Progressive Loss Of Lung Function Research Articles

Serum Vitamin D Status in Patients with Asthma-COPD Overlap

Introduction: Asthma-COPD overlap shared its risk factors with asthma and COPD, including development in the later decades of life, airway hyper-responsiveness, often tobacco smoke exposure, and progressive loss of lung function. It has been shown that this group of patients might possess vitamin D deficiency. By assessing the level of vitamin D we can identify the deficiency earlier and can give appropriate supplements. Objective: This study was done to assess the serum vitamin D status in patients with Asthma-COPD overlap. Materials and Methods: This cross-sectional study was carried out in the Department of Physiology of Bangabandhu Sheikh Mujib Medical University, Dhaka, from January 2018 to July 2018. Total 47 men subjects age ranged between 40-70 years were involved in this study. Among them 23 (twenty three) men (40-70 years) were involved as study group (Group II) and 24 (twenty four) men (40-70 years) were taken as control group (Group I). Results: The results were expressed as mean with standard error (mean±SEM). The data were statistically analyzed by Graphpad prism (Version 7) using independent sample ‘t’ test. The mean (±SEM) of serum vitamin D of Group I and Group II were 16.37±0.78 kg/m2 & 18.47±1.01 ng/ml respectively. Conclusion: Vitamin D deficiency is present in both groups. By this study we recommended that routine estimation of this parameter is important for early detection and prevention of complication related to Asthma-COPD overlap for managing a healthy life. Medicine Today 2024, Vol.36 (2): 120-123

Betanin protects against bleomycin-induced pulmonary fibrosis by regulating the NLRP3/IL-1β/TGF-β1 pathway-mediated epithelial-to-mesenchymal transition.

Idiopathic pulmonary fibrosis (IPF) is a life-threatening disease that leads to dyspnea and progressive loss of lung function. This study aimed to investigate the protective effect of betanin (BET), the major pigment in red beetroot, on pulmonary fibrosis induced by bleomycin (BLM) in rats and to assess the underlying mechanisms. In this view, total and differential cell counts and LDH activity in bronchoalveolar lavage fluid were estimated. Furthermore, MDA and GSH contents in the lungs were colorimetrically measured, while hydroxyproline, NLRP3, ASC, caspase-1, TGF-β1, and vimentin levels in lung tissue were evaluated using the ELISA technique. Moreover, IL-1β, E-cadherin, and α-SMA expressions were analyzed by immunostaining of lung specimens. BET treatment protects against pulmonary fibrosis as indicated by the reduction in total and differential cell counts, LDH activity, hydroxyproline, NLRP3, ASC, caspase-1, IL-1β, and TGF-β1 levels. MDA content was also decreased following BET administration, while GSH content was elevated. Additionally, BET suppressed the EMT process as evidenced by an increase in E-cadherin expression besides the reduction in vimentin and α-SMA expressions. To conclude, these results revealed the protective effect of BET against pulmonary fibrosis that might be attributed to the attenuation of the NLRP3/IL-1β/TGF-β1 signaling pathway and EMT process.

Molecular Mechanism in the Development of Pulmonary Fibrosis in Patients with Sarcoidosis.

Sarcoidosis is a multisystemic disease of unknown etiology characterized by the formation of granulomas in various organs, especially lung and mediastinal hilar lymph nodes. The clinical course and manifestations are unpredictable: spontaneous remission can occur in approximately two thirds of patients; up to 20% of patients have chronic course of the lung disease (called advanced pulmonary sarcoidosis, APS) resulting in progressive loss of lung function, sometimes life-threatening that can lead to respiratory failure and death. The immunopathology mechanism leading from granuloma formation to the fibrosis in APS still remains elusive. Recent studies have provided new insights into the genetic factors and immune components involved in the clinical manifestation of the disease. In this review we aim to summarize the clinical-prognostic characteristics and molecular pathways which are believed to be associated with the development of APS.

Adaptation of Nontypeable Haemophilus influenzae in Human Airways in COPD: Genome Rearrangements and Modulation of Expression of HMW1 and HMW2.

Chronic obstructive pulmonary disease (COPD) is a common debilitating disorder that is the third most common cause of death globally. Chronic lower airway infection by nontypeable Haemophilus influenzae (NTHi) in adults with COPD increases airway inflammation, causes increased symptoms, and accelerates progressive loss of lung function. Little is known about the mechanisms by which NTHi survives in COPD airways. To explore this question, the present study analyzes, in detail, 14 prospectively collected, serial isolates of a strain that persisted for 543 days in a patient with COPD, including analysis of four gap-free complete genomes. The NTHi genome underwent inversion of a ~400-kb segment three times during persistence. This inversion event resulted in switching of expression of the HMW1A and HMW2A adhesins as the inversion sites are in the promoter regions of HMW1 and HMW2. Regulation of the level of expression of HMW 1 and HMW2 in the human airways was controlled by the ~400-kb inversion and by 7-bp repeats in the HMW promoters. Analysis of knockout mutants of the persistent strain demonstrated that HMW1 and HMW2 proteins both function in the adherence of NTHi to human respiratory epithelial cells during persistence and that HMW1 also facilitates invasion of epithelial cells. An inverse relationship between biofilm formation and HMW1 expression was observed during persistence. This work advances understanding of the mechanisms of persistence of NTHi in COPD airways, which can inform the development of novel interventions to treat and prevent chronic NTHi infection in COPD. IMPORTANCE Nontypeable Haemophilus influenzae (NTHi) persists in the lower airways of adults with chronic obstructive pulmonary disease (COPD) for months to years, increasing airway inflammation that accelerates the progressive loss of lung function. Understanding the mechanisms of persistence in human airways by NTHi is critical in developing novel interventions. Here, in detail, we studied longitudinally collected sequential isolates of a strain of NTHi that persisted in an adult with COPD, including analysis of four gap-free genomes and knockout mutants to elucidate how the genome adapts in human airways. The NTHi genome underwent a genome rearrangement during persistence and this inversion impacted regulation of expression of key virulence phenotypes, including adherence to respiratory epithelial cells, invasion of epithelial cells and biofilm formation. These novel observations advance our understanding of the mechanisms of persistence of NTHi in the airways of adults with COPD.

Dysregulated lipid metabolism in lymphangioleiomyomatosis pathogenesis as a paradigm of chronic lung diseases.

A chronic inflammatory condition characterizes various lung diseases. Interestingly, a great contribution to inflammation is made by altered lipids metabolism, that can be caused by the deregulation of the mammalian target of rapamycin complex-1 (mTORC1) activity. There is evidence that one of mTOR downstream effectors, the sterol regulatory element-binding protein (SREBP), regulates the transcription of enzymes involved in the de novo fatty acid synthesis. Given its central role in cell metabolism, mTOR is involved in several biological processes. Among those, mTOR is a driver of senescence, a process that might contribute to the establishment of chronic lung disease because the characteristic irreversible inhibition of cell proliferation, associated to the acquisition of a pro-inflammatory senescence-associated secretory phenotype (SASP) supports the loss of lung parenchyma. The deregulation of mTORC1 is a hallmark of lymphangioleiomyomatosis (LAM), a rare pulmonary disease predominantly affecting women which causes cystic remodeling of the lung and progressive loss of lung function. LAM cells have senescent features and secrete SASP components, such as growth factors and pro-inflammatory molecules, like cancer cells. Using LAM as a paradigm of chronic and metastatic lung disease, here we review the published data that point out the role of dysregulated lipid metabolism in LAM pathogenesis. We will discuss lipids' role in the development and progression of the disease, to hypothesize novel LAM biomarkers and to propose the pharmacological regulation of lipids metabolism as an innovative approach for the treatment of the disease.

Comparative Study of Ectopic Lymphoid Aggregates in Sheep and Murine Models of Bleomycin-Induced Pulmonary Fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a chronic disease characterized by excessive deposition of extracellular matrix in the interstitial lung parenchyma, often manifested by dyspnea and progressive loss of lung function. The role of inflammation in the pathogenesis of IPF is not well understood. This study evaluated the histopathological and inflammatory components of bleomycin-induced pulmonary fibrosis in mouse and sheep models, in terms of their ability to translate to the human IPF. Merino sheep (n = 8) were bronchoscopically administered with two bleomycin infusions, two weeks apart, into a caudal lung segment, with a saline (control) administered into a caudal segment in the opposite lung. Balb/c mice were twice intranasally instilled, one week apart, with either bleomycin (n = 7); or saline (control, n = 7). Lung samples were taken for the histopathological assessment 28 days in sheep and 21 days in mice after the first bleomycin administration. We observed tertiary lymphoid aggregates, in the fibrotic lung parenchyma of sheep, but not in mouse lung tissues exposed to bleomycin. B-cell and T-cell infiltration significantly increased in sheep lung tissues compared to mouse lung tissues due to bleomycin injury. Statistical analysis showed that the fibrotic score, fibrotic fraction, and tissue fraction significantly increased in sheep lung tissues compared to murine lung tissues. The presence of tertiary lymphoid aggregates in the lung parenchyma and increased infiltration of T-cells and B-cells, in the sheep model, may be useful for the future study of the underlying inflammatory disease mechanisms in the lung parenchyma of IPF patients.

Progressive Disease With Low Survival in Adult Patients With Pulmonary Fibrosis Carrying Surfactant-Related Gene Mutations: An Observational Study

In some patients with progressive fibrosing interstitial lung disease (ILD), disease is caused by carriage of a mutation in a surfactant-related gene (SRG) such as SFTPC, SFTPA2, or ABCA3. However, no aggregated data on disease evolution and treatment outcome have been presented for these patients. In adult patients with ILD with an SRG mutation, what is the course of lung function after diagnosis and during treatment and the survival in comparison with patients with sporadic idiopathic pulmonary fibrosis (sIPF) and familial pulmonary fibrosis (FPF)? We retrospectively examined the clinical course of a cohort of adults with an SRG mutation by screening 48 patients from 20 families with an SRG mutation for availability of clinical follow-up data. For comparison, 248 patients with FPF and 575 patients with sIPF were included. Twenty-three patients with ILD (median age: 45 years; 11 men) with an SRG mutation fulfilled criteria. At diagnosis, patients with an SRG mutation were younger and less often male, but had lower FVC (72%predicted) and diffusing capacity of the lungs for carbon monoxide (46%predicted) compared with patients with FPF or sIPF. In the SRG mutation group, median FVC decline 6months after diagnosis was -40mL and median transplant-free survival was 44months and not different from patients with FPF or sIPF. FVC course was not different among the three cohorts; however, a significantly larger decrease in FVC was found while patients received immunomodulatory or antifibrotic treatment compared with those receiving no treatment. Subsequent analysis in the SRG group showed that patients with a surfactant mutation (n= 7) treated for 6months with antifibrotic drugs showed stable lung function with a median change in FVC of+40mL (interquartile range, -40 to 90mL), whereas patients with an SRG mutation treated with immunomodulatory drugs showed a variable response dependent on the gene involved. This study showed that patients with ILD carrying an SRG mutation experience progressive loss of lung function with severely reduced survival despite possible beneficial effects of treatment.

Prenatal exposure to air pollution: A susceptibility factor to develop Chronic Obstructive Pulmonary Disease?

Chronic obstructive pulmonary disease (COPD) is characterized by an irreversible airflow obstruction, accompanied by the progressive loss of lung function. COPD clinical onset occurs after 40ys, but the role of events occurring before entering adult life is more and more suggested. As exposure of adults or children to air pollution is associated with (functional) respiratory alterations, and perinatal exposure to air pollution has been reported to cause deleterious consequences on fetal growth and development, our hypothesis is that prenatal exposure to air pollution could represent a susceptibility factor to develop COPD at adult age. Our objective is therefore to address this issue thanks to an innovative approach based on the use of an atmospheric simulation chamber dedicated to the study of multiphasic atmospheric processes. Pregnant C57/BL6 J mice were exposed to Beijing- or Paris-type atmospheres (hereafter: Beijing or Paris) or to their respective Control air from 9th to 16th day of gestation. At adulthood (D60), the offspring are exposed to cigarette smoke, as a mice model of COPD. The effects on lung development, remodeling and function in the offspring were studied at different life stages. The kinetics of appearance of COPD and its severity were analyzed. Prenatal exposure to either Beijing or Paris simulated atmosphere is accompanied by a higher neonatal mortality as compared to their respective Control air. At adolescence (D17), morphological analyses show a delayed lung development in Beijing offspring as compared to its Control air. Interestingly, the lung of offspring “catches up” at adult age (D60), as a normal pulmonary structure is observed. After 3-month cigarette smoking (D150), we can observe a destruction of alveolar walls in Beijing offspring (characteristic of emphysema), as well as in their littermates exposed in utero to Control air. No such phenomena are observed in Paris offspring. The underlying molecular mechanisms are still under investigation. Prenatal exposure to high pollution simulated atmosphere leads to a delayed pulmonary development, followed by a catch-up at adult age. At the moment, our results do not allow us to state that this leads to a particular susceptibility to develop COPD later on.

Antibiotic therapy for chronic infection with Burkholderia cepacia complex in people with cystic fibrosis.

Cystic fibrosis (CF) a life-limiting inherited disease affecting a number of organs, but classically associated with chronic lung infection and progressive loss of lung function. Chronic infection by Burkholderia cepacia complex (BCC) is associated with increased morbidity and mortality and therefore represents a significant challenge to clinicians treating people with CF. This review examines the current evidence for long-term antibiotic therapy in people with CF and chronic BCC infection. The objective of this review is to assess the effects of long-term oral and inhaled antibiotic therapy targeted against chronic BCC lung infections in people with CF. The primary objective is to assess the efficacy of treatments in terms of improvements in lung function and reductions in exacerbation rate. Secondary objectives include quantifying adverse events, mortality and changes in quality of life associated with treatment. We searched the Cochrane Cystic Fibrosis Trials Register, compiled from electronic database searches and handsearching of journals and conference abstract books. We also searched online trial registries and the reference lists of relevant articles and reviews. Date of last search: 12 April 2021. Randomised controlled trials (RCTs) of long-term antibiotic therapy in people with CF and chronic BCC infection. Two authors independently extracted data, assessed risk of bias and assessed the quality of the evidence using GRADE. We included one RCT (100 participants) which lasted 52 weeks comparing continuous inhaled aztreonam lysine (AZLI) and placebo in a double-blind RCT for 24 weeks, followed by a 24-week open-label extension and a four-week follow-up period. The average participant age was 26.3 years, 61% were male and average lung function was 56.5% predicted. Treatment with AZLI for 24 weeks was not associated with improvement in forced expiratory volume in one second (FEV1), mean difference 0.91% (95% confidence interval (CI) -3.15 to 4.97) (moderate-quality evidence). The median time to the next exacerbation was 75 days in the AZLI group compared to 51 days in the placebo group, but the difference was not significant (P = 0.27) (moderate-quality evidence). Similarly, the number of participants hospitalised for respiratory exacerbations showed no difference between groups, risk ratio (RR) 0.88 (95% CI 0.53 to 1.45) (moderate-quality evidence). Overall adverse events were similar between groups, RR 1.08 (95% CI 0.98 to 1.19) (moderate-quality evidence). There were no significant differences between treatment groups in relation to mortality (moderate-quality evidence), quality of life or sputum density. In relation to methodological quality, the overall risk of bias in the study was assessed to be unclear to low risk. We found insufficient evidence from the literature to determine an effective strategy for antibiotic therapy for treating chronic BCC infection.

Phase 2 trial design of BMS-986278, a lysophosphatidic acid receptor 1 (LPA1) antagonist, in patients with idiopathic pulmonary fibrosis (IPF) or progressive fibrotic interstitial lung disease (PF-ILD)

IntroductionIdiopathic pulmonary fibrosis (IPF) and non-IPF, progressive fibrotic interstitial lung diseases (PF-ILD), are associated with a progressive loss of lung function and a poor prognosis. Treatment with antifibrotic agents can...

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.

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.

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.

The Predictive Role of Biomarkers and Genetics in Childhood Asthma Exacerbations.

Asthma exacerbations are associated with significant childhood morbidity and mortality. Recurrent asthma attacks contribute to progressive loss of lung function and can sometimes be fatal or near-fatal, even in mild asthma. Exacerbation prevention becomes a primary target in the management of all asthmatic patients. Our work reviews current advances on exacerbation predictive factors, focusing on the role of non-invasive biomarkers and genetics in order to identify subjects at higher risk of asthma attacks. Easy-to-perform tests are necessary in children; therefore, interest has increased on samples like exhaled breath condensate, urine and saliva. The variability of biomarker levels suggests the use of seriate measurements and composite markers. Genetic predisposition to childhood asthma onset has been largely investigated. Recent studies highlighted the influence of single nucleotide polymorphisms even on exacerbation susceptibility, through involvement of both intrinsic mechanisms and gene-environment interaction. The role of molecular and genetic aspects in exacerbation prediction supports an individual-shaped approach, in which follow-up planning and therapy optimization take into account not only the severity degree, but also the risk of recurrent exacerbations. Further efforts should be made to improve and validate the application of biomarkers and genomics in clinical settings.

Hyperinflammation and airway surface liquid dehydration in cystic fibrosis: purinergic system as therapeutic target.

The exacerbate inflammatory response contributes to the progressive loss of lung function in cystic fibrosis (CF), a genetic disease that affects the osmotic balance of mucus and mucociliary clearance, resulting in a microenvironment that favors infection and inflammation. The purinergic system, an extracellular signaling pathway characterized by nucleotides, enzymes and receptors, may have a protective role in the disease, through its action in airway surface liquid (ASL) and anti-inflammatory response. To make up this review, studies covering topics of CF, inflammation, ASL and purinergic system were selected from the main medical databases, such as Pubmed and ScienceDirect. We propose several ways to modulate the purinergic system as a potential therapy for CF, like inhibition of P2X7, activation of P2Y2, A2A and A2B receptors and blocking of adenosine deaminase. Among them, we postulate that the most suitable strategy is to block the action of adenosine deaminase, which culminates in the increase of Ado levels that presents anti-inflammatory actions and improves mucociliary clearance. Furthermore, it is possible to maintain the physiological levels of ATP to control the hydration of ASL. These therapies could correct the main mechanisms that contribute to the progression of CF.

There is detectable variation in the lipidomic profile between stable and progressive patients with idiopathic pulmonary fibrosis (IPF)

BackgroundIdiopathic pulmonary fibrosis (IPF) is a chronic interstitial lung disease characterized by fibrosis and progressive loss of lung function. The pathophysiological pathways involved in IPF are not well understood. Abnormal lipid metabolism has been described in various other chronic lung diseases including asthma and chronic obstructive pulmonary disease (COPD). However, its potential role in IPF pathogenesis remains unclear.MethodsIn this study, we used ultra-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-QTOF-MS) to characterize lipid changes in plasma derived from IPF patients with stable and progressive disease. We further applied a data-independent acquisition (DIA) technique called SONAR, to improve the specificity of lipid identification.ResultsStatistical modelling showed variable discrimination between the stable and progressive subjects, revealing differences in the detection of triglycerides (TG) and phosphatidylcholines (PC) between progressors and stable IPF groups, which was further confirmed by mass spectrometry imaging (MSI) in IPF tissue.ConclusionThis is the first study to characterise lipid metabolism between stable and progressive IPF, with results suggesting disparities in the circulating lipidome with disease progression.

Elexacaftor co-potentiates the activity of F508del and gating mutants of CFTR

Trikafta, the combination of elexacaftor (VX-445), tezacaftor (VX-661) and ivacaftor (VX-770), was approved for therapy of cystic fibrosis (CF) patients with at least one allele of the CFTR mutation F508del. While the corrector function of VX-445 is well established, here we investigated the putative potentiator activity of VX-445 alone and in combination with VX-770. Acute addition of VX-445 increased the VX-770-potentiated F508del- and G551D-CFTR current by ~24% and >70%, respectively, in human bronchial and nasal epithelia. Combinatorial profiling and cluster analysis of G551D- and G1244E-CFTR channel activation with potentiator pairs indicated a distinct VX-445 mechanism of action that is, at least, additive to previously identified potentiator classes, including the VX-770. Since VX-770 only partially normalizes the G551D-CFTR channel function and adult G551D patients still experience progressive loss of lung function, VX-445+VX-770 combination therapy could provide clinical benefit to CF patients with the G551D and other dual potentiator responsive mutants.

Asthma in Cystic Fibrosis: Definitions and Implications of This Overlap Syndrome.

Cystic fibrosis (CF) is a multisystem, autosomal recessive disease that leads to progressive loss of lung function. Respiratory symptoms for both CF and asthma include cough, wheezing, and dyspnea. There is debate within the CF community on how to best define and distinguish CF-asthma overlap syndrome (CFAOS) from asthma-like features, though CFAOS is well-recognized. We aim to review the epidemiology, diagnosis, and treatment of asthma in CF and explore areas where further research is needed. There has been considerable improvement in the understanding and treatment of asthma over the past two decades leading to novel therapies such as biologic agents that target the airway inflammation in asthmatics based on their asthma phenotype. These therapies are being studied in CFAOS and are promising treatments. This review provides a comprehensive overview of the definition, epidemiology, diagnosis, and current treatment of CFAOS.

The Potential Roles of Exosomes in Chronic Obstructive Pulmonary Disease.

Currently, chronic obstructive pulmonary disease (COPD) is one of the most common chronic lung diseases. Chronic obstructive pulmonary disease is characterized by progressive loss of lung function due to chronic inflammatory responses in the lungs caused by repeated exposure to harmful environmental stimuli. Chronic obstructive pulmonary disease is a persistent disease, with an estimated 384 million people worldwide living with COPD. It is listed as the third leading cause of death. Exosomes contain various components, such as lipids, microRNAs (miRNAs), long non-coding RNAs(lncRNAs), and proteins. They are essential mediators of intercellular communication and can regulate the biological properties of target cells. With the deepening of exosome research, it is found that exosomes are strictly related to the occurrence and development of COPD. Therefore, this review aims to highlight the unique role of immune-cell-derived exosomes in disease through complex interactions and their potentials as potential biomarkers new types of COPD.

Indoleamine 2,3-Dioxygenase in Hematopoietic Stem Cell-Derived Cells Suppresses Rhinovirus-Induced Neutrophilic Airway Inflammation by Regulating Th1- and Th17-Type Responses

Asthma exacerbations are a major cause of intractable morbidity, increases in health care costs, and a greater progressive loss of lung function. Asthma exacerbations are most commonly triggered by respiratory viral infections, particularly with human rhinovirus (hRV). Respiratory viral infections are believed to affect the expression of indoleamine 2,3-dioxygenase (IDO), a limiting enzyme in tryptophan catabolism, which is presumed to alter asthmatic airway inflammation. Here, we explored the detailed role of IDO in the progression of asthma exacerbations using a mouse model for asthma exacerbation caused by hRV infection. Our results reveal that IDO is required to prevent neutrophilic inflammation in the course of asthma exacerbation caused by an hRV infection, as corroborated by markedly enhanced Th17- and Th1-type neutrophilia in the airways of IDO-deficient mice. This neutrophilia was closely associated with disrupted expression of tight junctions and enhanced expression of inflammasome-related molecules and mucin-inducing genes. In addition, IDO ablation enhanced allergen-specific Th17- and Th1-biased CD4+ T-cell responses following hRV infection. The role of IDO in attenuating Th17- and Th1-type neutrophilic airway inflammation became more apparent in chronic asthma exacerbations after repeated allergen exposures and hRV infections. Furthermore, IDO enzymatic induction in leukocytes derived from the hematopoietic stem cell (HSC) lineage appeared to play a dominant role in attenuating Th17- and Th1-type neutrophilic inflammation in the airway following hRV infection. Therefore, IDO activity in HSC-derived leukocytes is required to regulate Th17- and Th1-type neutrophilic inflammation in the airway during asthma exacerbations caused by hRV infections.