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Journal of Thoracic Disease Dec 2023Some studies have reviewed lung explants histology to determine the frequency of pretransplant non-identified neoplasms or explore its diagnostic correlation with a...
BACKGROUND
Some studies have reviewed lung explants histology to determine the frequency of pretransplant non-identified neoplasms or explore its diagnostic correlation with a previous diagnosis of interstitial lung disease (ILD). This study aims to review the histopathology of explants from patients who underwent lung transplantation (LT).
METHODS
A retrospective, single-center study that included patients who underwent LT for emphysema between 01 January 2011 and 31 October 2021. The control group was composed of patients with lung cancer who underwent a lung resection between 01 November 2011 and 31 December 2019 and had a previous diagnosis of chronic obstructive pulmonary disease (COPD) prior to lung resection surgery. A systematic review was performed of histological findings to compare the frequency of additional histological diagnoses.
RESULTS
The study sample included 160 patients (43.8%) who received a lung transplant for emphysema and 205 patients with COPD and lung cancer treated surgically. Although the patients in the cancer group were significantly older and had more comorbidities and higher cumulative tobacco consumption, transplant recipients received an additional significative histologic diagnosis more frequently (58.1% 12.7%; P<0.001) including ILD, pneumoconiosis and others.
CONCLUSIONS
Significant additional histological findings were more frequent in the group of lung transplant recipients with emphysema. Notably, these findings were not explained by tobacco use, and they were significantly more frequent in transplant recipients than in patients with a previous diagnosis of COPD and higher cumulative tobacco consumption but with a better respiratory functional status.
PubMed: 38249891
DOI: 10.21037/jtd-23-1160 -
Respiratory Research Jan 2024No single pulmonary function test captures the functional effect of emphysema in idiopathic pulmonary fibrosis (IPF). Without experienced radiologists, other methods are...
BACKGROUND
No single pulmonary function test captures the functional effect of emphysema in idiopathic pulmonary fibrosis (IPF). Without experienced radiologists, other methods are needed to determine emphysema extent. Here, we report the development and validation of a formula to predict emphysema extent in patients with IPF and emphysema.
METHODS
The development cohort included 76 patients with combined IPF and emphysema at the Royal Brompton Hospital, London, United Kingdom. The formula was derived using stepwise regression to generate the weighted combination of pulmonary function data that fitted best with emphysema extent on high-resolution computed tomography. Test cohorts included patients from two clinical trials (n = 455 [n = 174 with emphysema]; NCT00047645, NCT00075998) and a real-world cohort from the Royal Brompton Hospital (n = 191 [n = 110 with emphysema]). The formula is only applicable for patients with IPF and concomitant emphysema and accordingly was not used to detect the presence or absence of emphysema.
RESULTS
The formula was: predicted emphysema extent = 12.67 + (0.92 x percent predicted forced vital capacity) - (0.65 x percent predicted forced expiratory volume in 1 second) - (0.52 x percent predicted carbon monoxide diffusing capacity). A significant relationship between the formula and observed emphysema extent was found in both cohorts (R = 0.25, P < 0.0001; R = 0.47, P < 0.0001, respectively). In both, the formula better predicted observed emphysema extent versus individual pulmonary function tests. A 15% emphysema extent threshold, calculated using the formula, identified a significant difference in absolute changes from baseline in forced vital capacity at Week 48 in patients with baseline-predicted emphysema extent < 15% versus ≥ 15% (P = 0.0105).
CONCLUSION
The formula, designed for use in patients with IPF and emphysema, demonstrated enhanced ability to predict emphysema extent versus individual pulmonary function tests.
TRIAL REGISTRATION
NCT00047645; NCT00075998.
Topics: Humans; Emphysema; Idiopathic Pulmonary Fibrosis; Lung; Pulmonary Emphysema; Retrospective Studies; Vital Capacity; Clinical Trials as Topic
PubMed: 38238788
DOI: 10.1186/s12931-023-02589-x -
American Journal of Respiratory and... Aug 2023
Topics: Humans; Cross-Sectional Studies; Pulmonary Emphysema; Pulmonary Disease, Chronic Obstructive; Emphysema; Lung
PubMed: 37450936
DOI: 10.1164/rccm.202307-1198ED -
Experimental & Molecular Medicine Oct 2023The interaction between the microbial environment and the host is important for immune homeostasis. Recent research suggests that microbiota dysbiosis can be involved in...
The interaction between the microbial environment and the host is important for immune homeostasis. Recent research suggests that microbiota dysbiosis can be involved in respiratory diseases. Emphysema is a chronic inflammatory disease, but it is unclear whether dysbiosis caused by antibiotics can affect disease progression. Here, we tried to elucidate the effect of systemic antibiotics on smoking-exposed emphysema models. In this study, the antibiotic mixture caused more alveolar destruction and airspace expansion in the smoking group than in the smoking only or control groups. This emphysema aggravation as a result of antibiotic exposure was associated with increased levels of inflammatory cells, IL-6, IFNγ and protein concentrations in bronchoalveolar lavage fluid. Proteomics analysis indicated that autophagy could be involved in antibiotic-associated emphysema aggravation, and increased protein levels of LC3B, atg3, and atg7 were identified by Western blotting. In microbiome and metabolome analyses, the composition of the gut microbiota was different with smoking and antibiotic exposure, and the levels of short-chain fatty acids (SCFAs), including acetate and propionate, were reduced by antibiotic exposure. SCFA administration restored emphysema development with reduced inflammatory cells, IL-6, and IFNγ and decreased LC3B, atg3, and atg7 levels. In conclusion, antibiotics can aggravate emphysema, and inflammation and autophagy may be associated with this aggravation. This study provides important insight into the systemic impact of microbial dysbiosis and the therapeutic potential of utilizing the gut microbiota in emphysema.
Topics: Humans; Anti-Bacterial Agents; Dysbiosis; Interleukin-6; Pulmonary Emphysema; Inflammation; Emphysema; Autophagy
PubMed: 37779147
DOI: 10.1038/s12276-023-01099-6 -
Molecules and Cells Sep 2023Chronic obstructive pulmonary disease (COPD) will be the third leading cause of death worldwide by 2030. One of its components, emphysema, has been defined as a lung...
Chronic obstructive pulmonary disease (COPD) will be the third leading cause of death worldwide by 2030. One of its components, emphysema, has been defined as a lung disease that irreversibly damages the lungs' alveoli. Treatment is currently unavailable for emphysema symptoms and complete cure of the disease. Hyaluronan (HA) and proteoglycan link protein 1 (HAPLN1), an HA-binding protein linking HA in the extracellular matrix to stabilize the proteoglycan structure, forms a bulky hydrogel-like aggregate. Studies on the biological role of the full-length HAPLN1, a simple structure-stabilizing protein, are limited. Here, we demonstrated for the first time that treating human alveolar epithelial type 2 cells with recombinant human HAPLN1 (rhHAPLN1) increased TGF-β receptor 1 (TGF-β RI) protein levels, but not TGF-β RII, in a CD44-dependent manner with concurrent enhancement of the phosphorylated Smad3 (p-Smad3), but not p-Smad2, upon TGF-β1 stimulation. Furthermore, rhHAPLN1 significantly increased sirtuins levels (i.e., SIRT1/2/6) without TGF-β1 and inhibited acetylated p300 levels that were increased by TGF-β1. rhHAPLN1 is crucial in regulating cellular senescence, including p53, p21, and p16, and inflammation markers such as p-NF-κB and Nrf2. Both senile emphysema mouse model induced via intraperitoneal rhHAPLN1 injections and porcine pancreatic elastase (PPE)-induced COPD mouse model generated via rhHAPLN1-containing aerosols inhalations showed a significantly potent efficacy in reducing alveolar spaces enlargement. Preclinical trials are underway to investigate the effects of inhaled rhHAPLN1-containing aerosols on several COPD animal models.
Topics: Mice; Humans; Animals; Swine; Pulmonary Emphysema; Sirtuins; Alveolar Epithelial Cells; Transforming Growth Factor beta1; Pulmonary Disease, Chronic Obstructive; Emphysema; Receptors, Transforming Growth Factor beta
PubMed: 37587649
DOI: 10.14348/molcells.2023.0097 -
Frontiers in Endocrinology 2023Obesity and chronic obstructive pulmonary disease (COPD) are prevailing worldwide, bringing a heavy medical burden. Clinical and pathophysiological relationship between...
BACKGROUND
Obesity and chronic obstructive pulmonary disease (COPD) are prevailing worldwide, bringing a heavy medical burden. Clinical and pathophysiological relationship between obesity and COPD is paradoxical and elusive. We aim to explore their inherent associations from clinical, genetic, and animal levels.
METHODS
We performed literature review and cohort analysis of patients with COPD to compare lung function, symptom, and prognosis among different weight groups. After retrieving datasets of obesity and COPD in Gene Expression Omnibus (GEO) database, we carried out differentially expressed gene analysis, functional enrichment, protein-protein interactions network, and weighted gene co-expression network analysis. Then, we acquired paraffin-embedded lung tissues of fatty acid-binding protein 4-Cre-BMPR2 conditional knockout (CKO) mice that were characterized by adipocyte-specific knockout of bone morphogenetic protein receptor 2 (BMPR2) for staining and analysis.
RESULTS
Our cohort study reports the effect of obesity on COPD is inconsistent with previous clinical studies. Lung function of overweight group was statistically superior to that of other groups. We also found that the inflammatory factors were significantly increased hub genes, and cytokine-associated pathways were enriched in white adipose tissue of patients with obesity. Similarly, injury repair-associated genes and pathways were further enhanced in the small airways of patients with COPD. CKO mice spontaneously developed lung injury, emphysema, and pulmonary vascular remodeling, along with increased infiltration of macrophages. BMPR2-defiecient adipocytes had dysregulated expression of adipocytokines.
CONCLUSION
Inflammation and abnormal repair might be potential mechanisms of the pathological association between obesity and COPD. BMPR2-associated adipocyte dysfunction promoted lung inflammation and aberrant repair, in which adipocytokines might play a role and thus could be a promising therapeutic target.
Topics: Humans; Animals; Mice; Cohort Studies; Pulmonary Disease, Chronic Obstructive; Pneumonia; Obesity; Adipokines
PubMed: 37886639
DOI: 10.3389/fendo.2023.1204744 -
American Journal of Human Genetics Oct 2023Emphysema and chronic obstructive pulmonary disease (COPD) most commonly result from the effects of environmental exposures in genetically susceptible individuals....
Emphysema and chronic obstructive pulmonary disease (COPD) most commonly result from the effects of environmental exposures in genetically susceptible individuals. Genome-wide association studies have implicated ADGRG6 in COPD and reduced lung function, and a limited number of studies have examined the role of ADGRG6 in cells representative of the airway. However, the ADGRG6 locus is also associated with DLCO/VA, an indicator of gas exchange efficiency and alveolar function. Here, we sought to evaluate the mechanistic contributions of ADGRG6 to homeostatic function and disease in type 2 alveolar epithelial cells. We applied an inducible CRISPR interference (CRISPRi) human induced pluripotent stem cell (iPSC) platform to explore ADGRG6 function in iPSC-derived AT2s (iAT2s). We demonstrate that ADGRG6 exerts pleiotropic effects on iAT2s including regulation of focal adhesions, cytoskeleton, tight junctions, and proliferation. Moreover, we find that ADGRG6 knockdown in cigarette smoke-exposed iAT2s alters cellular responses to injury, downregulating apical complexes in favor of proliferation. Our work functionally characterizes the COPD GWAS gene ADGRG6 in human alveolar epithelium.
Topics: Humans; Alveolar Epithelial Cells; Epithelial Cells; Genome-Wide Association Study; Induced Pluripotent Stem Cells; Lung; Pulmonary Disease, Chronic Obstructive; Receptors, G-Protein-Coupled
PubMed: 37734371
DOI: 10.1016/j.ajhg.2023.08.017 -
The Journal of Clinical Investigation Dec 2023Although chronic low-grade inflammation does not cause immediate clinical symptoms, over the longer term, it can enhance other insults or age-dependent damage to organ...
Although chronic low-grade inflammation does not cause immediate clinical symptoms, over the longer term, it can enhance other insults or age-dependent damage to organ systems and thereby contribute to age-related disorders, such as respiratory disorders, heart disease, metabolic disorders, autoimmunity, and cancer. However, the molecular mechanisms governing low-level inflammation are largely unknown. We discovered that Bcl-2-interacting killer (Bik) deficiency causes low-level inflammation even at baseline and the development of spontaneous emphysema in female but not male mice. Similarly, a single nucleotide polymorphism that reduced Bik levels was associated with increased inflammation and enhanced decline in lung function in humans. Transgenic expression of Bik in the airways of Bik-deficient mice inhibited allergen- or LPS-induced lung inflammation and reversed emphysema in female mice. Bik deficiency increased nuclear but not cytosolic p65 levels because Bik, by modifying the BH4 domain of Bcl-2, interacted with regulatory particle non-ATPase 1 (RPN1) and RPN2 and enhanced proteasomal degradation of nuclear proteins. Bik deficiency increased inflammation primarily in females because Bcl-2 and Bik levels were reduced in lung tissues and airway cells of female compared with male mice. Therefore, controlling low-grade inflammation by modifying the unappreciated role of Bik and Bcl-2 in facilitating proteasomal degradation of nuclear proteins may be crucial in treating chronic age-related diseases.
Topics: Male; Animals; Female; Humans; Mice; Apoptosis; Mitochondrial Proteins; Apoptosis Regulatory Proteins; Proto-Oncogene Proteins c-bcl-2; Inflammation; Nuclear Proteins; Emphysema; Hexosyltransferases; Proteasome Endopeptidase Complex
PubMed: 38113109
DOI: 10.1172/JCI170594 -
The American Journal of Cardiology Oct 2023Pulmonary vascular abnormalities, quantified from computed tomography scans, have frequently been observed in patients with pulmonary diseases. However, little is known...
Pulmonary vascular abnormalities, quantified from computed tomography scans, have frequently been observed in patients with pulmonary diseases. However, little is known about pulmonary vascular changes in patients with cardiac disease. Thus, we aimed to examine the cardiopulmonary relation in patients with atrial fibrillation (AF) by comparing pulmonary vascular volume (PVV) to echocardiographic measures and AF severity. A total of 742 patients (median age 63 years, 70% men) who underwent ablation for AF were included. Preprocedural cardiac computed tomography was used to measure the total and small-vessel PVV, along with the pulmonary artery to aorta ratio and the degree of emphysema. The association between PVV and echocardiographic parameters was evaluated using a multivariable linear regression analysis. Lower total and small-vessel PVV were associated with more impaired measures of cardiac structure and function, including but not limited to left ventricular ejection fraction and peak atrial longitudinal strain. Patients with reduced total and small-vessel PVV had higher odds of having persistent AF than paroxysmal AF in the unadjusted logistic regression analyses. However, after clinical and echocardiographic adjustments, only reduced small-vessel PVV remained independently associated with persistent AF (odds ratio 1.90, 95% confidence interval 1.26 to 2.87, p = 0.002). In conclusion, pulmonary vascular remodeling is associated with persistent AF and with more impaired measures of cardiac structure and function, providing further insights into heart-lung interactions in this patient group.
Topics: Male; Humans; Middle Aged; Female; Atrial Fibrillation; Stroke Volume; Ventricular Function, Left; Echocardiography; Heart Atria
PubMed: 37604065
DOI: 10.1016/j.amjcard.2023.07.119