Loss Of Lung Function Research Articles

Multi-Omics Study of Keystone Species in a Cystic Fibrosis Microbiome.

Ecological networking and in vitro studies predict that anaerobic, mucus-degrading bacteria are keystone species in cystic fibrosis (CF) microbiomes. The metabolic byproducts from these bacteria facilitate the colonization and growth of CF pathogens like Pseudomonas aeruginosa. Here, a multi-omics study informed the control of putative anaerobic keystone species during a transition in antibiotic therapy of a CF patient. A quantitative metagenomics approach combining sequence data with epifluorescence microscopy showed that during periods of rapid lung function loss, the patient’s lung microbiome was dominated by the anaerobic, mucus-degrading bacteria belonging to Streptococcus, Veillonella, and Prevotella genera. Untargeted metabolomics and community cultures identified high rates of fermentation in these sputa, with the accumulation of lactic acid, citric acid, and acetic acid. P. aeruginosa utilized these fermentation products for growth, as indicated by quantitative transcriptomics data. Transcription levels of P. aeruginosa genes for the utilization of fermentation products were proportional to the abundance of anaerobic bacteria. Clindamycin therapy targeting Gram-positive anaerobes rapidly suppressed anaerobic bacteria and the accumulation of fermentation products. Clindamycin also lowered the abundance and transcription of P. aeruginosa, even though this patient’s strain was resistant to this antibiotic. The treatment stabilized the patient’s lung function and improved respiratory health for two months, lengthening by a factor of four the between-hospitalization time for this patient. Killing anaerobes indirectly limited the growth of P. aeruginosa by disrupting the cross-feeding of fermentation products. This case study supports the hypothesis that facultative anaerobes operated as keystone species in this CF microbiome. Personalized multi-omics may become a viable approach for routine clinical diagnostics in the future, providing critical information to inform treatment decisions.

The Involvement of PDE4 in the Protective Effects of Melatonin on Cigarette-Smoke-Induced Chronic Obstructive Pulmonary Disease.

Chronic obstructive pulmonary disease (COPD) is a significant disease threatening human health. Currently, roflumilast, a phosphodiesterase (PDE)4 inhibitor, is recommended as a therapeutic agent for COPD. In this study, we investigated the therapeutic effects of melatonin against COPD, focusing on determining whether it is a PDE4 inhibitor via in vivo and in vitro experiment using cigarette smoke (CS) and cigarette smoke condensate (CSC), respectively. In the in vivo experiments, melatonin treatment reduced inflammatory responses, including inflammatory cell counts. Melatonin treatment also suppressed the CS-exposure-induced upregulation of cytokine and matrix metalloproteinase (MMP)-9, reduced the PDE4B expression, and elevated cAMP levels. In addition, these effects were synergistic, as melatonin and roflumilast cotreatment eventually ameliorated the CS-exposure-induced worsening of lung function. In the CSC-stimulated NCI-H292 cells, melatonin inhibited elevation in the levels of inflammatory cytokines, MMP-9, and PDE4, and elevated cAMP levels. Furthermore, melatonin and roflumilast cotreatment was more effective on inflammatory responses than only melatonin or roflumilast treatment. Our results indicate that melatonin relieves inflammatory response and loss of lung function in COPD, which is associated with decreased PDE4 expression. Therefore, we suggest that melatonin is a putative candidate for the treatment of COPD.

Post-infection pulmonary sequelae after COVID-19 among patients with lung transplantation.

BackgroundThere is limited data on outcomes among lung transplant (LT) patients who survive Coronavirus disease 2019 (COVID‐19).MethodsAny single or bilateral LT patients who tested positive for SARS‐CoV‐2 between March 1, 2020, to February 15, 2021 (n = 54) and survived the acute illness were included (final n = 44). Each patient completed at least 3 months of follow‐up (median: 4.5; range 3–12 months) after their index hospitalization for COVID‐19. The primary endpoint was a significant loss of lung functions (defined as > 10% decline in forced vital capacity (FVC) or forced expiratory volume in 1 s (FEV1) on two spirometries, at least 3 weeks apart compared to the pre‐infection baseline).ResultsA majority of the COVID‐19 survivors had persistent parenchymal opacities (n = 29, 65.9%) on post‐infection CT chest. Patients had significantly impaired functional status, with the majority reporting residual disabilities (Karnofsky performance scale score of 70% or worse; n = 32, 72.7%). A significant loss of lung function was observed among 18 patients (40.9%). Three patients met the criteria for new chronic lung allograft dysfunction (CLAD) following COVID‐19 (5.6%), with all three demonstrating restrictive allograft syndrome phenotype. An absolute lymphocyte count < 0.6 × 103/dl and ferritin > 150 ng/ml at the time of hospital discharge was independently associated with significant lung function loss.ConclusionsA significant proportion of COVID‐19 survivors suffer persistent allograft injury. Low absolute lymphocyte counts (ALC) and elevated ferritin levels at the conclusion of the hospital course may provide useful prognostic information and form the basis of a customized strategy for ongoing monitoring and management of allograft dysfunction.TweetTwitter handle: @AmitBangaMDLung transplant patients who survive COVID‐19 suffer significant morbidity with persistent pulmonary opacities, loss of lung functions, and functional deficits. Residual elevation of the inflammatory markers is predictive.

Fast decliner phenotype of chronic obstructive pulmonary disease (COPD): applying machine learning for predicting lung function loss

BackgroundChronic obstructive pulmonary disease (COPD) is a heterogeneous group of lung conditions challenging to diagnose and treat. Identification of phenotypes of patients with lung function loss may allow early intervention...

AEROBIC TRAINING MODULATE PULMONARY AND SYSTEMIC INFLAMMATORY AND FIBROTIC RESPONSE IN PATIENTS WITH ASTHMA

TOPIC: Pulmonary Rehabilitation TYPE: Original Investigations PURPOSE: Airway remodeling is a hallmark of asthma, characterized by structural changes in the airways, including epithelial metaplasia, subepithelial fibrosis, angiogenesis and thickening of smooth muscle. Airway remodeling promotes irreversible loss of lung function and subside the airway hyperresponsiveness and is associated with severity of the disease. In addition, airway remodeling is caused by an unresolved chronic inflammatory response, involving exacerbated release of profibrotic mediators. Aerobic exercise (AE) is the main component of pulmonary rehabilitation and in pre-clinical studies in models of asthma, AE reduced airway remodeling, by reducing the release of pro-fibrotic mediators and increasing the release of anti-fibrotic mediators. However, no clinical study has tested whether AE could promote any effect on airway remodeling in asthmatic patients. METHODS: Treadmill aerobic exercise (AE) (12 weeks, 3x/week, 40min/session, 60-80%MaxHR) was applied to 17 persistent moderate asthmatic patients (42.11±19.13). Body mass index (BMI), lung function, induced sputum, breath condensate, whole blood analysis and CD4+ cells proliferation, 6MWT, exhaled nitric oxide, was evaluated. RESULTS: AE improved VEF3 (L) (p<0.03) and PEF (L/min) (p<0.005) and PEF (%) (p<0.004), reduced the number of total leukocytes, eosinophils, neutrophils, lymphocytes and macrophages (p<0.01), as well as the levels of IL-1beta, IL-4, IL-5, IL-6, IL-8, IL-13, IL-17, IL-23 (p<0.01) in induced sputum. AE also reduced the levels of IL-1beta, IL-5, IL-6, IL-13, VEGF (p<0.01), while increased the levels of anti-inflammatory IL-1ra and IL-10 (p<0.01) and anti-fibrotic Relaxin 3 (p<0.01) in breath condensate. Systemically, AE reduced the number of eosinophils, neutrophils and lymphocytes (p<0.01), as well as the levels of IL-1beta, IL-5, IL-6, IL-13, VEGF (p<0.01), while increased anti-inflammatory IL-1ra, IL-10 (p<0.01) and anti-fibrotic Relaxin 3 (p<0.01) in plasma. AE improved 6MWT (p<0.01) and reduced exhaled nitric oxide (p<0.01) and CD4+ cells proliferation (p<0.01). CONCLUSIONS: In conclusion, AE improves airway and systemic inflammation reducing pro-inflammatory cytokines, while increased anti-inflammatory and anti-fibrotic mediators systemically and into the lungs. CLINICAL IMPLICATIONS: These findings present unprecedented findings on auxiliary treatment and prevention of the health consequences of people with asthma through the practice of physical exercise. From a social point of view, it demonstrates a low-cost and easily accessible intervention, while from a scientific point of view, it will promote research ideas in a promising field. DISCLOSURES: No relevant relationships by thiago alves, source=Web Response no disclosure on file for Helida Aquino-Santos; No relevant relationships by RENILSON FERREIRA, source=Web Response no disclosure on file for Claudio Frison; No relevant relationships by Victor Hugo Palmeira, source=Web Response No relevant relationships by 119 Maysa Alves Rodrigues Rangel, source=Web Response No relevant relationships by Anamei Silva-Reis, source=Web Response No relevant relationships by Rodolfo Vieira, source=Web Response

Thoracic Morphology and Bronchial Narrowing Are Related to Pulmonary Function in Adolescent Idiopathic Scoliosis.

In adolescent idiopathic scoliosis (AIS), lung function impairment is not necessarily related to the coronal spinal deformity. Recently, right-sided bronchial narrowing has been reported in thoracic AIS. The aim of this study was to describe the relation of chest and spinal deformity parameters, bronchial narrowing, and lung volumes with pulmonary function in preoperative AIS. Spinal radiographs, low-dose computed tomographic (CT) scans of the spine including the chest, and pulmonary function tests were retrospectively collected for 85 preoperative patients with thoracic AIS in 2 centers and were compared with 14 matched controls. Three-dimensional lung and airway reconstructions were acquired. Correlation analysis was performed in which radiographic spinal parameters, CT-based thoracic deformity parameters (rib-hump index [RHi], spinal penetration index, endothoracic hump ratio, hemithoracic-width ratio), lung volume asymmetry, and bronchial cross-sectional area were compared with percent-of-predicted spirometry results. Forty-one patients (48%) had a percent-of-predicted forced expiratory volume in 1 second (FEV1%) or percent-of-predicted forced vital capacity (FVC%) of <65%, and 17 patients (20%) had obstructive lung disease. All thoracic deformity parameters correlated significantly with FEV1% and FVC%; RHi was found to be the best correlate (rs = -0.52 for FEV1% and -0.54 for FVC%). Patients with AIS with impaired pulmonary function had hypokyphosis, a larger rib hump, increased spinal and thoracic rotation, a narrower right hemithorax, and increased intrusion of the spine into the chest. Spinal intrusion correlated with right-sided bronchial narrowing, relative right lung volume loss, and decreased FEV1% and FVC%. Multivariate regression including spinal and thoracic deformity parameters, lung volume asymmetry, and airway parameters could explain 57% of the variance in FEV1% and 54% of the variance in FVC%. Chest intrusion by the endothoracic hump is related to right-sided bronchial narrowing and lung function loss in preoperative AIS. The findings support the theory that ventilatory dysfunction in thoracic AIS is not only restrictive but frequently has an obstructive component, especially in patients with hypokyphosis. RHi is the most predictive chest parameter for lung function loss. Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.

Assessing the impact of exposome on the course of chronic obstructive pulmonary disease and cystc fibrosis: The REMEDIA European Project Approach.

Because of the direct interaction of lungs with the environment, respiratory diseases are among the leading causes of environment-related deaths in the world. Chronic obstructive pulmonary disease (COPD) and cystic fibrosis (CF) are two highly debilitating diseases that are of particular interest in the context of environmental studies; they both are characterized by a similar progressive loss of lung function with small bronchi alterations, and a high phenotypic variability of unknown origin, which prevents a good therapeutic efficacy. In the last years, there has been an evolution in the apprehension of the study of diseases going from a restricted “one exposure, one disease” approach to a broader concept with other associating factors, the exposome. The overall objective of the REMEDIA project is to extend the understanding of the contribution of the exposome to COPD and CF diseases. To achieve our aim, we will (1) exploit data from existing cohorts and population registries to create a unified global database gathering phenotype and exposome information; (2) develop a flexible individual sensor device combining environmental and biomarker toolkits; (3) use a versatile atmospheric simulation chamber to simulate the health effects of complex exposomes; (4) use machine learning supervised analyses and causal inference models to identify relevant risk factors; and (5) develop econometric and cost-effectiveness models to assess the costs, performance, and cost-effectiveness of a selection of prevention strategies. The results will be used to develop guidelines to better predict disease risks and constitute the elements of the REMEDIA toolbox. The multidisciplinary approach carried out by the REMEDIA European project should represent a major breakthrough in reducing the morbidity and mortality associated with COPD and CF diseases.

Barriers to identifying occupational asthma among primary healthcare professionals: a qualitative study

IntroductionOccupational asthma (OA) accounts for one in six cases of adult-onset asthma and is associated with a large societal cost. Many cases of OA are missed or delayed, leading to...

The effects of exercise training on the lungs and cardiovascular function of animals exposed to diesel exhaust particles and gases

Air pollution has been identified as one of the main environmental risks to health. Since exercise training seems to act as an anti-inflammatory modulator, our hypothesis is that exercise training prevents damage to respiratory and cardiovascular function caused by diesel exhaust particle (DEP) exposure. This study aimed to evaluate whether aerobic exercise training prior to DEP exposure prevents inflammatory processes in the pulmonary and cardiovascular systems. Therefore, BALB/C male mice were or were not submitted to a 10-week exercise training protocol (5×/week, 1 h/d), and after four weeks, they were exposed to DEP in a chamber with 24 μg/m3 PM2.5 or filtered air. Heart rate variability, lung mechanics and bronchoalveolar lavage fluid, cytokines and polymorphonuclear cells in the lung parenchyma were evaluated. Exposure to DEPs reduced heart rate variability and the elastance of the respiratory system and increased the number of cells in bronchoalveolar lavage fluid, as well as macrophages, neutrophils and lymphocytes, the density of polymorphonuclear cells and the proportion of collagen fibres in the lung parenchyma. Additionally, DEP-exposed animals showed increased expression of IL-23 and IL-12p40 (proinflammatory cytokines) and inducible nitric oxide synthase. Exercise training avoided the increases in all these inflammatory parameters, except the elastance of the respiratory system, the amount of collagen fibres and the expression of inducible nitric oxide synthase. Additionally, trained animals showed increased expression of the anti-inflammatory cytokine IL-1ra. Although our data showed a reduction in proinflammatory markers and an increase in markers of the anti-inflammatory pathway, these changes were not sufficient to prevent damage to the lung and cardiovascular function induced by DEPs. Based on these data, we propose that aerobic exercise training prevents the lung inflammatory process induced by DEPs, although it was not sufficient to avoid chronic damage, such as a loss of lung function or cardiovascular events.

The long-term consequences of Corona Virus Disease 2019 patients receiving Chinese herbal medicine treatments in acute phase: A protocol for systematic review and meta-analysis.

Background:In December 2019, the first case of Corona Virus Disease 2019 (COVID-19) associated with severe acute respiratory syndrome coronavirus-2 viral infection was described in Wuhan. Similar to SARS in 2003, COVID-19 also had a lasting impact. Approximately 76% of patients discharged after hospitalization for COVID-19 had neurological manifestations which could persist for 6 months, and some long-term consequences such as the gradual loss of lung function due to pulmonary interstitial fibrosis could have comprehensive effects on daily quality of life for people who were initially believed to have recovered from COVID-19.Methods and analysis:Our comprehensive search strategy developed in consultation with a research librarian. We will search these following electronic databases: PubMed, Cochrane Library, Web of Science, ScienceDirect, Scopus, Google Scholar, Embase, ProQuest, China Science and Technology Journal Database (VIP), China National Knowledge Infrastructure, WANFANG DATA, WHO covid-19 website, and Centers for Disease Control and the Prevention COVID-19 websites of the United States and China. The bias of publication will be confirmed via the P value of Egger test. The quality of studies will be evaluated by the Newcastle-Ottawa Scale.Ethics and dissemination:There are no ethical considerations associated with this study protocol for this systematic review which mainly focuses on the examination of secondary data. On completion of this analysis, we will prepare a manuscript for publication in a peer-reviewed medical journal.PROSPERO registration number:CRD42021258711.

Aerobic fitness is associated with extracellular DNA levels in the sputum of patients with cystic fibrosis.

Patients with cystic fibrosis (CF) develop with progressive loss of lung function and aerobic fitness. However, the precise mechanisms of exercise intolerance are still controversial and appear to be influenced by several factors. This study aimed to evaluate the association of aerobic fitness with free DNA levels in the sputum of patients with CF. This cross-sectional study included patients with CF older than 6 years, free from active exacerbations, but who were able to produce spontaneously expectorated sputum. Extracellular DNA in the sputum was quantified. Lung function (spirometry) and aerobic fitness (cardiopulmonary exercise testing [CPET]) were performed. In addition, demographic, anthropometric and clinical data were collected. Sixteen patients with a mean age of 19.4±6.9 years and mean forced expiratory volume in the first second (FEV1 ) of 51.8±28.1 (% of predicted) were included. Mean peak oxygen consumption (VO2 peak) was 32.8±5.2 mL•kg-1 •min-1 , oxygen saturation at the end of the test was 90.6%±6.3% and mean extracellular DNA levels was 305.3±153.6 μg/mL. Individuals with a VO2 peak ≤ 30 mL•kg-1 •min-1 (P = .03) and a SpO2 ≤ 90% at the end of the test (P = .03) had a greater amount of extracellular DNA in the sputum. The proportion of patients with reduced VO2 peak in the group of patients with the lowest concentration of DNA in the sputum (<243 μg/mL) was significantly lower (0% vs 100%; P = .04). There is an association between the presence of free DNA in sputum and aerobic fitness in patients with CF.

Autophagy, Apoptosis, the Unfolded Protein Response, and Lung Function in Idiopathic Pulmonary Fibrosis.

Autophagy, apoptosis, and the unfolded protein response (UPR) are fundamental biological processes essential for manifold cellular functions in health and disease. Idiopathic pulmonary fibrosis (IPF) is a progressive and lethal pulmonary disorder associated with aging that has limited therapies, reflecting our incomplete understanding. We conducted an observational study linking molecular markers of cell stress response pathways (UPR: BiP, XBP1; apoptosis: cleaved caspase-3; autophagy: LC3β) in lung tissues from IPF patients and correlated the expression of these protein markers to each subject’s lung function measures. We hypothesized that changes in lung tissue expression of apoptosis, autophagy, and UPR markers correlate with lung function deficits in IPF. The cell stress markers BiP, XBP1, LC3β puncta, and cleaved caspase-3 were found to be elevated in IPF lungs compared to non-IPF lungs, and, further, BiP and cleaved caspase-3 co-localized in IPF lungs. Considering lung function independently, we observed that increased XBP1, BiP, and cleaved caspase-3 were each associated with reduced lung function (FEV1, FVC, TLC, RV). However, increased lung tissue expression of LC3β puncta was significantly associated with increased diffusion capacity (DLCO), an indicator of alveolar–capillary membrane function. Similarly, the co-localization of UPR (XBP1, BiP) and autophagy (LC3β puncta) markers was positively correlated with increased lung function (FEV1, FVC, TLC, DLCO). However, the presence of LC3β puncta can indicate either autophagy flux inhibition or activation. While the nature of our observational cross-sectional study design does not allow conclusions regarding causal links between increased expression of these cell stress markers, lung fibrosis, and lung function decline, it does provide some insights that are hypothesis-generating and suggests that within the milieu of active UPR, changes in autophagy flux may play an important role in determining lung function. Further research is necessary to investigate the mechanisms linking UPR and autophagy in IPF and how an imbalance in these cell stress pathways can lead to progressive fibrosis and loss of lung function. We conclude by presenting five testable hypotheses that build on the research presented here. Such an understanding could eventually lead to the development of much-needed therapies for IPF.

PTX3 Regulation of Inflammation, Hemostatic Response, Tissue Repair, and Resolution of Fibrosis Favors a Role in Limiting Idiopathic Pulmonary Fibrosis.

PTX3 is a soluble pattern recognition molecule (PRM) belonging to the humoral innate immune system, rapidly produced at inflammatory sites by phagocytes and stromal cells in response to infection or tissue injury. PTX3 interacts with microbial moieties and selected pathogens, with molecules of the complement and hemostatic systems, and with extracellular matrix (ECM) components. In wound sites, PTX3 interacts with fibrin and plasminogen and favors a timely removal of fibrin-rich ECM for an efficient tissue repair. Idiopathic Pulmonary Fibrosis (IPF) is a chronic and progressive interstitial lung disease of unknown origin, associated with excessive ECM deposition affecting tissue architecture, with irreversible loss of lung function and impact on the patient’s life quality. Maccarinelli et al. recently demonstrated a protective role of PTX3 using the bleomycin (BLM)-induced experimental model of lung fibrosis, in line with the reported role of PTX3 in tissue repair. However, the mechanisms and therapeutic potential of PTX3 in IPF remained to be investigated. Herein, we provide new insights on the possible role of PTX3 in the development of IPF and BLM-induced lung fibrosis. In mice, PTX3-deficiency was associated with worsening of the disease and with impaired fibrin removal and subsequently increased collagen deposition. In IPF patients, microarray data indicated a down-regulation of PTX3 expression, thus suggesting a potential rational underlying the development of disease. Therefore, we provide new insights for considering PTX3 as a possible target molecule underlying therapeutic intervention in IPF.

Occupational exposure to crystalline silica and peripheral biomarkers: An update.

Peripheral biomarkers are important tools for detecting occupational exposures to prevent the onset and/or progression of diseases. Studies that reveal early peripheral biomarkers are highly important to preserve the health of workers and can potentially contribute to diagnosing and/or prognosing occupational pathologies. Exposure to crystalline silica is a problem in several workplaces because it increases the risk of chronic obstructive pulmonary disease (COPD), tuberculosis, cancer, and pulmonary fibrosis, clinically defined as silicosis. Silicosis is diagnosed by chest radiography and/or lung tomography in advanced stages when there is a severe loss of lung function. Peripheral biomarkers can help in diagnosing early changes prior to silicosis and represent a highly important technical-scientific advance that is minimally invasive. This review aimed to investigate the biomarkers studied for evaluating occupational exposure to crystalline silica and to understand the recent advances in this area. Potential oxidative, inflammatory, and immunological biomarkers were reviewed, as well as routine biomarkers such as biochemical parameters. It was found that biomarkers of effect such as serum CC16 and l-selectin levels could represent promising alternatives. Additionally, studies have shown that neopterin levels in urine and serum can be used to monitor worker exposure. However, further studies are needed that include a greater number of participants, different times of exposure to crystalline silica, and a combination of silicosis patients and healthy volunteers. Evaluating the concentration of crystalline silica in occupational environments, its impact on biomarkers of effect, and alterations in lung function could contribute to revealing early health alterations in workers in a more robust manner.

Association of serum vitamin D levels with disease severity, systemic inflammation, prior lung function loss and exacerbations in a cohort of patients with chronic obstructive pulmonary disease (COPD).

BackgroundVitamin D deficiency has been associated with chronic disorders including chronic obstructive pulmonary disease (COPD) but the relationships with inflammation, exacerbations and disease progression remain unclear.MethodsIn this monocentric cross-sectional observational study we analyzed the disease status, systemic inflammation, prior exacerbation frequency and loss in lung function in relation to serum 25-hydroxyvitamin D (25-OHD) levels in a cohort of 94 patients with COPD. Serum 25-OHD, C-reactive protein, interleukin-6 and tumor necrosis factor-α were quantified. Exacerbation frequencies and sunlight exposure were assessed. These parameters were analyzed in correlation to the current forced expiratory volume in 1 s (FEV1), the individual average 3-year FEV1 decline and the Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage.ResultsWe observed fair correlation between serum 25-OHD and the current FEV1 (r=0.38, P<0.001). Furthermore, mean serum 25-OHD was significantly altered between patients of GOLD stages I–IV (P=0.013). There was weak negative correlation of 25-OHD and the average annual change of the FEV1 (r=−0.26, P<0.05). Furthermore, we observed fair negative correlation between 25-OHD and C-reactive protein (r=−0.32, P<0.01) as well as weak negative correlation with interleukin-6 (r=−0.23, P<0.05). While the exacerbation frequency significantly differed between GOLD stages (P=0.04), there was no direct association between exacerbations and 25-OHD levels.ConclusionOur data confirm frequent vitamin D deficiency in COPD and point out correlations between 25-OHD levels, systemic inflammation, disease severity and progression.

Does peripheral blood eosinophil count predict lung function improvement in adult subjects with asthma?

Previous studies have investigated the contribution of the eosinophilic phenotype, as defined by the peripheral blood eosinophil count, in predicting asthma outcomes. There is evidence that the eosinophilic phenotype predicts uncontrolled symptoms and asthma exacerbations.1,2 We are aware of no prospective study evaluating whether the eosinophilic phenotype is a useful biomarker for predicting lung function trends in subjects with asthma who have used maintenance therapy. This is an important issue, because predicting loss of lung function is a meaningful goal of asthma monitoring, as lung function decline leads to irreversible airway obstruction and worse clinical outcomes.

Esomeprazole attenuates inflammatory and fibrotic response in lung cells through the MAPK/Nrf2/HO1 pathway

IntroductionIdiopathic pulmonary fibrosis (IPF) is an orphan disease characterized by progressive loss of lung function resulting in shortness of breath and often death within 3–4 years of diagnosis. Repetitive lung injury in susceptible individuals is believed to promote chronic oxidative stress, inflammation, and uncontrolled collagen deposition. Several preclinical and retrospective clinical studies in IPF have reported beneficial outcomes associated with the use of proton pump inhibitors (PPIs) such as esomeprazole. Accordingly, we sought to investigate molecular mechanism(s) by which PPIs favorably regulate the disease process.MethodsWe stimulated oxidative stress, pro-inflammatory and profibrotic phenotypes in primary human lung epithelial cells and fibroblasts upon treatment with bleomycin or transforming growth factor β (TGFβ) and assessed the effect of a prototype PPI, esomeprazole, in regulating these processes.ResultsOur study shows that esomeprazole controls pro-inflammatory and profibrotic molecules through nuclear translocation of the transcription factor nuclear factor-like 2 (Nrf2) and induction of the cytoprotective molecule heme oxygenase 1 (HO1). Genetic deletion of Nrf2 or pharmacological inhibition of HO1 impaired esomeprazole-mediated regulation of proinflammatory and profibrotic molecules. Additional studies indicate that activation of Mitogen Activated Protein Kinase (MAPK) pathway is involved in the process. Our experimental data was corroborated by bioinformatics studies of an NIH chemical library which hosts gene expression profiles of IPF lung fibroblasts treated with over 20,000 compounds including esomeprazole. Intriguingly, we found 45 genes that are upregulated in IPF but downregulated by esomeprazole. Pathway analysis showed that these genes are enriched for profibrotic processes. Unbiased high throughput RNA-seq study supported antifibrotic effect of esomeprazole and revealed several novel targets.ConclusionsTaken together, PPIs may play antifibrotic role in IPF through direct regulation of the MAPK/Nrf2/HO1 pathway to favorably influence the disease process in IPF.

Clinical characteristics, management practices, and outcomes among lung transplant patients with COVID-19

BackgroundThere are limited data on management strategies and outcomes among lung transplant (LT) patients with Coronavirus disease 2019 (COVID-19). We implemented management protocols based on the best available evidence and consensus among multidisciplinary teams. The current study reports our experience and outcomes using this protocol-based management strategy.MethodsWe included single or bilateral LT patients who tested positive for SARS-CoV-2 on nasopharyngeal swab between March 1, 2020, to December 15, 2020 (n = 25; median age: 60, range 20-73 years; M: F 17:8). A group of patients with Respiratory Syncytial Virus (RSV) infection during 2016-18 were included to serve as a comparator group (n = 36).ResultsAs compared to RSV, patients with COVID-19 were more likely to present with constitutional symptoms, spirometric decline, pulmonary opacities, new or worsening respiratory failure, and need for ventilator support. Patients with SARS-CoV-2 infection were less likely to receive a multimodality treatment strategy, and they experienced worse post-infection lung function loss, functional decline, and three-month survival. A significant proportion of patients with COVID-19 needed readmission for worsening allograft function (36.4%), and chronic kidney disease at initial presentation was associated with this complication. Lower pre-morbid FEV1 appeared to increase the risk of new or worsening respiratory failure, which was associated with worse outcomes.Overall hospital survival was 88% (n = 22). Follow-up data was available for all discharged patients (median: 43.5 days, range 15-287 days). A majority had persistent radiological opacities (19/22, 86.4%), with nearly half of the patients with available post-COVID-19 spirometry showing > 10% loss in lung function (6/13, median loss: 14.5%, range 10%-31%).ConclusionsDespite similar demographic characteristics and predispositions, LT patients with COVID-19 are sicker and experience worse outcomes as compared to RSV. Despite the availability of newer therapeutic agents, COVID-19 continues to be associated with significant morbidity and mortality.

Rifampicin and Letermovir as potential repurposed drug candidate for COVID-19 treatment: insights from an in-silico study.

IntroductionDrug repurposing is the need of the hour considering the medical emergency caused by the COVID-19 pandemic. Recently, cytokine storm by the host immune system has been linked with high viral load, loss of lung function, acute respiratory distress syndrome (ARDS), multiple organ failure, and subsequent fatal outcome. ObjectiveThis study aimed to identify potential FDA approved drugs that can be repurposed for COVID-19 treatment using an in-silico analysis.MethodsIn this study, virtual screening of selected FDA approved drugs was performed by targeting the main protease (Mpro) of SARS-CoV-2 and the key molecules involved in the ‘Cytokine storm’ in COVID-19 patients. Based on our preliminary screening supported by extensive literature search, we selected FDA approved drugs to target the SARS-CoV-2 main protease (Mpro) and the key players of cytokine storm, TNF-α, IL-6, and IL-1β. These compounds were examined based on systematic docking studies and further validated using a combination of molecular dynamics simulations and molecular mechanic/generalized/Born/Poisson-Boltzmann surface area (MM/G/P/BSA) free energy calculations. ResultsBased on the findings, Rifampicin and Letermovir appeared as the most promising drug showing a very good binding affinity with the main protease of SARS-CoV-2 and TNF-α, IL-6, and IL-1β. However, it is pertinent to mention here that our findings need further validation by in vitro analysis and clinical trials.ConclusionThis study provides an insight into the drug repurposing approach in which several FDA approved drugs were examined to inhibit COVID-19 infection by targeting the main protease of SARS-COV-2 and the cytokine storm.Graphic abstract Supplementary InformationThe online version contains supplementary material available at 10.1007/s43440-021-00228-0.

Downregulation of DUOX1 function contributes to aging-related impairment of innate airway injury responses and accelerated senile emphysema.

Aging is associated with a gradual loss of lung function due to increased cellular senescence, decreased regenerative capacity, and impaired innate host defense. One important aspect of innate airway epithelial host defense to nonmicrobial triggers is the secretion of alarmins such as IL-33 and activation of type 2 inflammation, which were previously found to depend on activation of the NADPH oxidase (NOX) homolog DUOX1, and redox-dependent signaling pathways that promote alarmin secretion. Here, we demonstrate that normal aging of C57BL/6J mice resulted in markedly decreased lung innate epithelial type 2 responses to exogenous triggers such as the airborne allergen Dermatophagoides pteronyssinus, which was associated with marked downregulation of DUOX1, as well as DUOX1-mediated redox-dependent signaling. DUOX1 deficiency was also found to accelerate age-related airspace enlargement and decline in lung function but did not consistently affect other features of lung aging such as senescence-associated inflammation. Intriguingly, observations of age-related DUOX1 downregulation and enhanced airspace enlargement due to DUOX1 deficiency in C57BL/6J mice, which lack a functional mitochondrial nicotinamide nucleotide transhydrogenase (NNT), were much less dramatic in C57BL/6NJ mice with normal NNT function, although the latter mice also displayed impaired innate epithelial injury responses with advancing age. Overall, our findings indicate a marked aging-dependent decline in (DUOX1-dependent) innate airway injury responses to external nonmicrobial triggers, but the impact of aging on DUOX1 downregulation and its significance for age-related senile emphysema development was variable between different C57BL6 substrains, possibly related to metabolic alterations due to differences in NNT function.