Macrophage chitinase 1 stratifies chronic obstructive lung disease.
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ABSTRACT:
SUBMITTER: Agapov E
PROVIDER: S-EPMC2746984 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Introduction:Tobacco use and other cardiovascular risk factors often accompany chronic obstructive pulmonary disease (COPD). This study derived and validated the Summit Score to predict mortality in people with COPD and cardiovascular risks. Methods:SUMMIT trial subjects (N=16,485) ages 40-80 years with COPD were randomly assigned 50%/50% to derivation (N=8181) and internal validation (N=8304). Three external COPD validations from Intermountain Healthcare included outpatients with cardiovascular risks (N=9251), outpatients without cardiovascular risks (N=8551), and inpatients (N=26,170). Cox regression evaluated 40 predictors of all-cause mortality. SUMMIT treatments including combined fluticasone furoate (FF) 100?g/vilanterol 25?g (VI) were not included in the score. Results:Mortality predictors were FEV1, heart rate, systolic blood pressure, body mass index, age, smoking pack-years, prior COPD hospitalizations, myocardial infarction, heart failure, diabetes, anti-thrombotics, anti-arrhythmics, and xanthines. Combined in the Summit Score (derivation: c=0.668), quartile 4 vs 1 had HR=4.43 in SUMMIT validation (p<0.001, 95% CI=3.27, 6.01, c=0.662) and HR=8.15 in Intermountain cardiovascular risk COPD outpatients (p<0.001, 95% CI=5.86, 11.34, c=0.736), and strongly predicted mortality in the other Intermountain COPD populations. Among all SUMMIT subjects with scores 14-19, FF 100?g/VI 25?g vs placebo had HR=0.76 (p=0.0158, 95% CI=0.61, 0.95), but FF 100?g/VI 25?g was not different from placebo for scores <14 or >19. Conclusion:In this post hoc analysis of SUMMIT trial data, the Summit Score was derived and validated in multiple Intermountain COPD populations. The score was used to identify a subpopulation in which mortality risk was lower for FF 100?g/VI 25?g treatment. Trial Registration:The SUMMIT trial is registered at ClinicalTrials.gov as number NCT01313676.
| S-EPMC7381787 | biostudies-literature
Project description:RationaleInteractions of nontypeable Haemophilus influenzae (NTHI) with macrophages are implicated in the pathogenesis of chronic obstructive pulmonary disease (COPD). However, the immunologic mechanisms that mediate NTHI-macrophage inflammation are poorly understood. Outer membrane protein (OMP) P6 and lipooligosaccharide (LOS) of NTHI are potent immunomodulators. We theorized that alveolar macrophages in COPD possess fundamental immune defects that permit NTHI to evade host responses.ObjectiveTo test this hypothesis, we obtained human alveolar and blood macrophages from exsmokers with COPD, exsmokers without COPD, and nonsmokers.MethodsAlveolar and blood macrophages from each donor were incubated with purified LOS and OMP P6 and with OMP P2 and the total outer membrane preparation (0.1-1 microg/ml).MeasurementsSupernatants (24 h) were assayed for IL-1beta, TNF-alpha, IL-10, IL-12, and IL-8 by multianalyte multiplexed flow cytometry.ResultsComparative induction of COPD and non-COPD alveolar macrophages by LOS and OMP P6 revealed diminished IL-8, TNF-alpha, and IL-1beta responses of COPD alveolar macrophages (p < or = 0.03 for each). COPD alveolar macrophages also had diminished responses to total outer membrane (p < or = 0.03 for each). In contrast, COPD blood macrophages had no significant differences among donor groups in IL-8, TNF-alpha, or IL-1beta responsiveness to NTHI antigens. Diminished IL-12 responses of COPD blood macrophages to NTHI antigens, compared with nonsmokers, could not be independently dissociated from group differences in age and pack-years.ConclusionsThese findings support a paradigm of defective immune responsiveness of alveolar macrophages, but not blood macrophages, in COPD.
| S-EPMC2662920 | biostudies-literature
Project description: Not available
| S-EPMC7068819 | biostudies-literature
Project description:Background: Metabolic plasticity involving shifts between mitochondrial respiration and glycolysis is emerging as a crucial component of efficient innate immune cell responses. Alveolar macrophages (AMs), the most abundant antigen-presenting cells in the lung, are dramatically increased in the lungs of patients with chronic obstructive pulmonary disease (COPD). However, COPD AMs exhibit dysfunctional responses to infection with lower phagocytic ability and impairment of mitochondrial reactive oxygen species (ROS) generation. Little is known about the mitochondrial function or respiration of these cells and whether alterations in their mitochondrial or glycolytic activities may contribute to the pathogenesis of COPD.
2020-04-17 | GSE130928 | GEO
Project description:Identifying protein biomarkers for chronic obstructive pulmonary disease (COPD) has been challenging. Most previous studies have utilized individual proteins or pre-selected protein panels measured in blood samples. To identify COPD protein biomarkers by applying comprehensive mass spectrometry proteomics in lung tissue samples. We utilized mass spectrometry proteomic approaches to identify protein biomarkers from 152 lung tissue samples representing COPD cases and controls.
2022-01-07 | PXD024124 | Pride
Project description:Diaphragm muscles in Chronic Obstructive Pulmonary Disease (COPD) patients undergo an adaptive fast to slow transformation that includes cellular adaptations. This project studies the signaling mechanisms responsible for this transformation. Keywords: other
2003-07-16 | GSE475 | GEO
Project description:The pathogenesis of chronic obstructive pulmonary disease (COPD) remains poorly understood. Cellular senescence and apoptosis contribute to the development of COPD; however, crucial regulators of these underlying mechanisms remain unknown. Macrophage migration inhibitory factor (MIF) is a pleiotropic cytokine that antagonizes both apoptosis and premature senescence and may be important in the pathogenesis of COPD. This study examines the role of MIF in the pathogenesis of COPD. Mice deficient in MIF (Mif(-/-)) or the MIF receptor CD74 (Cd74(-/-)) and wild-type (WT) controls were aged for 6 mo. Both Mif(-/-) and Cd74(-/-) mice developed spontaneous emphysema by 6 mo of age compared with WT mice as measured by lung volume and chord length. This was associated with activation of the senescent pathway markers p53/21 and p16. Following exposure to cigarette smoke, Mif(-/-) mice were more susceptible to the development of COPD and apoptosis compared with WT mice. MIF plasma concentrations were measured in a cohort of 224 human participants. Within a subgroup of older current and former smokers (n = 72), MIF concentrations were significantly lower in those with COPD [8.8, 95%CI (6.7-11.0)] compared with those who did not exhibit COPD [12.7 ng/ml, 95%CI (10.6-14.8)]. Our results suggest that both MIF and the MIF receptor CD74 are required for maintenance of normal alveolar structure in mice and that decreases in MIF are associated with COPD in human subjects.
| S-EPMC3949087 | biostudies-literature
Project description:In chronic obstructive pulmonary disease (COPD/emphysema) we have shown a reduced ability of lung and alveolar (AM) macrophages to phagocytose apoptotic cells (defective 'efferocytosis'), associated with evidence of secondary cellular necrosis and a resultant inflammatory response in the airway. It is unknown whether this defect is present in cancer (no COPD) and if so, whether this results from soluble mediators produced by cancer cells. We investigated efferocytosis in AM (26 controls, 15 healthy smokers, 37 COPD, 20 COPD+ non small cell lung cancer (NSCLC) and 8 patients with NSCLC without COPD) and tumor and tumor-free lung tissue macrophages (21 NSCLC with/13 without COPD). To investigate the effects of soluble mediators produced by lung cancer cells we then treated AM or U937 macrophages with cancer cell line supernatant and assessed their efferocytosis ability. We qualitatively identified Arachidonic Acid (AA) metabolites in cancer cells by LC-ESI-MSMS, and assessed the effects of COX inhibition (using indomethacin) on efferocytosis. Decreased efferocytosis was noted in all cancer/COPD groups in all compartments. Conditioned media from cancer cell cultures decreased the efferocytosis ability of both AM and U937 macrophages with the most pronounced effects occurring with supernatant from SCLC (an aggressive lung cancer type). AA metabolites identified in cancer cells included PGE2. The inhibitory effect of PGE2 on efferocytosis, and the involvement of the COX-2 pathway were shown. Efferocytosis is decreased in COPD/emphysema and lung cancer; the latter at least partially a result of inhibition by soluble mediators produced by cancer cells that include PGE2.
| S-EPMC3637201 | biostudies-literature
Project description:Chronic obstructive pulmonary disease (COPD) is a critical condition with high morbidity and mortality. Although several medications are available, there are no definite treatments. However, recent advances in the understanding of stem and progenitor cells in the lung, and molecular changes during re-alveolization after pneumonectomy, have made it possible to envisage the regeneration of damaged lungs. With this background, numerous studies of stem cells and various stimulatory molecules have been undertaken, to try and regenerate destroyed lungs in animal models of COPD. Both the cell and drug therapies show promising results. However, in contrast to the successes in laboratories, no clinical trials have exhibited satisfactory efficacy, although they were generally safe and tolerable. In this article, we review the previous experimental and clinical trials, and summarize the recent advances in lung regeneration therapy for COPD. Furthermore, we discuss the current limitations and future perspectives of this emerging field.
| S-EPMC5256352 | biostudies-literature
Project description:BACKGROUND:COPD patients are at increased risk of developing non-small cell lung carcinoma that has a worse prognosis. Oxidative stress contributes to carcinogenesis and is increased in COPD patients due to mitochondrial dysfunction. We determined whether mitochondrial dysfunction is a contributing factor to the reduced survival of COPD patients with non-small cell lung carcinoma (NSCLC). METHODS:Using a transcriptomic database and outcome data of 3553 NSCLC samples, we selected mitochondrial-related genes whose levels in the tumour correlated with patient mortality. We further selected those genes showing a???2 fold expression in cancer compared to normal tissue. Cell-type specific expression of these proteins in lung tissue from NSCLC patients who were non-smokers or smokers with or without COPD (healthy smokers) was determined by immunohistochemistry. Gene set variation analysis was used in additional NSCLC datasets to determine the relative expression of specific macrophage transcriptomic signatures within lung cancer tissue. RESULTS:The expression of 14 mitochondrial-related genes was correlated with patient mortality and these were differentially expressed between cancer and normal lung tissue. We studied further the expression of one of these genes, PGAM5 which is a regulator of mitochondrial degradation by mitophagy. In background lung tissue, PGAM5 was only expressed in alveolar macrophages, with the highest expression in smokers with COPD compared to healthy smokers and non-smokers. In cancerous tissue, only the malignant epithelial cells and associated macrophages at the periphery of the cancer expressed PGAM5. Pre-neoplastic epithelium also showed the expression of PGAM5. There was no difference in expression in cancer tissue between COPD, healthy smoker and non-smoker groups. Macrophages at the edge of the cancer from COPD patients showed a trend towards higher expression of PGAM5 compared to those from the other groups. There was a significant correlation between PGAM5 expression in cancer tissue and the level of expression of 9 out of 49 previously-defined macrophage transcriptomic signatures with a particular one associated with patient mortality (p?<?0.05). CONCLUSION:PGAM5 is expressed in pre-neoplastic tissue and NSCLC, but not in normal epithelium. The association between PGAM5 expression and patient mortality may be mediated through the induction of specific macrophage phenotypes.
| S-EPMC6288964 | biostudies-literature