Metabolomic Profiling Reveals Sex Specific Associations with Chronic Obstructive Pulmonary Disease and Emphysema.
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ABSTRACT:
SUBMITTER: Gillenwater LA
PROVIDER: S-EPMC7999201 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Within the chronic obstructive pulmonary disease (COPD) spectrum, lung emphysema presents, as a primarily histopathologic feature, the destruction of pulmonary parenchyma and, accordingly, an increase in the airflow obstruction distal to the terminal bronchiole. Notwithstanding the significant advances in prevention and treatment of symptoms, no effective or curative therapy has been accomplished. In this context, cellular therapy with stem cells (SCs) arises as a new therapeutic approach, with a wide application potential. The purpose of this study is to evaluate the safety of SCs infusion procedure in patients with advanced COPD (stage IV dyspnea). After selection, patients underwent clinical examination and received granulocyte colony-stimulating factor, immediately prior to the bone marrow harvest. The bone marrow mononuclear cells (BMMC) were isolated and infused into a peripheral vein. The 12-month follow-up showed a significant improvement in the quality of life, as well as a clinical stable condition, which suggest a change in the natural process of the disease. Therefore, the proposed methodology in this study for BMMC cell therapy in sufferers of advanced COPD was demonstrated to be free of significant adverse effects. Although a larger sample and a greater follow-up period are needed, it is possible to infer that BMMC cell therapy introduces an unprecedented change in the course or in the natural history of emphysema, inhibiting or slowing the progression of disease. This clinical trial was registered with ClinicalTrials.gov (NCT01110252) and was approved by the Brazilian National Committee of Ethics in Research (registration no. 14764, CONEP report 233/2009).
| S-EPMC3034284 | biostudies-literature
Project description:The major sites of obstruction in chronic obstructive pulmonary disease (COPD) are small airways (<2 mm in diameter). We wanted to determine whether there was a relationship between small-airway obstruction and emphysematous destruction in COPD.We used multidetector computed tomography (CT) to compare the number of airways measuring 2.0 to 2.5 mm in 78 patients who had various stages of COPD, as judged by scoring on the Global Initiative for Chronic Obstructive Lung Disease (GOLD) scale, in isolated lungs removed from patients with COPD who underwent lung transplantation, and in donor (control) lungs. MicroCT was used to measure the extent of emphysema (mean linear intercept), the number of terminal bronchioles per milliliter of lung volume, and the minimum diameters and cross-sectional areas of terminal bronchioles.On multidetector CT, in samples from patients with COPD, as compared with control samples, the number of airways measuring 2.0 to 2.5 mm in diameter was reduced in patients with GOLD stage 1 disease (P=0.001), GOLD stage 2 disease (P=0.02), and GOLD stage 3 or 4 disease (P<0.001). MicroCT of isolated samples of lungs removed from patients with GOLD stage 4 disease showed a reduction of 81 to 99.7% in the total cross-sectional area of terminal bronchioles and a reduction of 72 to 89% in the number of terminal bronchioles (P<0.001). A comparison of the number of terminal bronchioles and dimensions at different levels of emphysematous destruction (i.e., an increasing value for the mean linear intercept) showed that the narrowing and loss of terminal bronchioles preceded emphysematous destruction in COPD (P<0.001).These results show that narrowing and disappearance of small conducting airways before the onset of emphysematous destruction can explain the increased peripheral airway resistance reported in COPD. (Funded by the National Heart, Lung, and Blood Institute and others.).
| S-EPMC3238466 | biostudies-literature
Project description:Endothelial injury is implicated in the pathogenesis of COPD and emphysema; however the role of endothelial progenitor cells (EPCs), a marker of endothelial cell repair, and circulating endothelial cells (CECs), a marker of endothelial cell injury, in COPD and its subphenotypes is unresolved. We hypothesized that endothelial progenitor cell populations would be decreased in COPD and emphysema and that circulating endothelial cells would be increased. Associations with other subphenotypes were examined. The Multi-Ethnic Study of Atherosclerosis COPD Study recruited smokers with COPD and controls age 50-79 years without clinical cardiovascular disease. Endothelial progenitor cell populations (CD34+KDR+ and CD34+KDR+CD133+ cells) and circulating endothelial cells (CD45dimCD31+CD146+CD133-) were measured by flow cytometry. COPD was defined by standard spirometric criteria. Emphysema was assessed qualitatively and quantitatively on CT. Full pulmonary function testing and expiratory CTs were measured in a subset. Among 257 participants, both endothelial progenitor cell populations, and particularly CD34+KDR+ endothelial progenitor cells, were reduced in COPD. The CD34+KDR+CD133+ endothelial progenitor cells were associated inversely with emphysema extent. Both endothelial progenitor cell populations were associated inversely with extent of panlobular emphysema and positively with diffusing capacity. Circulating endothelial cells were not significantly altered in COPD but were inversely associated with pulmonary microvascular blood flow on MRI. There was no consistent association of endothelial progenitor cells or circulating endothelial cells with measures of gas trapping. These data provide evidence that endothelial repair is impaired in COPD and suggest that this pathological process is specific to emphysema.
| S-EPMC5349667 | biostudies-literature
Project description:Rationale: Within chronic obstructive pulmonary disease (COPD), emphysema is characterized by a significant yet partially understood B cell immune component. Objectives: To characterize the transcriptomic signatures from lymphoid follicles (LFs) in ever-smokers without COPD and patients with COPD with varying degrees of emphysema. Methods: Lung sections from 40 patients with COPD and ever-smokers were used for LF proteomic and transcriptomic spatial profiling. Formalin- and O.C.T.-fixed lung samples obtained from biopsies or lung explants were assessed for LF presence. Emphysema measurements were obtained from clinical chest computed tomographic scans. High-confidence transcriptional target intersection analyses were conducted to resolve emphysema-induced transcriptional networks. Measurements and Main Results: Overall, 115 LFs from ever-smokers and Global Initiative for Chronic Obstructive Lung Disease (GOLD) 1-2 and GOLD 3-4 patients were analyzed. No LFs were found in never-smokers. Differential gene expression analysis revealed significantly increased expression of LF assembly and B cell marker genes in subjects with severe emphysema. High-confidence transcriptional analysis revealed activation of an abnormal B cell activity signature in LFs (q-value = 2.56E-111). LFs from patients with GOLD 1-2 COPD with emphysema showed significantly increased expression of genes associated with antigen presentation, inflammation, and B cell activation and proliferation. LFs from patients with GOLD 1-2 COPD without emphysema showed an antiinflammatory profile. The extent of centrilobular emphysema was significantly associated with genes involved in B cell maturation and antibody production. Protein-RNA network analysis showed that LFs in emphysema have a unique signature skewed toward chronic B cell activation. Conclusions: An off-targeted B cell activation within LFs is associated with autoimmune-mediated emphysema pathogenesis.
| S-EPMC10870877 | biostudies-literature
Project description:Genetic variants annotated to the hedgehog interacting protein (HHIP) are robustly associated with chronic obstructive pulmonary disease (COPD). Hhip haploinsufficiency in mice leads to increased susceptibility towards the development of emphysema following exposure to chronic cigarette smoke (CS). To explore the molecular pathways which contribute to increased susceptibility, we performed metabolomic profiling using high performance liquid chromatography tandem mass spectroscopy (LC/MS-MS) on plasma, urine, and lung tissue of Hhip +/- heterozygotes and wild type (Hhip +/+) C57/BL6 mice exposed to either room-air or CS for six months. Univariate comparisons between groups were made with a combined fold change ≥2 and Student's t-test p-value < 0.05 to denote significance; associations with mean alveolar chord length (MACL), a quantitative measure of emphysema, and gene-by-environment interactions were examined using empiric Bayes-mediated linear models. Decreased urinary excretion of cotinine despite comparable plasma levels was observed in Hhip +/- heterozygotes; a strong gene-by-smoking association was also observed. Correlations between MACL and markers of oxidative stress such as urinary methionine sulfoxide were observed in Hhip +/- but not in Hhip +/+ mice. Metabolite set enrichment analyses suggest reduced antioxidant capacity and alterations in macronutrient metabolism contribute to increased susceptibility to chronic CS-induced oxidative stress in Hhip haploinsufficiency states.
| S-EPMC5451406 | biostudies-literature
Project description:BackgroundWith advancing age, the composition of leukocyte subpopulations in peripheral blood is known to change, but how this change differs between men and women and how it relates to frailty is poorly understood. Our aim in this exploratory study was to investigate whether frailty is associated with changes in immune cell subpopulations and whether this differs between men and women. Therefore, we performed in-depth immune cellular profiling by enumerating a total of 37 subpopulations of T cells, B cells, NK cells, monocytes, and neutrophils in peripheral blood of 289 elderly people between 60-87 years of age. Associations between frailty and each immune cell subpopulation were tested separately in men and women and were adjusted for age and CMV serostatus. In addition, a random forest algorithm was used to predict a participant's frailty score based on enumeration of immune cell subpopulations.ResultsIn the association study, frailty was found to be associated with increased numbers of neutrophils in both men and in women. Frailer women, but not men, showed higher numbers of total and CD16- monocytes, and lower numbers of both CD56+ T cells and late differentiated CD4+ TemRA cells. The random forest algorithm confirmed all the findings of the association studies in men and women. In men, the predictive accuracy of the algorithm was too low (5.5%) to warrant additional conclusions on top of the ones derived from the association study. In women however, the predictive accuracy was higher (23.1%), additionally revealing that total T cell numbers and total lymphocyte numbers also contribute in predicting frailty.ConclusionsIn-depth immune cellular profiling revealed consistent associations of frailty with elevated numbers of myeloid cell subpopulations in both men and women. Furthermore, additional associations were found between frailty and lower numbers of some T cell subpopulations, in women only. Thus, our study indicates sex-specific associations of immune subpopulations with frailty. We hope that our study will prompt further investigation into the sex-specific immune mechanisms associated with the development of frailty.
| S-EPMC7310472 | biostudies-literature
Project description:Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease characterized by chronic inflammation, emphysema, airway remodeling, and altered lung function. Despite the canonical classification of COPD as a neutrophilic disease, blood and airway eosinophilia are found in COPD patients. Identifying the tools to assess eosinophilic airway inflammation in COPD models during stable disease and exacerbations will enable the development of novel anti-eosinophilic treatments. We developed different animal models to mimic the pathological features of COPD. Our results show that eosinophils accumulated in the lungs of pancreatic porcine elastase-treated mice, with emphysema arising from the alveolar septa. A lipopolysaccharide challenge significantly increased IL-17 levels and induced a swift change from a type-2 response to an IL-17-driven inflammatory response. However, lipopolysaccharides can exacerbate cigarette smoking-induced airway inflammation dominated by neutrophil infiltration and airway remodeling in COPD models. Our results suggest that eosinophils may be associated with emphysema arising from the alveolar septa, which may be different from the small airway disease-associated emphysema that is dominated by neutrophilic inflammation in cigarette smoke-induced models. The characterization of heterogeneity seen in the COPD-associated inflammatory signature could pave the way for personalized medicine to identify new and effective therapeutic approaches for COPD.
| S-EPMC8689000 | biostudies-literature
Project description:Exercise limitation is common in chronic obstructive pulmonary disease (COPD). We determined the impact of pulmonary emphysema on the physiological response to exercise independent of contemporary measures of COPD severity. Smokers 40-79 years old with COPD underwent computed tomography, pulmonary function tesing, and symptom-limited incremental exercise testing. COPD severity was quantified according to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) by spirometry (GOLD 1-4); and symptom burden and exacerbation risk (GOLD A-D). Emphysema severity was quantified as the percent lung volume <-950 Hounsfield units. Regression models adjusted for age, gender, body size, smoking status, airflow limitation, symptom burden and exacerbation risk. Among 67 COPD subjects (age 67 ± 8 years; 75% male; GOLD 1-4: 11%, 43%, 30%, 16%), median percent emphysema was 11%, and peak power output (PPO) was 61 ± 32 W. Higher percent emphysema independently predicted lower PPO (-24 W per 10% increment in emphysema; 95%CI -41 to -7 W). Throughout exercise, higher percent emphysema predicted 1) higher minute ventilation, ventilatory equivalent for CO2, and heart rate; and 2) lower oxy-hemoglobin saturation, and end-tidal PCO2. Independent of contemporary measures of COPD severity, the extent of pulmonary emphysema predicts lower exercise capacity, ventilatory inefficiency, impaired gas-exchange and increased heart rate response to exercise.
| S-EPMC6200804 | biostudies-other
Project description:BackgroundAirflow limitation in chronic obstructive pulmonary disease (COPD) is caused by a mixture of small airway disease and emphysema, the relative contributions of which may vary among patients. Phenotypes of COPD classified purely based on severity of emphysema are not well defined and may be different from the classic phenotypes of "pink puffers" and "blue bloaters".MethodsTo characterise clinical phenotypes based on severity of emphysema, 274 subjects with COPD were recruited, excluding those with physician-diagnosed bronchial asthma. For all subjects a detailed interview of disease history and symptoms, quality of life (QOL) measurement, blood sampling, pulmonary function tests before and after inhalation of salbutamol (0.4 mg) and high-resolution CT scanning were performed.ResultsSeverity of emphysema visually evaluated varied widely even among subjects with the same stage of disease. No significant differences were noted among three groups of subjects classified by severity of emphysema in age, smoking history, chronic bronchitis symptoms, blood eosinophil count, serum IgE level or bronchodilator response. However, subjects with severe emphysema had significantly lower body mass index (BMI) and poorer QOL scores, evaluated using St George's Respiratory Questionnaire (SGRQ), than those with no/mild emphysema (mean (SD) BMI 21.2 (0.5) vs 23.5 (0.3) kg/m(2), respectively; SGRQ total score 40 (3) vs 28 (2), respectively; p<0.001 for both). These characteristics held true even if subjects with the same degree of airflow limitation were chosen.ConclusionsThe severity of emphysema varies widely even in patients with the same stage of COPD, and chronic bronchitis symptoms are equally distributed irrespective of emphysema severity. Patients with the phenotype in which emphysema predominates have lower BMI and poorer health-related QOL.
| S-EPMC2117136 | biostudies-literature
Project description:Extensive inflammation and apoptosis in structural cells of the lung are responsible for the progression and pathogenesis of chronic obstructive pulmonary disease (COPD). Myotubularin-related protein 14 (MTMR14) has been shown to participate in various biological processes, including apoptosis, inflammation, and autophagy. Nonetheless, the role of MTMR14 in COPD remains elusive. In the present study, we explored the expression of MTMR14 in human lung tissues and investigated the effects of overexpressed MTMR14 on in vitro and in vivo COPD models. Moreover, one of the possible mechanisms of MTMR14 alleviating COPD was explored based on mitochondrial function and mitophagy homeostasis. The results showed that MTMR14 expression was reduced in COPD patients' lungs in comparison to control subjects. MTMR14 overexpression inhibited cigarette smoke extract-induced inflammation and apoptosis and improved mitochondrial function and mitophagy in vitro. Further verification was carried out in COPD model mice. MTMR14 overexpression inhibited lung inflammation and reduced levels of IL-6 and KC in bronchoalveolar lavage fluid, as well as prevented emphysema and a decline in lung function. Furthermore, MTMR14 overexpression improved mitochondrial function and mitophagy to a certain extent. Collectively, our data support the hypothesis that MTMR14 participates in the pathogenesis of COPD. Improving mitochondrial function and mitophagy homeostasis may be one of the mechanisms by which MTMR14 alleviates COPD and may potentially be a novel therapeutic target for COPD.
| S-EPMC8759842 | biostudies-literature