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Cell and Tissue Research Mar 2017The cellular mechanisms that result in the initiation and progression of emphysema are clearly complex. A growing body of human data combined with discoveries from mouse... (Review)
Review
The cellular mechanisms that result in the initiation and progression of emphysema are clearly complex. A growing body of human data combined with discoveries from mouse models utilizing cigarette smoke exposure or protease administration have improved our understanding of emphysema development by implicating specific cell types that may be important for the pathophysiology of chronic obstructive pulmonary disease. The most important aspects of emphysematous damage appear to be oxidative or protease stress and sustained macrophage activation and infiltration of other immune cells leading to epithelial damage and cell death. Despite the identification of these associated processes and cell types in many experimental studies, the reasons why cigarette smoke and other pollutants result in unremitting damage instead of injury resolution are still uncertain. We propose an important role for macrophages in the sequence of events that lead and maintain this chronic tissue pathologic process in emphysema. This model involves chronic activation of macrophage subtypes that precludes proper healing of the lung. Further elucidation of the cross-talk between epithelial cells that release damage-associated signals and the cellular immune effectors that respond to these cues is a critical step in the development of novel therapeutics that can restore proper lung structure and function to those afflicted with emphysema.
Topics: Animals; Disease Models, Animal; Immunity; Inflammation; Mice; Models, Biological; Pulmonary Emphysema
PubMed: 28164246
DOI: 10.1007/s00441-016-2567-7 -
Respirology (Carlton, Vic.) Dec 2022
Topics: Humans; Pneumonectomy; Pulmonary Emphysema; Bronchoscopy; Treatment Outcome
PubMed: 36104311
DOI: 10.1111/resp.14371 -
Respiratory Medicine Jan 2019The prevalence of classifiable and unclassifiable causes of lung fibrosis and its implications for survival are mostly unknown in combined pulmonary fibrosis and...
BACKGROUND
The prevalence of classifiable and unclassifiable causes of lung fibrosis and its implications for survival are mostly unknown in combined pulmonary fibrosis and emphysema (CPFE).
MATERIALS AND METHODS
Patients with >10% involvement of both emphysema and lung fibrosis seen over 11 years at our institution were reviewed independently by expert radiologists for fibrotic and emphysematous findings and overall fibrotic CT pattern. Underlying interstitial lung disease (ILD) diagnoses and baseline demographic and clinical characteristics were collated and assessed for predictors of comparative survival.
RESULTS
In this retrospective cohort, 179 CPFE patients were identified and categorized as 58 usual interstitial pneumonia/idiopathic pulmonary fibrosis (UIP/IPF) (32%), 42 secondary ILD (23%), and 79 unclassifiable ILD (44%). The most prevalent (47%) radiologic pattern was 'unclassifiable', followed by 'consistent' and 'possible' UIP pattern in 38%. Adjusted predictors of mortality for the cohort as a whole included age (HR 1.03[1.01-1.06], P = 0.002), percent predicted diffusing capacity for carbon monoxide (unit HR 0.97 [0.96-0.99], P = 0.001), honeycombing (HR 1.58 [1.02-2.43], P = 0.04), and right ventricular dysfunction (HR 2.28 [1.39-3.97], P = 0.002). Survival was similar between CPFE with secondary ILD and CPFE with UIP/IPF, while CPFE with unclassifiable ILD had better comparative survival (Log rank = 0.026).
CONCLUSIONS
Our findings suggest only about a third of CPFE patients represent suspected UIP/IPF; the majority were clinically and radiologically unclassifiable ILD whose survival was comparatively better. Identifiable or secondary causes of lung fibrosis in CPFE occurred in about a fifth of presenting patients.
Topics: Aged; Female; Humans; Lung Diseases, Interstitial; Male; Middle Aged; Prevalence; Pulmonary Emphysema; Pulmonary Fibrosis; Survival Analysis
PubMed: 30665507
DOI: 10.1016/j.rmed.2018.12.003 -
Respiratory Research Jan 2019Retinoid X receptors (RXRs) are members of the nuclear receptor (NR) superfamily that mediate signalling by 9-cis retinoic acid, a vitamin A derivative. RXRs play key...
BACKGROUND
Retinoid X receptors (RXRs) are members of the nuclear receptor (NR) superfamily that mediate signalling by 9-cis retinoic acid, a vitamin A derivative. RXRs play key roles not only as homodimers but also as heterodimeric partners, e.g., for retinoic acid receptors, vitamin D receptors, and peroxisome proliferator-activated receptors. The NR family may also play important roles in the development of emphysema. However, the role of RXRs in the pathogenesis of emphysema is not well defined.
METHODS
We developed a novel RXR partial agonist (NEt-4IB) and investigated its effect and mechanism compared to a full agonist (bexarotene) in a murine model of emphysema. For emphysema induction, BALB/c mice received intraperitoneal cigarette smoke extract (CSE) or intratracheal porcine pancreas elastase (PPE). Treatment with RXR agonists was initiated before or after emphysema induction.
RESULTS
Treatment with NEt-4IB significantly suppressed the increase in static lung compliance and emphysematous changes in CSE-induced emphysema and PPE-induced established and progressive emphysema. NEt-4IB significantly suppressed PPE-induced neutrophilic airway inflammation and the levels of keratinocyte chemoattractant (KC), C-X-C motif ligand5 (CXCL5), interferon (IFN)-γ and IL-17. NEt-4IB also improved the matrix metalloproteinase-9 (MMP-9)/tissue inhibitor of metalloproteinase-1 (TIMP-1) imbalance and the reduced anti-oxidant activity in bronchoalveolar lavage (BAL) fluid. NEt-4IB suppressed PPE-induced vascular endothelial growth factor (VEGF) expression in the airway. Treatment with NEt-4IB and bexarotene significantly suppressed the increase in static lung compliance and emphysematous changes. However, adverse effects of RXR agonists, including hypertriglyceridemia and hepatomegaly, were observed in bexarotene-treated mice but not in NEt-4IB-treated mice.
CONCLUSION
These data suggest that RXRs play crucial roles in emphysema and airway inflammation, and novel partial RXR agonists could be potential therapeutic strategies for the treatment of PPE- and CSE-induced emphysema.
Topics: Animals; Bexarotene; Cigarette Smoking; Female; Inflammation; Mice; Mice, Inbred BALB C; Pulmonary Emphysema; Retinoid X Receptors
PubMed: 30606200
DOI: 10.1186/s12931-018-0963-0 -
Respiratory Research Jan 2022There is a strong need for biomarkers to better characterize individuals with COPD and to take into account the heterogeneity of COPD. The blood protein sRAGE has been...
BACKGROUND
There is a strong need for biomarkers to better characterize individuals with COPD and to take into account the heterogeneity of COPD. The blood protein sRAGE has been put forward as promising biomarker for COPD in general and emphysema in particular. Here, we measured plasma sRAGE levels using quantitative LC-MS and assessed whether the plasma sRAGE levels associate with (changes in) lung function, radiological emphysema parameters, and radiological subtypes of emphysema.
METHODS
Three hundred and twenty-four COPD patients (mean FEV: 63%predicted) and 185 healthy controls from the COPDGene study were selected. Plasma sRAGE was measured by immunoprecipitation in 96-well plate methodology to enrich sRAGE, followed by targeted quantitative liquid chromatography-mass spectrometry. Spirometry and HRCT scans (inspiration and expiration) with a 5-year follow-up were used; both subjected to high quality control standards.
RESULTS
Lower sRAGE values significantly associated with the presence of COPD, the severity of airflow obstruction, the severity of emphysema on HRCT, the heterogeneous distribution of emphysema, centrilobular emphysema, and 5-year progression of emphysema. However, sRAGE values did not associate with airway wall thickness or paraseptal emphysema.
CONCLUSIONS
Rather than being a general COPD biomarker, sRAGE is especially a promising biomarker for centrilobular emphysema. Follow-up studies should elucidate whether sRAGE can be used as a biomarker for other COPD phenotypes as well.
Topics: Aged; Biomarkers; Female; Humans; Lung; Male; Middle Aged; Pulmonary Emphysema; Receptor for Advanced Glycation End Products; Tomography, X-Ray Computed; Vital Capacity
PubMed: 35073932
DOI: 10.1186/s12931-022-01934-w -
The Journal of the American Osteopathic... Aug 2017
Topics: Adult; Humans; Male; Pulmonary Emphysema; Radiography, Thoracic; Syndrome
PubMed: 28759097
DOI: 10.7556/jaoa.2017.106 -
Scientific Reports Oct 2018Exercise limitation is common in chronic obstructive pulmonary disease (COPD). We determined the impact of pulmonary emphysema on the physiological response to exercise...
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 CO, and heart rate; and 2) lower oxy-hemoglobin saturation, and end-tidal PCO. 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.
Topics: Aged; Exercise Tolerance; Female; Heart Rate; Humans; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Pulmonary Emphysema; Respiratory Function Tests; Smoking; Tomography, X-Ray Computed
PubMed: 30356114
DOI: 10.1038/s41598-018-34014-5 -
The American Journal of Pathology Aug 2019Marfan syndrome (MFS) is a connective tissue disorder caused by mutations in fibrillin-1 (Fbn1). Although aortic rupture is the major cause of mortality in MFS, patients...
Marfan syndrome (MFS) is a connective tissue disorder caused by mutations in fibrillin-1 (Fbn1). Although aortic rupture is the major cause of mortality in MFS, patients also experience pulmonary complications, which are poorly understood. Loss of basal nitric oxide (NO) production and vascular integrity has been implicated in MFS aortic root disease, yet their contribution to lung complications remains unknown. Because of its capacity to potentiate the vasodilatory NO/cyclic guanylate monophosphate signaling pathway, we assessed whether the phosphodiesterase-5 inhibitor, sildenafil (SIL), could attenuate aortic root remodeling and emphysema in a mouse model of MFS. Despite increasing NO-dependent vasodilation, SIL unexpectedly elevated mean arterial blood pressure, failed to inhibit MFS aortic root dilation, and exacerbated elastic fiber fragmentation. In the lung, early pulmonary artery dilation observed in untreated MFS mice was delayed by SIL treatment, and the severe emphysema-like alveolar destruction was prevented. In addition, improvements in select parameters of lung function were documented. Subsequent microarray analyses showed changes to gene signatures involved in the inflammatory response in the MFS lung treated with SIL, without significant down-regulation of connective tissue or transforming growth factor-β signaling genes. Because phosphodiesterase-5 inhibition leads to improved lung histopathology and function, the effects of SIL against emphysema warrant further investigation in the settings of MFS despite limited efficacy on aortic root remodeling.
Topics: Animals; Female; Male; Marfan Syndrome; Mice; Mice, Mutant Strains; Pulmonary Artery; Pulmonary Emphysema; Sildenafil Citrate; Vasodilation
PubMed: 31125551
DOI: 10.1016/j.ajpath.2019.05.003 -
Respirology (Carlton, Vic.) Jan 2019Combined pulmonary fibrosis and emphysema (CPFE) is characterized by preserved lung volume and slower lung function decline. However, it is unclear at what extent...
BACKGROUND AND OBJECTIVE
Combined pulmonary fibrosis and emphysema (CPFE) is characterized by preserved lung volume and slower lung function decline. However, it is unclear at what extent emphysema begins to impact respiratory physiology and prognostic characteristics in idiopathic pulmonary fibrosis (IPF). We estimated the extent of emphysema that could be used to define CPFE in IPF.
METHODS
The extent of emphysema was observed on high-resolution computed tomography scans and measured by a texture-based automated quantification system in 209 IPF patients. We analysed the impact of differences in the extent of emphysema on the annual decline rate and prognostic significance of lung function parameters.
RESULTS
The extent of emphysema was ≥5% in 53 patients (25%), ≥10% in 23 patients (11%) and ≥15% in 12 patients (6%). Patients with emphysema to an extent of ≥5% were more frequently men and ever-smokers; they had more preserved lung volume and lower forced vital capacity (FVC) decline rates than those with no or trivial emphysema. The FVC decline rate was a significant predictor of mortality in patients with no or trivial emphysema (hazard ratio (HR): 0.933, P < 0.001) and in patients with an extent of emphysema ≥5% (HR: 0.906, P < 0.001). However, diffusing capacity of the lung for carbon monoxide (DL ) was the most significant prognostic factor in those patients with an extent of emphysema ≥10% (HR: 0.972, P = 0.040) and ≥15% (HR: 0.942, P = 0.023). A 10% cut-off value for the extent of emphysema created the most significant difference in the annual FVC decline rate in IPF patients.
CONCLUSION
In IPF, emphysema to an extent of ≥10% affects both the annual decline rate and the prognostic significance of FVC. This extent could be used to define CPFE.
Topics: Aged; Computing Methodologies; Female; Humans; Idiopathic Pulmonary Fibrosis; Lung; Male; Middle Aged; Prognosis; Proportional Hazards Models; Pulmonary Emphysema; Respiratory Function Tests; Tomography, X-Ray Computed; Vital Capacity
PubMed: 30136753
DOI: 10.1111/resp.13387 -
American Journal of Respiratory and... Jan 2024Within chronic obstructive pulmonary disease (COPD), emphysema is characterized by a significant yet partially understood B cell immune component. To characterize the...
Within chronic obstructive pulmonary disease (COPD), emphysema is characterized by a significant yet partially understood B cell immune component. To characterize the transcriptomic signatures from lymphoid follicles (LFs) in ever-smokers without COPD and patients with COPD with varying degrees of emphysema. 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. 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 (-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. An off-targeted B cell activation within LFs is associated with autoimmune-mediated emphysema pathogenesis.
Topics: Humans; Pulmonary Emphysema; Proteomics; Pulmonary Disease, Chronic Obstructive; Gene Expression Profiling; Lymphadenopathy; Emphysema
PubMed: 37934672
DOI: 10.1164/rccm.202303-0507LE