Lung Chronic Obstructive Pulmonary Disease Research Articles

Cancer incidence following non-neoplastic medical conditions: a prospective population-based cohort study.

Many non-neoplastic diseases have been established to be tumorigenic, and cancers are sometimes misdiagnosed as non-neoplastic diseases. We conducted a comprehensive registry-based study of site-specific cancer diagnosis risk following the diagnosis of any preceding medical condition (PMC) encoded by the International Classification of Diseases (ICD)-10 classification. We analyzed healthcare data and cancer data for a random population-based sample of 2.5 million individuals living in Finland on January 1, 2000. Hazard ratios for each PMC and cancer pair were estimated using piecewise constant hazard regression models. P-values were corrected for multiple testing with the Bonferroni method. Several lifestyle-related PMCs were associated with the risk of cancer diagnosis, exemplified by chronic obstructive pulmonary disease and subsequent lung cancer diagnosis risk (female hazard ratio [HR] = 9.91, 95% confidence interval [CI]: 9.18-19.7, p-adj. < 0.0001; male HR = 5.69, 95% CI: 5.43-5.96, p-adj. < 0.0001). Diagnosis risk of ill-defined cancers appeared to increase following diagnosis of Alzheimer's disease (AD). We identified rare PMCs of potential interest. A considerable proportion of the statistically significant associations were explainable by tobacco smoking and alcohol use. The enrichment of ill-defined cancer diagnoses in persons with AD, together with the overall inverse association between AD and cancer, may reflect underdiagnosis of cancer in this patient population. Our results provide a useful resource for research on the prevention and early detection of cancer.

FSP1 Acts in Parallel with GPX4 to Inhibit Ferroptosis in COPD.

Glutathione peroxidase 4 (GPX4) has recently been reported to play an important role in the pathogenesis of chronic obstructive pulmonary disease (COPD). Ferroptosis suppressor protein-1 (FSP1) is a protein that defends against ferroptosis in parallel with GPX4, but its role in the pathogenesis of COPD remains unexplored, and further research is needed. Normal and COPD lung tissues were obtained from lobectomy and lung transplant specimens, respectively. FSP1-overexpressing mice were established by monthly transfection with AAV9-FSP1 through modified intranasal administration. The expression of FSP1, GPX4, and prostaglandin-endoperoxide synthase 2 (PTGS2) was measured by Western blotting, immunohistochemistry and other methods. The correlation between FSP1 and ferroptosis and the role of FSP1 in COPD were explored by screening the expression of ferroptosis-related genes in a COPD cell model after the inhibition and overexpression of FSP1. We then explored the underlying mechanism of low FSP1 expression in patients with COPD in vitro by methylated RNA immunoprecipitation (MeRIP)-qPCR. We found that cigarette smoke exposure can lead to an increase in lipid peroxide production and ultimately ferroptosis, which is negatively regulated by FSP1 activity. FSP1 overexpression can prevent ferroptosis and alleviate emphysema. Next, we found that decreased FSP1 expression was caused by increased m6A modification of FSP1 mRNA. Moreover, the level of FSP1 decreased in a YTHDF2-dependent manner. These results indicate that METTL3-induced FSP1 mRNA methylation leading to low FSP1 expression is a potential therapeutic target for COPD. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Triple Therapy De-Escalation and Withdrawal of Inhaled Corticosteroids to Dual Bronchodilator Therapy in Patients with Chronic Obstructive Pulmonary Disease (COPD): A Systematic Review and Meta-Analysis.

Background/Objectives: The interpretation of evidence on the de-escalation of triple therapy with the withdrawal of inhaled corticosteroids (ICSs) to dual bronchodilator therapy with a long-acting muscarinic antagonist (LAMA) and a long-acting beta-agonist (LABA) in patients with chronic obstructive pulmonary disease (COPD) is conflicting. We evaluated the efficacy and safety of ICS discontinuation from LABA-LAMA-ICS triple therapy compared to its continuation. Methods: We searched PubMed, Embase, Scopus, Web Of Science, clinicaltrial.gov, and CENTRAL for RCTs and observational studies from inception to 22 March 2024, investigating the effect of triple therapy de-escalation with the withdrawal of ICSs to dual therapy on the risk of COPD exacerbation, pneumonia, and lung function. This study was registered with PROSPERO, CRD42024527942. Results: A total of 3335 studies was screened; 3 RCTs and 3 real-world non-interventional studies were identified as eligible. The analysis of the time to the first moderate or severe exacerbation showed a pooled HR of 0.96 (95% CI, 0.80-1.15; I2 = 77%) for ICS withdrawal compared to triple therapy continuation. The analysis according eosinophil levels showed that COPD subjects with ≥300 eosinophils/µL had a significant increase in the incidence of moderate or severe exacerbations when de-escalated to LABA/LAMA (pooled HR: 1.35, 95% CI: 1.00-1.82; I2: 56%). ICS withdrawal did not significantly affect the risk of mortality and pneumonia. Conclusions: The de-escalation of triple therapy with ICS withdrawal does not affect the main outcomes evaluated (moderate or severe exacerbations, change in trough FEV1). COPD patients with high blood eosinophils (≥2% or ≥300 cells/µL) are most likely to benefit from continuing triple therapy.

Interplay between Lung Diseases and Viral Infections: A Comprehensive Review.

The intricate relationship between chronic lung diseases and viral infections is a significant concern in respiratory medicine. We explore how pre-existing lung conditions, including chronic obstructive pulmonary disease, asthma, and interstitial lung diseases, influence susceptibility, severity, and outcomes of viral infections. We also examine how viral infections exacerbate and accelerate the progression of lung disease by disrupting immune responses and triggering inflammatory pathways. By summarizing current evidence, this review highlights the bidirectional nature of these interactions, where underlying lung diseasesincrease vulnerability to viral infections, while these infections, in turn, worsen the clinical course. This review underscores the importance of preventive measures, such as vaccination, early detection, and targeted therapies, to mitigate adverse outcomes in patients with chronic lung conditions. The insights provided aim to inform clinical strategies that can improve patient management and reduce the burden of chronic lung diseases exacerbated by viral infections.

Chronic Respiratory Diseases: Innovations in Treatment and Management

Chronic Respiratory Diseases (CRDs) include diseases of the airways and the lung and are among the major causes of morbidity and mortality worldwide. The major CRDs include asthma, chronic obstructive pulmonary disease (COPD), pulmonary sarcoidosis, pneumoconiosis and interstitial lung diseases (ILDs). The common symptoms of CRDs include wheezing, chest tightness, shortness of breath and cough [1]. These diseases affect millions of people across the globe and have significant impacts on patients’ quality of life and healthcare. Over the past few decades, however, improvement in the pharmacotherapy has provided a considerable progress. For example, biologics have given a new insight in the management of severe asthma by modulating certain inflammatory processes. Medications like omalizumab, dupilumab, and Mepolizumab are aimed at adjusting the immune response and significantly decrease the frequency of exacerbations and increase overall lung function. In addition, innovations in the field of stem cell therapy and tissue engineering are targeted to repair or replace diseased lung tissue, thus, being aimed at treating the origin of the diseases rather than simply alleviating the symptoms. Furthermore, Nanoparticles can be orally given, intravenously injected or inhaled using nanoparticle aerosols. Nanoparticles can also be used in the molecular imaging of chronic lung diseases such as COPD. Advanced inhalers, developed with sensors, can monitor the usage of medication and provide feedback in real-time to ensure compliance to prescriptions and other salient treatment plans. COPD pulmonary rehabilitation programs of exercise and education together with psychological support for individuals have been documented to enhance quality of life. The use of AI and a machine learning system has now moved to the ability to forecast disease exacerbations and provide individualized recommendations for treatment of CRDs. As a result, people with COPD receive care through various healthcare professions like doctors, nurses, and physiotherapists, which may have diverse roles, such as prescribing medications, supporting their self‐management or patient education, or delivering exercise training. The aim of an Integrated Disease Management (IDM) programme is that various aspects of care through which healthcare providers are working in coordination to deliver improved and optimum care to patients. Similarly Advancements in the treatment of ILD are being conducted, and recently, some new FDA-approved drugs have been advised for the management of patients. Among these are Nintedanib is a tyrosine kinase inhibitor, Pirfenidone an anti-fibrotic and anti-thrombotic agent and Treprostinil is an analogue of prostacyclin. These drugs have opened a new path for the treatment of ILD and have improved the recovery outcomes of patients [2]. Rituximab has also been found to be effective in more than half of patients treated in a small prospective open-label trial of refractory pulmonary disease in sarcoidosis[3]. Overall, there is a renewed emphasis on CRD management as a burgeoning field. With the advancement in the research in the personalized, proactive and integrative strategy the efforts made will lay down new avenues of better health outcomes for millions of people suffering from the CRDs. The future of respiratory health is bright as it is a growing field that has no sign of discontinuing its steady development and pushing for the comforts and breakthroughs for many patients across the globe.

MAP2K1 dampens cigarette smoke-induced inflammation via suppression of type I interferon pathway activation.

Chronic obstructive pulmonary disease (COPD), comprised of chronic bronchitis and emphysema, is a leading cause of morbidity and mortality worldwide. Mitogen-activated protein 2 kinase (MAP2K) pathway activation is present in COPD lung tissue and a genetic polymorphism in Map2k1 associates with FEV1 decline in COPD, suggesting it may contribute to disease pathogenesis. To test the functional contribution of Map2k1 in cigarette smoke (CS)-induced lung inflammation, we used a short-term CS exposure model in mice deficient in myeloid Map2k1 (LysmCre+Mek1fl) and wild-type mice (Mek1fl). Mice deficient in myeloid Map2k1 had enhanced CS-induced lung inflammation characterized by increased neutrophil recruitment, vascular leak, augmented expression of elastolytic matrix metalloproteinases, and increased type I interferon-stimulated gene expression. The augmented neutrophilic inflammatory response could be abrogated by IFNAR1 blockade. These findings indicate that myeloid Map2k1 regulates the immune response to CS via inhibition of the type I interferon pathway. Overall, these results suggest that Map2k1 is a critical determinant in modulating the severity of CS-induced lung inflammation and its expression is protective.NEW & NOTEWORTHY Activation of the mitogen-activated protein kinases (MAPK)-ERK1/2 pathway is present in COPD lung tissue compared with healthy lungs. Our study using mice deficient in myeloid Map2k1 reveals that Map2k1 is a critical determinant in modulating the severity of CS-induced lung inflammation via suppression of type I interferon responses, and its expression is protective.

CSP7 Protects Alveolar Epithelial Cells by Targeting p53-Fibrinolytic Pathways During Lung Injuries.

Impaired alveolar epithelial regeneration in patients with idiopathic pulmonary fibrosis (IPF) and chronic obstructive pulmonary disease (COPD) is attributed to telomere dysfunction in type II alveolar epithelial cells (A2Cs). Genetic susceptibility, aging, and toxicant exposures, including tobacco smoke (TS), contribute to telomere dysfunction in A2Cs. Here we investigated whether improvement of telomere function plays a role in CSP7-mediated protection of A2Cs against ongoing senescence and apoptosis during bleomycin (BLM)-induced pulmonary fibrosis (PF) as well as alveolar injury caused by chronic TS exposure. We found a significant telomere shortening in A2Cs isolated from IPF and COPD lungs in line with other studies. These cells showed increased p53 in addition to its post-translational modification with induction of activated caspase-3 and β-galactosidase, suggesting a p53-mediated loss of A2C renewal. Further, we found increased expression of SIAH-1, a p53-inducible E3 ubiquitin ligase known to down-regulate telomere repeats binding factor 2 (TRF2). Consistent with the loss of TRF2 and upregulation of TRF1, telomerase reverse transcriptase (TERT) was downregulated in A2Cs. A2Cs from fibrotic lungs of mice either repeatedly instilled with BLM or isolated from chronic TS exposure-induced lung injury model showed reduced telomere length along with induction of p53, PAI-1, SIAH1 and TRF1 as well as loss of TRF2 and TERT, which were reversed in wild-type mice after treatment with CSP7. Interestingly, PAI-1-/- mice, or those lacking microRNA-34a expression in A2Cs, resisted telomere dysfunction, while uPA-/- mice failed to respond to CSP7 treatment, suggesting p53-microRNA-34a feed-forward induction and p53-uPA pathway contributes to telomere dysfunction.

Practice review: Pharmacological management of severe chronic breathlessness in adults with advanced life-limiting diseases.

Severe and refractory chronic breathlessness is a common and burdensome symptom in patients with advanced life-limiting disease. Its clinical management is challenging because of the lack of effective interventions. To provide practice recommendations on the safe use of pharmacological therapies for severe chronic breathlessness. Scoping review of (inter)national guidelines and systematic reviews. We additionally searched for primary studies where no systematic review could be identified. Consensus on the recommendations was reached by 75% approval within an international expert panel. Searches in MEDLINE, Cochrane Library and Guideline International Network until March 2023. Inclusion of publications on the use of antidepressants, benzodiazepines, opioids or corticosteroids for chronic breathlessness in adults with cancer, chronic obstructive pulmonary disease, interstitial lung disease or chronic heart failure. Overall, the evidence from eight guidelines, 14 systematic reviews and 3 randomised controlled trials (RCTs) on antidepressants is limited. There is low quality evidence favouring opioids in patients with chronic obstructive pulmonary disease, cancer and interstitial lung disease. For chronic heart failure, evidence is inconclusive. Benzodiazepines should only be considered for anxiety associated with severe breathlessness. Antidepressants and corticosteroids should not be used. Management of breathlessness remains challenging with only few pharmacological options with limited and partially conflicting evidence. Therefore, pharmacological treatment should be reserved for patients with advanced disease under monitoring of side effects, after optimisation of the underlying condition and use of evidence-based non-pharmacological interventions as first-line treatment.

Mirtazapine to alleviate severe breathlessness in patients with COPD or interstitial lung diseases (BETTER-B): an international, multicentre, double-blind, randomised, placebo-controlled, phase 3 mixed-method trial

Breathlessness frequently becomes severe among people with respiratory disease. Mirtazapine, a widely used antidepressant, has shown promise in the modulation of respiratory sensation and the response to it, as well as reducing feelings of panic, which often accompanies breathlessness. We aimed to determine the effectiveness of mirtazapine to alleviate severe persisting breathlessness. This international, multicentre, phase 3, parallel-group, double-blind, randomised, placebo-controlled trial across 16 centres in seven countries (Australia, Germany, Ireland, Italy, New Zealand, Poland, and the UK), recruited adults with chronic obstructive pulmonary disease (COPD), interstitial lung diseases, or both, and grade 3 or 4 of the modified Medical Research Council breathlessness scale. Consenting participants were randomly assigned (1:1) to receive oral mirtazapine or matching placebo for 56 days. Randomisation was by minimisation. The initial mirtazapine dose was 15 mg, escalating to a maximum of 45 mg per day, tapered at treatment end. Participants, caregivers, assessors, and investigators were masked to group assignment. The primary outcome was worst breathlessness in the preceding 24 h measured on a 0-10 numerical rating scale (NRS), at 56 days post-treatment start, with follow-up to 180 days. The primary analysis was performed in the modified intention-to-treat population using multivariable multi-level repeated measures model. This trial was registered with ISRCTN (ISRCTN10487976 and ISRCTN15751764 [Australia and New Zealand]) and EudraCT (2019-002001-21) and is complete. Between Feb 4, 2021 and March 28, 2023, we enrolled 225 eligible participants (148 men and 77 women, 113 to the mirtazapine group and 112 to the placebo group). The median age was 74 years (IQR 67-78). No evidence of a difference was found in worst breathlessness at day 56 between mirtazapine and placebo (difference in adjusted mean NRS score was 0·105 [95% CI -0·407 to 0·618]; p=0·69). Although the study was underpowered, the primary endpoint effect did not reach the pre-specified treatment effect of 0·55 for worst breathlessness score reduction that the study was powered to detect for the primary analysis. There were 215 adverse reactions in 72 (64%) of 113 participants in the mirtazapine group versus 116 in 44 (40%) of 110 participants in the placebo group; 11 serious adverse events in six (5%) participants in the mirtazapine group versus eight in seven (6%) participants in the placebo group; and one (1%) suspected unexpected serious adverse reaction in the mirtazapine group. At day 56, there were three deaths in the mirtazapine group and two deaths in the placebo group. At day 180, there were seven deaths in the mirtazapine group and 11 deaths in the placebo group. Our findings suggested that mirtazapine of doses 15 to 45 mg daily over 56 days does not improve severe breathlessness among patients with COPD or interstitial lung diseases and might cause adverse reactions. Based on these findings, we do not recommend mirtazapine as a treatment to alleviate severe breathlessness. EU Horizon 2020 (grant agreement No. 825319); Cicely Saunders International Breathlessness Programme; National Institute for Health and Care Research Applied Research Collaboration South London; Australian National Health and Medical Research Council-EU (application ID: APP1170731).

Influence of Bronchopulmonary Diseases on the Course and Outcome of COVID-19: a Literature Review

The SARS-CoV‑2 coronavirus has become a major global health concern. Infection with SARS-CoV‑2 has caused millions of deaths worldwide, and the case fatality rate has been found to be largely related to pre-existing clinical conditions. The main clinical manifestation of COVID‑19 is the presence of respiratory symptoms. Severe complications of COVID‑19 are most often observed in people with significant medical histories. The SARS-CoV‑2 virus primarily attacks the respiratory system, causing pneumonia and acute respiratory distress syndrome, which can lead to severe systemic inflammation, multiple organ dysfunction, and death, especially in patients with pre-existing comorbidities. A number of meta-analyses strongly suggest that comorbid respiratory diseases, including chronic obstructive pulmonary disease and interstitial lung diseases, are factors in the development of severe forms of COVID‑19, worsening patient outcomes and survival rates. Studies have shown an association between adverse outcomes of COVID‑19 and the expression level of the angiotensin-­converting enzyme 2 (ACE2) in these patients. Regarding other respiratory system pathologies, such as bronchial asthma and cystic fibrosis, it is known that the main unfavorable factor is long-term immunosuppressive pharmacotherapy preceding infection. In this article, we highlight the main respiratory comorbidities to better understand the pathogenesis of COVID‑19.

Flavonoid intakes, chronic obstructive pulmonary disease, adult asthma, and lung function: a cohort study in the UK Biobank

BackgroundGiven their antioxidative stress, anti-allergic, anti-inflammatory, and immune-modulating effects, flavonoids are hypothesized to play a role in preventing chronic obstructive pulmonary disease (COPD) and asthma. ObjectivesThis cohort study aimed to examine associations between flavonoid intake and COPD, asthma, and lung function. MethodsAmong 119,466 participants of the UK Biobank, median [interquartile range] age of 60 [53, 65] y, we estimated intakes of flavonoids, flavonoid-rich foods, and a flavodiet score from 24-h diet assessments. Prospective associations with both incident COPD and asthma and cross-sectional associations with measures of lung function [%predicted forced expiratory volume in 1s (FEV1); and FEV1/forced vital capacity (FVC)] were examined using multivariable-adjusted Cox proportional hazards and linear regression models, respectively. We investigated mediation by inflammation––represented by the INFLA score––and stratified analyses by smoking status. ResultsCompared with low intakes, moderate intakes of total flavonoids, flavonols, theaflavins + thearubigins, and flavanones, and moderate-to-high intakes of flavanol monomers, proanthocyanidins, anthocyanins, flavones, and the flavodiet score were associated with up to an 18% lower risk of incident COPD {e.g., [hazard ratio (95% confidence interval) for total flavonoids: 0.83 (0.75, 0.92)]} but not incident asthma. Furthermore, compared with low intakes, higher intakes of all flavonoid subclasses (except theaflavins + thearubigins), and the flavodiet score were associated with better percent predicted FEV1 baseline. Associations were most apparent in ever (current or former) smokers. Flavonoid intakes were inversely associated with the INFLA score, which appeared to mediate 11%–14% of the association between intakes of proanthocyanidins and flavones and incident COPD. ConclusionsModerate-to-high flavonoid intakes were associated with a lower risk of COPD and better lung function, particularly among ever smokers. Promoting intakes of healthy flavonoid-rich foods, namely, tea, apples, and berries, may improve respiratory health and lower COPD risk, particularly in individuals with a smoking history.

Palliative care needs and integration in severe COPD and ILD: Protocol of a mixed method study (PCIntegCOPD-ILD)

Background and Aim Chronic Obstructive Pulmonary Disease (COPD) and Interstitial Lung Disease (ILD) have high symptom burden, serious health-related suffering, and mortality that necessitate palliative care (PC) integration. There is an information gap on PC needs, symptom burden, anxiety and depression in COPD and ILD, and the feasibility of PC integration from low-middle-income countries (LMICs). The PCIntegCOPD-ILD study aims to identify PC needs, symptom burden, and psychological distress in severe COPD/ ILD and assess the feasibility of PC integration within standard care. It will also explore experiences and unmet needs relating to disease and PC services for patients and informal carers. Methods and Design This mixed-methods study will assess PC needs, symptom burden, and psychological distress in patients with severe COPD (stages C, D) and ILD (stages II, III). Assessment will be done at recruitment (T0) and third (T3) month (face-to-face) and first (T1) and second (T2) month (phone call). After initial recruitment, patients will be provided PC interventions as required. At T3, patients’ and informal carers’ experiences and unmet needs of disease and PC services will be explored through semi-structured interviews. Impact and feasibility of integration of PC within standard care will also be assessed. Discussion The PCIntegCOPD-ILD study will provide robust data on PC needs, symptom burden, psychological distress and understanding of patient and caregiver perspecitves in severe COPD and ILD. An objective information on feasibility of PC integration will inform development and evaluation of similar models in the management of other progressive chronic diseases in LMICs.

Characterization of IL-6R-expressing monocytes in the lung of patients with chronic obstructive pulmonary disease

BackgroundMonocytes play a crucial role in innate immune responses for host defense, however, their involvement in chronic obstructive pulmonary disease (COPD) remains poorly understood. We previously identified a subset of monocytes in COPD lung tissues characterized by high interleukin-6 receptor (IL-6R) expression. This study aimed to characterize the phenotypes of IL-6Rhi monocytes in the lungs of COPD patients. MethodsUsing flow cytometry, we assessed the abundance of pulmonary CD14+IL-6Rhi cells in never smokers (CNS), control ex-smokers (CES) and COPD patients. IL-6 expression in CD14+ monocytes isolated from the peripheral blood of patients with COPD was also examined. CD45+CD206–CD14+IL-6Rhi and CD45+CD206–CD14+IL-6R–/lo cells were isolated from COPD lung tissues for transcriptome analysis. A monocyte line THP1 cell with constitutive IL-6R expression was stimulated with recombinant IL-6, followed by RNA sequencing to evaluate the IL-6 responsiveness of IL-6R+ monocytes. ResultsThe number of pulmonary CD14+IL-6Rhi monocytes was elevated in COPD patients compared to CNS, whereas CD14+ monocytes in the peripheral blood of COPD patients did not express IL-6R. Upregulated mRNA expression in CD14+IL-6Rhi monocytes was associated with chemotaxis, monocyte differentiation, fatty acid metabolism and integrin-mediated signaling pathway. Stimulation of THP1 cells with recombinant IL-6 induced changes in the expression of genes linked to chemotaxis and organism development. ConclusionIn patients with COPD, CD14+IL-6Rhi monocytes are increased in lung tissues compared to those in CNS. They exhibit a transcriptome profile different from that of CD14+IL-6R–/lo monocytes.

SCARF2 is a target for chronic obstructive pulmonary disease: Evidence from multi-omics research and cohort validation.

Age-related chronic inflammatory lung diseases impose a threat on public health, including idiopathic pulmonary fibrosis (IPF) and chronic obstructive pulmonary disease (COPD). However, their etiology and potential targets have not been clarified. We performed genome-wide meta-analysis for IPF with the largest sample size (2883 cases and 741,929 controls) and leveraged the summary statistics of COPD (17,547 cases and 617,598 controls). Transcriptome-wide and proteome-wide Mendelian randomization (MR) designs, together with genetic colocalization, were implemented to find robust targets. The mediation effect was assessed using leukocyte telomere length (LTL). The single-cell transcriptome analysis was performed to link targets with cell types. Individual-level data from UK Biobank (UKB) were used to validate our findings. Sixteen genetically predicted plasma proteins were causally associated with the risk of IPF and 6 proteins were causally associated with COPD. Therein, genetically-elevated plasma level of SCARF2 protein should reduce the risk of both IPF (odds ratio, OR = 0.9974 [0.9970, 0.9978]) and COPD (OR = 0.7431 [0.6253, 0.8831]) and such effects were not mediated by LTL. Genetic colocalization further corroborated these MR results of SCARF2. The transcriptome-wide MR confirmed that higher expression level of SCARF2 was associated with a reduced risk of both. However, the single-cell RNA analysis indicated that SCARF2 expression level was only relatively lower in epithelial cells of COPD lung tissue compared to normal lung tissue. UKB data implicated an inverse association of serum SCARF2 protein with COPD (hazard ratio, HR = 1.215 [1.106, 1.335]). The SCARF2 gene should be a novel target for COP.

Binary fabrication of decellularized lung extracellular matrix hybridgels for in vitro chronic obstructive pulmonary disease modeling

Limited treatments and a lack of appropriate animal models have spurred the study of scaffolds to mimic lung disease in vitro. Decellularized human lung and its application in extracellular matrix (ECM) hydrogels has advanced the development of these lung ECM models. Controlling the biochemical and mechanical properties of decellularized ECM hydrogels continues to be of interest due to inherent discrepancies of hydrogels when compared to their source tissue. To optimize the physiologic relevance of ECM hydrogel lung models without sacrificing the native composition we engineered a binary fabrication system to produce a Hybridgel composed of an ECM hydrogel reinforced with an ECM cryogel. Further, we compared the effect of ECM-altering disease on the properties of the gels using elastin poor Chronic Obstructive Pulmonary Disease (COPD) vs non-diseased (ND) human lung source tissue. Nanoindentation confirmed the significant loss of elasticity in hydrogels compared to that of ND human lung and further demonstrated the recovery of elastic moduli in ECM cryogels and Hybridgels. These findings were supported by similar observations in diseased tissue and gels. Successful cell encapsulation, distribution, cytotoxicity, and infiltration were observed and characterized via confocal microscopy. Cells were uniformly distributed throughout the Hybridgel and capable of survival for 7 days. Cell-laden ECM hybridgels were found to have elasticity similar to that of ND human lung. Compositional investigation into diseased and ND gels indicated the conservation of disease-specific elastin to collagen ratios. In brief, we have engineered a composited ECM hybridgel for the 3D study of cell-matrix interactions of varying lung disease states that optimizes the application of decellularized lung ECM materials to more closely mimic the human lung while conserving the compositional bioactivity of the native ECM. Statement of significanceThe lack of an appropriate disease model for the study of chronic lung diseases continues to severely inhibit the advancement of treatments and preventions of these otherwise fatal illnesses due to the inability to recapture the biocomplexity of pathologic cell-ECM interactions. Engineering biomaterials that utilize decellularized lungs offers an opportunity to deconstruct, understand, and rebuild models that highlight and investigate how disease specific characteristics of the extracellular environment are involved in driving disease progression. We have advanced this space by designing a binary fabrication system for a ECM Hybridgel that retains properties from its source material required to observe native matrix interactions. This design simulates a 3D lung environment that is both mechanically elastic and compositionally relevant when derived from non-diseased tissue and pathologically diminished both mechanically and compositionally when derived from COPD tissue. Here we describe the ECM hybridgel as a model for the study of cell-ECM interactions involved in COPD.

The disruptive effects of COPD exacerbation-associated factors on epithelial repair responses.

Exacerbations of chronic obstructive pulmonary disease (COPD) increase mortality risk and can lead to accelerated loss of lung function. The increased inflammatory response during exacerbations contributes to worsening of airflow limitation, but whether it also impacts epithelial repair is unclear. Therefore, we studied the effect of the soluble factor micro-environment during COPD exacerbations on epithelial repair using an exacerbation cocktail (EC), composed of four factors that are increased in COPD lungs during exacerbations (IL-1β, IL-6, IL-8, TNF-α). Mouse organoids (primary CD31-CD45-Epcam+ cells co-cultured with CCL206 fibroblasts) were used to study epithelial progenitor behavior. Mature epithelial cell responses were evaluated using mouse precision cut lung slices (PCLS). The expression of epithelial supportive factors was assessed in CCL206 fibroblasts and primary human lung fibroblasts. EC exposure increased the number and size of organoids formed, and upregulated Lamp3, Muc5ac and Muc5b expression in day 14 organoids. In PCLS, EC imparted no effect on epithelial marker expression. Pre-treatment of CCL206 fibroblasts with EC was sufficient to increase organoid formation. Additionally, the expression of Il33, Tgfa and Areg was increased in CCL206 fibroblasts from EC treated organoids, but these factors individually did not affect organoid formation or size. However, TGF-α downregulated Foxj1 expression and upregulated Aqp5 expression in day 14 organoids. EC exposure stimulates organoid formation and growth, but it alters epithelial differentiation. EC changes the epithelial progenitor support function of fibroblasts which contributes to observed effects on epithelial progenitors.

Lipid-Laden Macrophages in Pulmonary Diseases.

Pulmonary surfactants play a crucial role in managing lung lipid metabolism, and dysregulation of this process is evident in various lung diseases. Alternations in lipid metabolism lead to pulmonary surfactant damage, resulting in hyperlipidemia in response to lung injury. Lung macrophages are responsible for recycling damaged lipid droplets to maintain lipid homeostasis. The inflammatory response triggered by external stimuli such as cigarette smoke, bleomycin, and bacteria can interfere with this process, resulting in the formation of lipid-laden macrophages (LLMs), also known as foamy macrophages. Recent studies have highlighted the potential significance of LLM formation in a range of pulmonary diseases. Furthermore, growing evidence suggests that LLMs are present in patients suffering from various pulmonary conditions. In this review, we summarize the essential metabolic and signaling pathways driving the LLM formation in chronic obstructive pulmonary disease, pulmonary fibrosis, tuberculosis, and acute lung injury.

Using spirometry for screening and diagnosis of chronic respiratory diseases in primary health care: findings from a community health project in rural India

Background Chronic respiratory diseases (CRDs) such as Chronic obstructive pulmonary disease (COPD), Asthma and post-tuberculosis lung disease (PTLD) are a growing public health concern in India. Early diagnosis and management of CRDs require a good quality spirometry test, a technician to conduct spirometry and a chest physician to interpret the results. In India, these are not available at the primary care level. This study reports the feasibility of a large-scale CRD diagnosis and management program in primary care using a unique point-of-care spirometry solution, Briota PFT in a Box™. # Methods A community-based cross-sectional study was conducted among 15,602 adults in Dindori Taluka (subdivision), Nashik, Maharashtra state. This study was part of a holistic CRD diagnosis and management program SAVE™ (Spirometry Assisted Virtually Early). Make In India point of care solution Briota PFT in a Box™ was used. A House‐to‐house community-based assessment checklist (CBAC) survey, 4-parameter spirometry test, 15-parameter pre and post-bronchodilator spirometry test and a software-assisted medical examination by the medical officer at primary care were conducted. Software was used to generate CRD diagnosis and lung health score (LHS™). The diagnosis was verified by the chest physician. Confirmed diagnosed patients were provided treatment and offered a patient support program. Interviews were conducted with the patients, nurses, doctors and public health officials for understanding feasibility and documenting learning from program SAVE™. # Results Out of 15,602 adults surveyed, total 4,937 (31.6%) were identified as “CRD high risk”. 1231 participants based on medical examination, spirometry tests and software analysis were identified as CRD candidates by medical officers at primary care. 1154 participants out of 15,602 (7.4%) were confirmed diagnosed as CRD patients post independent evaluation by chest physicians. At the time of follow-up, 537 patients (75% of 712 patients enrolled in patient support program) reported improvement in symptoms and high satisfaction with the program. District health officer, Medical officers, nurses, Accredited Social Health Activist (ASHA) from the primary health care centers confirmed ease of use and feasibility of using Briota PFT in a Box™ in program SAVE™. Outcome and learning from program SAVE™ was documented and submitted to Ministry of Health and Family Welfare Government of India. # Conclusions CRD diagnosis and management in large scale settings in primary healthcare level using a point of care spirometry solution Briota PFT in a Box™ is highly feasible.

Effects of Pulmonary Rehabilitation with Occupational Therapy on Occupational Performance

Aims 1) Explore occupational challenges of individuals participating in pulmonary rehabilitation (PR), and 2) examine impacts of occupational therapy, embedded within PR, on performance of, satisfaction with, dyspnea in and experience of challenging occupations. Methods A mixed methods cohort study recruited adults from a 8-week community-based PR program which incorporated targeted occupational therapy. Participant perspectives of the occupational therapy were explored using the Canadian Occupational Performance Measure (COPM) and Modified Borg Dyspnea Scale. Results Seventeen participants with either Chronic Obstructive Pulmonary Disease, Bronchiectasis, or Interstitial Lung Disease were recruited (age 71 ± 7(SD) identifying 269 problematic occupations. Nine participants completed the program obtaining clinically and statistically significant improvements in COPM performance, satisfaction scores and Modified Borg Dyspnea Scale, maintained at 12 wk, and validated through participants reporting they ‘now do things differently’. Conclusion People with chronic respiratory conditions are occupational beings. Occupational therapy embedded within PR can influence participants’ engagement in challenging occupations.

Lung Tissue Multilayer Network Analysis Uncovers the Molecular Heterogeneity of Chronic Obstructive Pulmonary Disease.

Rationale: Chronic obstructive pulmonary disease (COPD) is a heterogeneous condition. Objectives: We hypothesized that the unbiased integration of different COPD lung omics using a novel multilayer approach might unravel mechanisms associated with clinical characteristics. Methods: We profiled mRNA, microRNA and methylome in lung tissue samples from 135 former smokers with COPD. For each omic (layer), we built a patient network on the basis of molecular similarity. The three networks were used to build a multilayer network, and optimization of multiplex modularity was used to identify patient communities across the three distinct layers. Uncovered communities were related to clinical features. Measurements and Main Results: We identified five patient communities in the multilayer network that were molecularly distinct and related to clinical characteristics, such as FEV1 and blood eosinophils. Two communities (C#3 and C#4) had both similarly low FEV1 values and emphysema but were molecularly different: C#3, but not C#4, presented B- and T-cell signatures and a downregulation of secretory (SCGB1A1/SCGB3A1) and ciliated cells. A machine learning model was set up to discriminate C#3 and C#4 in our cohort and to validate them in an independent cohort. Finally, using spatial transcriptomics, we characterized the small airway differences between C#3 and C#4, identifying an upregulation of T-/B-cell homing chemokines and bacterial response genes in C#3. Conclusions: A novel multilayer network analysis is able to identify clinically relevant COPD patient communities. Patients with similarly low FEV1 and emphysema can have molecularly distinct small airways and immune response patterns, indicating that different endotypes can lead to similar clinical presentation.