 0.0001). The second instillation resulted in hyperinflated alveoli, increased mean linear intercept, and reduced elastic fiber content in lung parenchyma compared to C (p = 0.0197). Following the third instillation, neutrophils and collagen fiber content in alveolar septa and airways increased, whereas static lung elastance was reduced compared to C (p = 0.0094). After the fourth instillation, the percentage of M1 macrophages in lungs; levels of interleukin-1β (IL-1β), keratinocyte-derived chemokine, hepatocyte growth factor (HGF), and vascular endothelial growth factor (VEGF); and collagen fiber content in the pulmonary vessel wall were increased compared to C (p = 0.0096). At this time point, pulmonary arterial hypertension was apparent, with increased diastolic right ventricular wall thickness. In conclusion, the initial phase of emphysema was characterized by lung inflammation with predominance of mononuclear cells, whereas at the late stage, impairment of pulmonary and cardiovascular functions was observed. This model enables analysis of therapies at different time points during controlled progression of emphysema. Accordingly, early interventions could focus on the inflammatory process, while late interventions should focus on restoring cardiorespiratory function.

Project description:BackgroundChronic obstructive pulmonary disease (COPD) patients with different phenotypes show different clinical characteristics. Therefore, we conducted a meta-analysis to explore the clinical characteristics between the non-exacerbator (NE) phenotype and the frequent exacerbator with chronic bronchitis (FE-CB) phenotype among patients with COPD.MethodsCNKI, Wan fang, Chongqing VIP, China Biology Medicine disc, PubMed, Cochrane Library, and EMBASE databases were searched from the times of their inception to April 30, 2019. All studies that reported the clinical characteristics of the COPD phenotypes and which met the inclusion criteria were included. The quality assessment was analyzed by Cross-Sectional/Prevalence Study Quality recommendations. The meta-analysis was carried out using RevMan5.3.ResultsTen cross-sectional observation studies (n = 8848) were included. Compared with the NE phenotype, patients with the FE-CB phenotype showed significantly lower forced expiratory volume in 1 s percent predicted (FEV1%pred) (mean difference (MD) -8.50, 95% CI -11.36--5.65, P < 0.001, I2 = 91%), forced vital capacity percent predicted (FVC%pred) [MD - 6.69, 95% confidence interval (CI) -7.73--5.65, P < 0.001, I2 = 5%], and forced expiratory volume in 1 s/forced vital capacity (FEV1/FVC) (MD -3.76, 95% CI -4.58--2.95,P < 0.001, I2 = 0%); in contrast, Charlson comorbidity index (MD 0.47, 95% CI 0.37-0.58, P < 0.001, I2 = 0], COPD assessment test (CAT) score (MD 5.61, 95% CI 4.62-6.60, P < 0.001, I2 = 80%), the quantity of cigarettes smoked (pack-years) (MD 3.09, 95% CI 1.60-4.58, P < 0.001, I2 = 41%), exacerbations in previous year (2.65, 95% CI 2.32-2.97, P < 0.001, I2 = 91%), modified Medical British Research Council (mMRC) score (MD 0.72, 95% CI 0.63-0.82, P < 0.001, I2 = 57%), and body mass index (BMI), obstruction, dyspnea, exacerbations (BODEx) (MD 1.78, 95% CI 1.28-2.28, P < 0.001, I2 = 91%), I2 = 34%) were significantly higher in patients with FE-CB phenotype. No significant between-group difference was observed with respect to BMI (MD-0.14, 95% CI -0.70-0.42, P = 0.62, I2 = 75%).ConclusionCOPD patients with the FE-CB phenotype had worse pulmonary function and higher CAT score, mMRC scores, frequency of acute exacerbations, and the quantity of cigarettes smoked (pack-years) than those with the NE phenotype.

Project description:BackgroundThe frequent exacerbator phenotype of acute exacerbations of chronic obstructive pulmonary disease (AECOPD) is characterized by experiencing at least two exacerbations per year, leading to a significant economic burden on healthcare systems worldwide. Although several biomarkers have been shown to be effective in assessing AECOPD severity in recent years, there is a lack of studies on markers to predict the frequent exacerbator phenotype of AECOPD. The current study aimed to develop a new predictive model for the frequent exacerbator phenotype of AECOPD based on rapid, inexpensive, and easily obtained routine markers.MethodsThis was a single-center, retrospective study that enrolled a total of 2,236 AECOPD patients. The participants were divided into two groups based on the frequency of exacerbations: infrequent group (n=1,827) and frequent group (n=409). They underwent a complete blood count, as well as blood biochemistry, blood lipid and coagulation testing, and general characteristics were also recorded. Univariate analysis and binary multivariate logistic regression analyses were used to explore independent risk factors for the frequent exacerbator phenotype of AECOPD, which could be used as components of a new predictive model. The receiver operator characteristic (ROC) curve was used to assess the predictive value of the new model, which consisted of all significant risk factors predicting the primary outcome. The nomogram risk prediction model was established using R software.ResultsAge, gender, length of stay (LOS), neutrophils, monocytes, eosinophils, direct bilirubin (DBil), gamma-glutamyl transferase (GGT), and the glucose-to-lymphocyte ratio (GLR) were independent risk factors for the frequent exacerbator phenotype of AECOPD. The area under the curve (AUC) of the new predictive model was 0.681 [95% confidence interval (CI): 0.653-0.708], and the sensitivity was 63.6% (95% CI: 58.9-68.2%) and the specificity was 65.0% (95% CI: 60.3-69.6%).ConclusionsA new predictive model based on demographic characteristics and blood parameters can be used to predict the frequency of acute exacerbations in the management of chronic obstructive pulmonary disease (COPD).

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Development and multimodal characterization of an elastase-induced emphysema mouse disease model for the COPD frequent bacterial exacerbator phenotype.

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