Lung Function Decline Research Articles

Efficacy and Safety of Admilparant, an LPA1 Antagonist, in Pulmonary Fibrosis: A Phase 2 Randomized Clinical Trial.

Rationale: Idiopathic pulmonary fibrosis (IPF) and progressive pulmonary fibrosis (PPF) have high morbidity and mortality; thus, novel treatments are needed. Objectives: Assess efficacy and safety of admilparant (BMS-986278), an oral lysophosphatidic acid receptor 1 antagonist, in patients with IPF and PPF. Methods: This phase 2, randomized, double-blind, placebo-controlled trial included parallel cohorts of patients with IPF (n = 278 randomized, n = 276 treated) or PPF (n = 125 randomized, n = 123 treated) who received 30 mg of admilparant, 60 mg of admilparant, or placebo (1:1:1) twice daily for 26 weeks. Background antifibrotics (both cohorts) and immunosuppressants (PPF only) were permitted. Measurements and Main Results: Rates of change in percentage of predicted FVC over 26 weeks for IPF were -2.7% (placebo), -2.8% (30 mg), and -1.2% (60 mg) and for PPF were -4.3% (placebo), -2.9% (30 mg), and -1.1% (60 mg). Treatment differences between 60-mg admilparant and placebo were 1.4% (95% confidence interval, -0.1 to 3.0) for IPF and 3.2% (95% confidence interval, 0.7 to 5.7) for PPF. Treatment effect was observed with or without background antifibrotics in both cohorts. Diarrhea occurred at similar frequencies in admilparant arms versus placebo. Transient Day 1 postdose blood pressure reductions were observed in all arms in both cohorts but were greater with admilparant. Treatment discontinuations because of adverse events were similar across IPF arms and lower with admilparant (2.5% [30 mg]; 0% [60 mg]) versus placebo (17.1%) for PPF. Conclusions: In this first phase 2 study to evaluate antifibrotic treatment in parallel IPF and PPF cohorts, 60-mg admilparant slowed lung function decline and was safe and well tolerated, supporting further evaluation in phase 3 trials. Clinical trial registered with clinicaltrials.gov identifier (NCT04308681).

Effect of Human Immunodeficiency Virus on Lung Function and Structure: A Systematic Review and Meta-Analysis.

Rationale: Obstructive lung disease (OLD) pathogenesis includes inhalational (e.g., smoking) and noninhalational mechanisms (e.g., infections). Human immunodeficiency virus (HIV) has been suggested as a novel OLD risk factor. Substantial data have recently emerged about its effects on lung function and structure, especially in low- to middle-income countries and regarding longitudinal lung function. Objectives: To assess the association of HIV infection with OLD, impaired gas exchange, and emphysema. Methods: In this systematic review and meta-analysis, we searched PubMed, Embase, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, Web of Science, Scopus, Cumulative Index to Nursing and Allied Health Literature, and Global Index Medicus through April 2023 for controlled and observational studies of people living with and without HIV reporting pulmonary function and/or emphysema. Primary outcomes were OLD by spirometry, gas exchange impairment by diffusing capacity of the lung for carbon monoxide, and visual emphysema by computed tomography. We performed random-effects meta-analyses using odds ratios (ORs) with 95% confidence intervals (CIs). This study was registered in PROSPERO (CRD42021268498). Results: We included 95 publications pertaining to 43 unique studies. HIV was associated with OLD (OR, 1.29; 95% CI, 1.02-1.63), impaired gas exchange (OR, 2.63; 95% CI, 0.96-7.24), emphysema (OR, 1.46; 95% CI, 1.02-2.09), and faster lung function decline. OLD risk was greatest in Africans with HIV. There were no gas exchange or emphysema data from Africa. The certainty of evidence was low to very low, primarily because of studies' observational design. Conclusions: People living with HIV have increased risk for OLD, gas exchange impairment, faster lung function decline, and emphysema. OLD risk in HIV varies regionally. We recommend that both spirometry and diffusing capacity of the lung for carbon monoxide be measured in people living with HIV and respiratory symptoms. Future studies should develop and validate HIV-specific screening and case-finding strategies for chronic lung disease.

Expiration CT Gas Trapping Measures with Texture-Based Radiomics Improves Association with Lung Function and Lung Function Decline in COPD.

Several methods quantify gas-trapping on expiration computed tomography (CT) images, but they do not consider the spatial relationship of voxels. The objective of this study was to determine if the addition of expiration CT texture-based radiomics features to existing gas-trapping measurements improves model performance for lung function, lung function decline, COPD classification and visual gas-trapping. CanCOLD participants performed spirometry, plethysmography and CT chest imaging at full-inspiration/expiration with radiologist-assessed gas-trapping. Quantitative CT measurements were performed: low attenuation areas≤-856HU (LAA856), ratio of expiratory-to-inspiratory mean lung attenuation (E/I MLA), and difference between expiratory-inspiratory lung volumes between -856 and -950 HU (RVC856-950). Texture-based radiomics analysis generated 95 features; LASSO regression coefficients were summed to create a representative variable (RadScore). Multivariable linear regression models determined associations for baseline RV/TLC, FEV1/FVC, FEV1, FEF25-75, and 6-year ΔFEV1, with established CT gas-trapping and RadScore. Binary logistic regression determined associations for COPD classification and visual gas-trapping. 1111 participants were investigated (n=234 never-smokers, n=325 at-risk, n=314 mild COPD, n=238 moderate-severe COPD). In separate models for baseline RV/TLC, FEV1/FVC, FEV1, and FEF25-75, ΔFEV1, COPD classification and visual gas-trapping, all CT gas-trapping and CT RadScore measurements were independently significant (p<0.05). When CT gas-trapping and CT RadScore were included in the same model, all model performance metrics improved significantly (p<0.05). CT measures extracted from full-expiratory images that quantify the distribution, not just extent, of gas-trapping provide important information related to lung function and lung function decline in COPD. Full-expiratory CT texture-based radiomics improves model performance when used in combination with conventional gas-trapping measurements for lung function and lung function decline, COPD classification and presence of visual gas-trapping.

NTHi killing activity is reduced in COPD patients and is associated with a differential microbiome

Chronic obstructive pulmonary disease (COPD) is a chronic lung disease characterized by airway obstruction and inflammation. Non-typeable Haemophilus influenzae (NTHi) lung infections are common in COPD, promoting frequent exacerbations and accelerated lung function decline. The relationship with immune responses and NTHi are poorly understood. Herein, we comprehensively characterized the respiratory microbiome and mycobiome of patients while investigating microbial dynamics and host immune changes attributable to NTHi killing activity. Mild-to-moderate COPD patients encompassing frequent and infrequent exacerbators and healthy volunteers (HV) were enrolled. Microbial composition, proteomics and NTHi killing activity was analyzed using bronchoalveolar lavage fluid (BALF). In addition, antigen–antibody titers in sera to COPD pathogens were determined using a multiplex assay. Differential abundance analysis revealed an enrichment of Actinobacteria and Bacteroidetes in the BALF of COPD and HV subjects respectively. Significant differences in the IgA titer response were observed against NTHi antigens in COPD vs. HV. Notably, there was also significantly greater killing activity against NTHi in BALF from COPD vs. HV subjects (OR = 5.64; 95% CI = 1.75–20.20; p = 0.001). Stratification of COPD patients by NTHi killing activity identified unique microbial and protein signatures wherein Firmicutes, Actinobacteria and haptoglobin were enriched in patients with killing activity. We report that differences in host immune responses and NTHi-killing activity are associated with microbiome changes in mild-to-moderate COPD. This is suggestive of a potential link between the respiratory microbiome and immune activity against NTHi in the context of COPD pathogenesis even at this disease stage.

Quality of life in idiopathic pulmonary fibrosis in Latin American countries

BackgroundIdiopathic pulmonary fibrosis (IPF) is the most common Interstitial Lung Disease (ILD). It is characterized by dyspnoea and a progressive decline in lung function, which negatively affects life. This study aimed to evaluate Health-Related Quality of Life (HRQoL) in IPF patients in Latin American countries.MethodsSix countries (Argentina, Bolivia, Colombia, Chile, Mexico, and the Dominican Republic) enrolled patients with IPF. They answered the Saint George’s Respiratory Questionnaire for Idiopathic Pulmonary Fibrosis (SGRQ-I) and the Hospital Anxiety and Depression Scale (HADS). Demographic characteristics, the Torvan index, and a lung function test were also assessed. IPF was diagnosed according to the ATS/ERS/JRS/ALAT 2018 criteria.ResultsWe enlisted 75 patients diagnosed with IPF; 81% were male, with an average age of 74 ± 7. The total SGRQ-I score was 49 ± 23, with a higher score in the activity domain of 70 ± 23. Torvan index average was 17 ± 6. We found that 28% presented anxiety and 35% depression. Besides, we observed that patients requiring oxygen had a worse quality of life (total SGRQ-I 62 ± 22 vs. 45 ± 22, p = 0.003) without finding differences in antifibrotic therapy. We did not find differences in HRQoL when dividing groups according to their altitude above sea level, except for a higher frequency of anxiety in patients living at sea level.ConclusionsWe found similar data compared to those reported in real-life European populations. We also found that anxiety and depression are prevalent. However, they are often underdiagnosed and, therefore, left untreated.

The Comorbidity of Lung Cancer and ILD: A Review.

Patients with interstitial lung disease (ILD) and especially with idiopathic pulmonary fibrosis(IPF) suffer from reduced survival expectation and risk of exacerbations. Lung cancer is a relevant comorbidity in ILD patients and associated with impaired survival.The most frequent ILD among patients with NSCLC (Non-small cell lung cancer) is idiopathic pulmonary fibrosis (IPF), which is associated with an greater decline in lung function and a higher risk of death.The prevalence of lung cancer in patients with ILD is up to 10% and in autopsy studies a prevalence up to 48% has been found.There are no guidelines for patients with lung cancer and ILD. Moreover, no adequate evidence is available.Therefore, we reviewed currently available literature to present an overview of the state of the art.In this review we focus on staging and treatment of the comorbidity of lung cancer and ILD.

Flow cytometric measurement of CFTR-mediated chloride transport in human neutrophils.

Immune cells express a variety of ion channels and transporters in the plasma membrane and intracellular organelles, responsible of the transference of charged ions across hydrophobic lipid membrane barriers. The correct regulation of ion transport ensures proper immune cell function, activation, proliferation, and cell death. Cystic fibrosis (CF) is a genetic disease in which the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) chloride channel gene is defective, consequently, the CFTR protein is dysfunctional, and the chloride efflux in CF cells is markedly impaired. Cystic fibrosis is characterized by chronic inflammation in the airways, mainly triggered by neutrophilic infiltration and recurring bacterial infections, causing the decline of lung function and eventually respiratory failure. Novel modulator-based therapies have improved lung function in people with Cystic Fibrosis (pwCF) by increasing expression and function of CFTR in the plasma membrane of lung cells, however, the effects of these drugs in the lung recruited inflammatory cells, specifically neutrophils, remains unknown. Given the complex biology of neutrophils and their short lifespan, we aimed to develop a fluorometric method to evaluate CFTR-mediated chloride transport in human neutrophils by using flow cytometry and the intracellular chloride-binding MQAE dye. Our results show that CFTR-mediated chloride transport in human neutrophils or human neutrophil-like cell lines can be consistently evaluated in vitro by this methodology. Additionally, this assay measured increased chloride efflux in neutrophils collected from pwCF under modulator therapy, as compared to healthy donors, indicating this method can evaluate restoration of CFTR-mediated chloride transport in CF neutrophils.

Lymphangioleiomyomatosis and Pregnancy-Do We Have All the Answers for a Woman Who Desires to Conceive?-Literature Review.

Lymphangioleiomyomatosis (LAM) is a rare, progressive, and poor-prognosis systemic disorder that primarily affects women of reproductive age, with a higher prevalence among individuals of Caucasian origin. However, there are limited reliable data on the prevalence of LAM during pregnancy. The fulminant respiratory clinical presentation that often includes progressive dyspnea on exertion, cough, or hemoptysis, frequently complicated by pneumothorax, and the increased risk of spontaneous abortion due to increased estrogen and progesterone production during gestation, are arguments that most often make the diagnosed woman avoid pregnancy. Elevated levels of vascular endothelial growth factor D (VEGF-D), decline in respiratory function, and radiological findings are sufficient arguments in favor of the diagnosis in the pregnant woman. Sirolimus, an mTOR inhibitor, has demonstrated effectiveness in slowing the decline of lung function. Although sirolimus treatment is often recommended to be discontinued before conception due to the increased risk of fetal growth restriction, maintaining a dose level of <5 pcg/mL, with serum drug levels of 3-5 pcg/L, has been considered safe. Given the potential risks, individualized decisions about pregnancy are advised for patients with LAM. For those who choose to proceed, close monitoring by a multidisciplinary team is essential to manage complications effectively. Ongoing research aims to provide clearer guidance to optimize outcomes for both mother and child.

Aspergillus fumigatus is responsible for inflammation in a murine model of chronic obstructive pulmonary disease exacerbation

BackgroundIn patients with chronic obstructive pulmonary disease (COPD), a sensitization to A. fumigatus has been related to a decline in lung function, but the role of fungal agents in the disease pathogenesis remains unclear. The main purpose of the present study was to investigate whether cell inflammation could worsen after exposure to A. fumigatus spores in vitro and then, in mice, following chronic exposure to cigarette smoke mimicking COPD.MethodsThe inflammatory response to cigarette smoke alone or with A. fumigatus was investigated in cell culture models of murine macrophages and alveolar epithelial cells. In an animal model, mice were exposed daily to two cigarettes smoke over 14 weeks, and two intranasal instillations of 105 spores at weeks 7 and 14. Then, their lungs were recovered to perform inflammatory and histopathological analyses.ResultsIn co-cultures of macrophages and epithelial cells treated with both cigarette smoke extracts (CSE) and A. fumigatus compared to CSE alone there were significant inductions in TNF-α (6.2-fold) and CXCL-2 (21.5-fold) gene expression, confirmed by significant increases in the corresponding protein secretion. In the murine model, histological analyses of the lung after chronic smoke exposure showed an increase in airspace enlargement. Moreover, a Bio-Plex approach on bronchoalveolar lavage of cigarette smoke and A. fumigatus-treated mice showed significant increases in multiple inflammatory proteins secreted in the lung.ConclusionsThere was a stronger inflammatory response after cigarette smoke exposure with A. fumigatus compared to cigarette smoke alone. These findings were correlated with histopathological changes in the mouse lung in vivo.

Identification and validation of SPP1 as a potential biomarker for COPD through comprehensive bioinformatics analysis.

Chronic Obstructive Pulmonary Disease (COPD) is a challenging respiratory condition characterized by persistent airflow limitation and progressive lung function decline. The identification of robust biomarkers is crucial for early diagnosis, monitoring disease progression, and guiding therapeutic strategies. In this study, we employed a comprehensive bioinformatics approach utilizing multiple Gene Expression Omnibus (GEO) datasets to identify potential COPD biomarkers. Differentially expressed genes (DEGs) were identified from GSE38974 and GSE76925, and Weighted Gene Co-expression Network Analysis (WGCNA) on GSE76925 revealed significant gene modules associated with COPD traits. Integrative analysis highlighted five candidate genes, with Secreted Phosphoprotein 1 (SPP1) emerging as a promising biomarker. SPP1 exhibited consistent negative correlations with lung function parameters in human datasets (GSE103174) and significant upregulation in COPD-relevant animal models (GSE36174 and GSE52509). Moreover, SPP1 levels were elevated across various respiratory samples, including alveolar epithelium, alveolar macrophages, sputum, and lung tissue, from COPD patients. These findings highlight the potential of SPP1 as a diagnostic and prognostic biomarker for COPD, emphasizing the need for further investigation into its role in COPD pathogenesis and its effectiveness in clinical applications.

Occupation and 11-year lung function decline in the HUNT Study.

The association between occupational titles and lung function has mostly been examined through cross-sectional studies. Preventive measures are expected to mitigate adverse effects; hence, updated estimates are necessary. To study change in lung function measured by spirometry across occupations. This population-based prospective cohort study comprised 5618 working adult participants of the Trøndelag Health Study (HUNT3, 2005-07), Norway. Among these, 3800 individuals (43% men, mean age 42 years, range 20-55) also attended HUNT4 (2017-19). We analysed longitudinal decline in forced expiratory volume in 1 second (FEV1) z-score during the 11-year follow-up by occupation (white-collar workers as reference category), in mixed models, adjusting for age, sex and smoking. We assessed the prevalence of self-reported respiratory symptoms and disease in the working population in HUNT4 (n = 32 124) and HUNT3 (n = 32 070). Compared with white-collar workers, agricultural workers and 'drivers and mobile plant operators', had larger declines in FEV1 z-score during follow-up. In sex-stratified analyses, men defined as agricultural workers and 'drivers and mobile plant operators' had larger declines than white-collar workers. Among women, who were underrepresented in many blue-collar jobs, workers classified as 'machine operators and assemblers' experienced greater declines. In the working population in HUNT4, the prevalence of respiratory symptoms in connection with work was 8%, and lower among white-collar workers (6%) than blue-collar workers (14%). Although certain workers in Norway remain at risk for occupational lung function decline, there were modest differences between occupations. The findings encourage continuous efforts to implement preventive measures in high-risk jobs.

An FGF2-Derived Short Peptide Attenuates Bleomycin-Induced Pulmonary Fibrosis by Inhibiting Collagen Deposition and Epithelial-Mesenchymal Transition via the FGFR/MAPK Signaling Pathway.

Following the COVID-19 pandemic, the prevalence of pulmonary fibrosis has increased significantly, placing patients at higher risk and presenting new therapeutic challenges. Current anti-fibrotic drugs, such as Nintedanib, can slow the decline in lung function, but their severe side effects highlight the urgent need for safer and more targeted alternatives. This study explores the anti-fibrotic potential and underlying mechanisms of an endogenous peptide (P5) derived from fibroblast growth factor 2 (FGF2), developed by our research team. Using a bleomycin-induced pulmonary fibrosis mouse model, we observed that P5 alleviated fibrosis by inhibiting collagen deposition, as confirmed by CT scans and histological staining. In TGF-β-induced cell models, P5 effectively suppressed collagen deposition and epithelial-mesenchymal transition (EMT). Transcriptome analysis highlighted pathways related to receptor binding, extracellular matrix organization, and cell adhesion, with KEGG analysis confirming FGFR/MAPK signaling inhibition as the primary mechanism underlying its anti-fibrotic effects. In summary, our study demonstrates that P5 significantly attenuates pulmonary fibrosis through the inhibition of EMT, collagen deposition, and FGFR/MAPK signaling, providing a promising therapeutic approach for fibrosis.

Upper lobe CT imaging features improve prediction of lung function decline in COPD

BackgroundIt is unknown if prediction models for lung function decline using computed tomography (CT) imaging-derived features from the upper-lobes improve performance compared to globally-derived features in individuals at risk of and with COPD.Materials and MethodsIndividuals at risk (current or former smokers) and those with COPD from the Canadian Cohort Obstructive Lung Disease (CanCOLD), a retrospective study, were investigated. A total of 103 CT features were extracted globally and regionally, and were used with 12 clinical features (demographics, questionnaires, and spirometry) to predict rapid lung function decline for individuals at risk and those with COPD. Machine learning models were evaluated in a hold-out test set using the area under the receiver operating characteristic curve (AUC) with DeLong's test for comparison.ResultsA total of 780 participants were included (n=276 at risk; n=298 GOLD 1 COPD; n=206 GOLD 2+ COPD). For predicting rapid lung function decline in those at risk, the upper-lobe CT model obtained a significantly higher AUC (AUC=0.80) than the lower-lobe CT model (AUC=0.63) and global model (AUC=0.66; p&lt;0.05). For predicting rapid lung function decline in COPD, there was no significant differences between the upper-lobe (AUC=0.63), lower-lobe (AUC=0.59) or global CT features model (AUC=059; p&gt;0.05).ConclusionCT features extracted from the upper-lobes obtained significantly improved prediction performance compared to globally extracted features for rapid lung function decline in early/mild COPD.

SignalingviaCD131 regulates pulmonary inflammation, alveolar cell death and emphysema in COPD

BackgroundChronic Obstructive Pulmonary Disease (COPD) is a heterogenous disease where chronic inflammation is implicated in airway remodeling and emphysema. The CD131 receptor is indispensable for signaling by the beta common (βc) family of cytokines encompassing GM-CSF, IL-5 and IL-3, which instigate both Type-2 and non-Type-2 inflammatory responses. This study aims to determine whether antagonising CD131 signaling can prevent pulmonary inflammation, alveolar cell death and emphysema development.MethodsWe performed in-house andin silicotranscriptomic analysis to investigate the gene expression of CD131 (CSF2RB) and pathway enrichment for βc cytokine signaling in blood, sputum and lung biopsies of COPD patients. To model emphysema, transgenic mice expressing human CD131 were exposed to elastase or cigarette smoke (CS) and a fully human monoclonal antibody (CSL311) was employed to inhibit CD131 signaling.ResultsCD131 gene expression was significantly increased in COPD, along with an enrichment of gene set for βc cytokine signaling. In transgenic mice subjected to emphysema models, CD131 antagonism effectively prevented lung injury, alveolar cell death and emphysema development. Mechanistically, RNA sequencing identified pathway enrichment for myeloid cell activation, Type-2 immune response and macrophage alternative activation in elastase-induced emphysematous mice, mirroring human COPD. Blocking CD131 signaling almost completely reversed the global gene expression alterations associated with emphysema development.ConclusionsCD131 signaling orchestrates pulmonary inflammation in COPD, resulting in immunopathology that underpins emphysema and lung function decline. Antagonising CD131 therefore represents a unique strategy to simultaneously target multiple pathogenic myeloid cell populations.

Deciphering the cellular and molecular landscape of pulmonary fibrosis through single-cell sequencing and machine learning

Pulmonary fibrosis is characterized by progressive lung scarring, leading to a decline in lung function and an increase in morbidity and mortality. This study leverages single-cell sequencing and machine learning to unravel the complex cellular and molecular mechanisms underlying pulmonary fibrosis, aiming to improve diagnostic accuracy and uncover potential therapeutic targets. By analyzing lung tissue samples from pulmonary fibrosis patients, we identified distinct cellular phenotypes and gene expression patterns that contribute to the fibrotic process. Notably, our findings revealed a significant enrichment of activated B cells, CD4 T cells, macrophages, and specific fibroblast subpopulations in fibrotic versus normal lung tissue. Machine learning analysis further refined these observations, resulting in the development of a diagnostic model with enhanced precision, based on key gene signatures including TMEM52B, PHACTR1, and BLVRB. Comparative analysis with existing diagnostic models demonstrates the superior accuracy and specificity of our approach. Through In vitro experiments involving the knockdown of PHACTR1, TMEM52B, and BLVRB genes demonstrated that these genes play crucial roles in inhibiting the expression of α-SMA and collagen in lung fibroblasts induced by TGF-β. Additionally, knockout of the PHACTR1 gene reduced inflammation and collagen deposition in a bleomycin-induced mouse model of pulmonary fibrosis in vivo. Additionally, our study highlights novel gene signatures and immune cell profiles associated with pulmonary fibrosis, offering insights into potential therapeutic targets. This research underscores the importance of integrating advanced technologies like single-cell sequencing and machine learning to deepen our understanding of pulmonary fibrosis and pave the way for personalized therapeutic strategies.

Erdosteine: Reigniting a Thiol Mucolytic for Management of Chronic Obstructive Pulmonary Disease.

Chronic obstructive pulmonary disease (COPD) is a major health burden globally and in India. Oxidative stress plays a pivotal role in the pathogenesis of COPD, causing mucus hypersecretion, bronchoconstriction, and accelerated lung function decline. An important class of pharmacological agents that are often less discussed are the thiol mucolytic agents, which have a two-pronged effect of serving as both a mucolytic and an antioxidant. One of these agents which has reignited interest lately is erdosteine, with recent evidence demonstrating advantages over traditionally used N-acetylcysteine. In this review, we have summarized the key available evidence for the role of erdosteine in COPD, with takeaways on its place in therapy.

Mesenchymal stromal cells reduce inflammation and improve lung function in a mouse model of cystic fibrosis lung disease

Mesenchymal stromal cells (MSCs) are multipotent adult stem cells which possess immunomodulatory and repair capabilities. In this study, we investigated whether MSC therapy could modulate inflammation and lung damage in the lungs of Scnn1b-transgenic mice overexpressing the β-subunit of the epithelial sodium channel (β-ENaC), a model with features of Cystic Fibrosis lung disease. Human bone marrow derived MSC cells were intravenously delivered to mice, prior to collection of bronchoalveolar lavage (BALF) and tissue. BALF analysis revealed a significant reduction in inflammatory cells after MSC administration, with both monocytic cells and neutrophils significantly reduced. Pro-inflammatory cytokines keratinocyte-derived chemokine (KC) and osteopontin were also significantly reduced. Histological tissue analysis revealed a reduction in emphysema in Scnn1b-TG mice treated with MSCs and consistent with these findings, improvements in lung function after MSC therapy were observed. Furthermore, MSCs enhanced Ki67 staining in alveolar cells, which may indicate regeneration of the destroyed parenchyma. Mechanistically, restoration of peroxisome proliferator-activated receptor-γ (PPARγ) expression and its transcriptional program were identified after MSC treatment. Our data demonstrate that MSC therapy can reduce inflammation, damage, and lung function decline in the chronically inflamed lung of Scnn1b-Tg mice, suggesting that MSCs may provide an effective tool in the treatment of muco-obstructive diseases such as cystic fibrosis.

Changes in muscle-to-fat ratio are associated with lung function decline and airflow obstruction in the general population

BackgroundThe long-term relationship between body composition and lung function has not yet been fully demonstrated. We investigated the longitudinal association between muscle-to-fat (MF) ratio and lung function among middle-aged general population.MethodsParticipants were enrolled from a community-based prospective cohort between 2005 and 2014. Lung function parameters (forced vital capacity [FVC], forced expiratory volume in 1 s [FEV1], and FEV1/FVC) and the MF ratio (total body muscle mass [kg]/fat mass [kg]) were assessed biannually via spirometry and bioelectrical impedance analysis, respectively.ResultsWe followed up 4,712 participants (age 53.9 ± 7.9 years, men 45.8%) for 8 years. With an increase in MF ratio of 1, in men, the FVC increased by 43.9 mL, FEV1 by 37.6 mL, and FEV1/FVC by 0.320%, while in non-smoking women, the FVC increased by 55.8 mL, FEV1 by 44.3 mL, and FEV1/FVC by 0.265% (all P < 0.001). The MF ratio-decreased group showed further annual deterioration in lung function than the MF ratio-increased group (men: FVC − 44.1 mL vs. -28.4 mL, FEV1 -55.8 mL vs. -39.7 mL, FEV1/FVC − 0.53% vs. -0.42%; non-smoking women: FVC − 34.2 mL vs. -30.3 mL, FEV1 -38.0 mL vs. -35.2 mL; all P < 0.001, except FEV1 in non-smoking women; P = 0.005). The odds ratio for the incidence of airflow obstruction according to the MF ratio was 0.77 (95% CI, 0.68–0.87) in men and 0.85 (95% CI, 0.74–0.97) in non-smoking women.ConclusionsLong-term changes in the MF ratio are related to lung function deterioration and incidence of airflow obstruction in middle-aged general population.

An overview of proactive monitoring and management of respiratory issues in ataxia-telangiectasia in a specialist and shared care pediatric clinic

Ataxia-telangiectasia (A-T) is an ultrarare autosomal recessive disorder and occurs in all racial and ethnic backgrounds. Clinically, children and young people with A-T are affected by sinopulmonary infections, neurological deterioration with concomitant bulbar dysfunction, increased sensitivity to ionizing radiation, immunodeficiency, a decline in lung function, chronic liver disease, endocrine abnormalities, cutaneous and deep-organ granulomatosis, and early death. Pulmonary complications become more frequent in the second decade of life and are a leading cause of death in individuals with A-T. Oropharyngeal dysphagia is common, progressive, and a risk factor for frequent respiratory infections. Immunodeficiency is non-progressive in most patients with A-T. If severe infections occur, one should be aware of other possible causes, such as aspiration. We provide an overview of current best practice recommendations, which are based on combinations of extrapolation from other diseases and expert opinion. These include proactive surveillance, monitoring, and early management to improve lung health in this devastating multisystem disease.

Infections, autoimmunity and immunodeficiencies are the leading etiologies of non-cystic fibrosis bronchiectasis in adults from the southwest of Colombia.

Non-cystic fibrosis bronchiectasis is a complex medical condition with multiple etiologies, characterized by chronic productive cough and radiologic evidence of airway lumen dilation and wall thickening. Associated exacerbations and declining lung function contribute to increasing disability and mortality. There are no data about the prevalence of non-cystic fibrosis bronchiectasis etiologies in the Colombian population. To investigate non-cystic fibrosis bronchiectasis etiology and clinical characteristics in adults evaluated in the southwest of Colombia. We conducted a cross-sectional, non-interventional study. Subjects diagnosed with non-cystic fibrosis bronchiectasis were referred to by their healthcare providers and then enrolled between October 2018 and April 2021. Medical records and radiological studies were evaluated. Participants underwent laboratory tests, including complete blood count, serum immunoglobulin levels, and, in some cases, additional tests. We included 161 subjects. The average age was 50 years old, and 59% were females. Bronchiectasis etiology was identified in 84.6% of the cases. Postinfectious (34.6%) and immune disorders (25.3%), represented by autoimmunity (13.6%) and immunodeficiency (11.7%), were the leading causes. Gender differences were noted in autoimmune (females: 18.8% versus males: 6.1%, p = 0.021) and immunodeficiency-related bronchiectasis (males: 21.2% versus females 5.2%, p = 0.002). Immunodeficiencies-associated bronchiectases were more frequent in subjects under 50 years of age, while chronic obstructive pulmonary disease-associated bronchiectases were common in subjects over 50 years of age. The etiologies of non-cystic fibrosis bronchiectasis in Colombia are diverse, exhibiting notable differences from other global regions. Serum immunoglobulin levels and clinical immunologist consultation should be prioritized in diagnosing patients with unclear bronchiectasis etiology, particularly those with recurrent sinopulmonary infections.