Treatment Of Obstructive Lung Diseases Research Articles

Causal relationship between frailty and chronic obstructive pulmonary disease or asthma: A two sample bidirectional Mendelian randomization study

BackgroundObservational studies have established a strong association between frailty and obstructive lung diseases. However, the causal nature of this association remains unclear. To address this gap, we conducted a bidirectional Mendelian randomization (MR) study to investigate the causal relationship between frailty, as measured by the frailty index (FI), and chronic obstructive pulmonary disease (COPD) or asthma. MethodsThe latest meta-analysis of genome-wide association studies for FI, which included individuals of European ancestry from UK Biobank and TwinGene (N = 175,226), yielded the genetic instruments for frailty and outcome summary statistics. The genetic instrument for COPD and asthma, as well as the outcome summary data, were derived from the GWAS conducted on individuals of European ancestry from the FinnGen, with a sample size of 16,410 cases and 283,589 controls for COPD, and 37,253 cases and 187,112 controls for asthma. The analysis of MR was conducted employing the inverse-variance weighted (IVW) method, complemented by the weighted median method, MR-Egger regression, and MR pleiotropy residual sum and outlier (MR-PRESSO) test. ResultsOur results showed that genetically predicted higher FI was significantly associated with increased risk of COPD (odds ratio [OR] 1.75, 95 % confidence interval [CI] 1.29–2.36) and asthma (OR 2.10, 95 % CI 1.44–3.16). In the reverse direction analysis, genetic liability to both COPD (beta 0.06, 95 % CI 0.01–0.10) and asthma (beta 0.08, 95 % CI 0.06–0.11) showed significant associations with a higher FI. ConclusionsOur research has reinforced the existing evidence supporting a reciprocal causal relationship between frailty and obstructive lung diseases. A deeper comprehension of this interconnection is imperative for the prevention and treatment of obstructive lung diseases.

Drug consumption in the treatment of obstructive lung diseases in the Republic of Serbia in the period from 2011 to 2020

Drug consumption in the treatment of obstructive lung diseases in the Republic of Serbia in the period from 2011 to 2020

Selective Signal Capture from Multidimensional GPCR Outputs with Biased Agonists: Progress Towards Novel Drug Development.

G protein coupled receptors (GPCRs) are a superfamily of transmembrane-spanning receptors that are activated by multiple endogenous ligands and are the most common target for agonist or antagonist therapeutics across a broad spectrum of diseases. Initial characterization within the superfamily suggested that a receptor activated a single intracellular pathway, depending on the G protein to which it coupled. However, it has become apparent that a given receptor can activate multiple different pathways, some being therapeutically desirable, while others are neutral or promote deleterious signaling. The activation of pathways that limit effectiveness of a primary pathway or promote unwanted signals has led to abandonment of some GPCRs as drug targets. However, it is now recognized that the conformation of the receptor in its ligand-bound state can be altered by the structure of the agonist or antagonist to achieve pathway selectivity, a property termed biased signaling. Biased ligands could dramatically expand the number of novel drugs acting at GPCRs for new indications. However, the field struggles with the complexity and uncertainty of these structure-functions relationships. In this review we define the theoretical underpinnings of the biased effect, discuss the methods for measuring bias, and the pitfalls that can lead to incorrect assignments of bias. Using the recent elucidation of a β2-adrenergic receptor agonist that is biased in favor of Gs coupling over β-arrestin binding, we provide an example of how large libraries of compounds that are impartial to preconceived notions of agonist binding can be utilized to discover pathway-specific agonists. In this case, an agonist that lacks tachyphylaxis for the treatment of obstructive lung diseases was uncovered, with a structure that was distinctly different from other agonists. We show how biased characteristics were ascertained analytically, and how molecular modeling and simulations provide a structural basis for a restricted signaling repertoire.

Biased β-Agonists Favoring Gs over β-Arrestin for Individualized Treatment of Obstructive Lung Disease.

Signals from G-protein-coupled receptors (GPCRs) are the most frequently targeted pathways of currently prescribed therapeutics. Rather than being a simple switch, it is now evident that a given receptor can directly initiate multiple signals, and biasing to achieve signal selectivity based on agonist structure is possible. Biased agonists could direct therapeutically favorable pathways while avoiding counterproductive or adverse reaction pathways. For obstructive lung diseases, β2-adrenergic receptor (β2AR) agonists act at these receptors on airway smooth muscle (ASM) cells to open the airways by relaxing ASM, improving airflow and morbidity. However, these receptors signal to the G protein Gs (increasing cAMP and promoting relaxation), but also to β-arrestin (promoting desensitization and a loss of effectiveness). Indeed, β-agonist use is associated with adverse events in asthma pathogenesis and clinical outcomes which are related to desensitization. β-agonists favoring Gs coupling over β-arrestin binding would provide a means of tailoring bronchodilator therapy. In this review, we show how combinatorial methods with a 40 million compound agnostic library led to a new class of biased β-agonists that do not desensitize, providing an opportunity to personalize therapy in patients who experience poor efficacy or adverse effects from traditional balanced agonists.

Inhaled β2 Adrenergic Agonists and Other cAMP-Elevating Agents: Therapeutics for Alveolar Injury and Acute Respiratory Disease Syndrome?

Inhaled long-acting β-adrenergic agonists (LABAs) and short-acting β-adrenergic agonists are approved for the treatment of obstructive lung disease via actions mediated by β2 adrenergic receptors (β2-ARs) that increase cellular cAMP synthesis. This review discusses the potential of β2-AR agonists, in particular LABAs, for the treatment of acute respiratory distress syndrome (ARDS). We emphasize ARDS induced by pneumonia and focus on the pathobiology of ARDS and actions of LABAs and cAMP on pulmonary and immune cell types. β2-AR agonists/cAMP have beneficial actions that include protection of epithelial and endothelial cells from injury, restoration of alveolar fluid clearance, and reduction of fibrotic remodeling. β2-AR agonists/cAMP also exert anti-inflammatory effects on the immune system by actions on several types of immune cells. Early administration is likely critical for optimizing efficacy of LABAs or other cAMP-elevating agents, such as agonists of other Gs-coupled G protein-coupled receptors or cyclic nucleotide phosphodiesterase inhibitors. Clinical studies that target lung injury early, prior to development of ARDS, are thus needed to further assess the use of inhaled LABAs, perhaps combined with inhaled corticosteroids and/or long-acting muscarinic cholinergic antagonists. Such agents may provide a multipronged, repurposing, and efficacious therapeutic approach while minimizing systemic toxicity. SIGNIFICANCE STATEMENT: Acute respiratory distress syndrome (ARDS) after pulmonary alveolar injury (e.g., certain viral infections) is associated with ∼40% mortality and in need of new therapeutic approaches. This review summarizes the pathobiology of ARDS, focusing on contributions of pulmonary and immune cell types and potentially beneficial actions of β2 adrenergic receptors and cAMP. Early administration of inhaled β2 adrenergic agonists and perhaps other cAMP-elevating agents after alveolar injury may be a prophylactic approach to prevent development of ARDS.

WHAT'S LUPUS GOT TO DO WITH IT? A CASE OF ACUTE HYPERCAPNIC RESPIRATORY FAILURE IN A PATIENT UNDERGOING KIDNEY TRANSPLANTATION

SESSION TITLE: Medical Student/Resident Pulmonary Vascular Disease Posters SESSION TYPE: Med Student/Res Case Rep Postr PRESENTED ON: October 18-21, 2020 INTRODUCTION: Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease that is classically associated with constitutional symptoms, joint pain, and erythematous rash. However, patients with SLE can also have multiple cardiopulmonary comorbidities, making management difficult. In this report we present a patient with severe pulmonary arterial hypertension (PAH) and obstructive lung disease due to SLE who experienced a brief arrest during kidney transplantation. CASE PRESENTATION: A 41-year-old female with PAH and end-stage renal disease (ESRD) secondary to SLE presented in 2015 with the following right heart catheter (RHC) findings: RA 5, PAP 73/24 (40), PCWP of 9 mmHg, cardiac index of 1.93 L/min, and PVR of 9.7 Wood units. Alternative causes of PAH were assessed and ruled out via standard diagnostic testing. Treatment was initiated with sildenafil and inhaled treprostinil, but side effects eventually necessitated transition to ambrisentan and selexipag. A repeat RHC in 2017 showed the following: RA 5, PAP 30/17 (21), PCWP of 12 mmHg, cardiac output 3.12 L/min, PVR of 1.8. These improvements strongly suggested a component of Group 1 PAH that responded well to therapy. The patient was listed for renal transplant, and in Feb 2018 this was attempted but aborted due to intraoperative difficulty ventilating, yielding acute hypercapnic respiratory failure and brief cardiac arrest. After recovery and hospital discharge, repeat evaluation showed stable echocardiogram and RHC findings, but severe obstructive lung disease (FEV1/FVC 54, FEV 1 of .92 (40%), RV 161%, and DLCO 57%). Because the pathophysiology of acute hypercapnic respiratory failure does not correspond with acute PAH exacerbation or right ventricular failure, we suspected that severe air trapping secondary to SLE-induced bronchial inflammation led to her intraoperative respiratory arrest. Treatment of obstructive lung disease was then initiated with a fluticasone/salmeterol inhaler and advanced to 500/50 dosage, which led to significant improvement in subsequent FEV1. The patient was then relisted for renal transplant and underwent successful renal transplantation in Oct 2019. She did not require hemodialysis following the transplant, recovered quickly, and was discharged. At this time, 6 months after surgery, she remains functional class II and continues to do very well in the posttransplant setting. DISCUSSION: In this report, despite successful management of our patient's PAH, it was only after treatment of her concurrent SLE-related bronchitis that she was able to successfully receive a renal transplant. CONCLUSIONS: SLE is a systemic condition that can have multiple concurrent cardiopulmonary abnormalities, including obstructive lung disease due to bronchial inflammation and pulmonary arterial hypertension. Therefore, it is important for clinicians to look carefully at treatment options for each related cardiopulmonary condition. Reference #1: Hachulla E, Jais X, Cinquetti G, et al. Pulmonary Arterial Hypertension Associated With Systemic Lupus Erythematosus. Chest. 2018;153(1):143-151. https://doi.org/10.1016/j.chest.2017.08.014https://doi.org/10.1016/j.chest.2017.08.014 Reference #2: Kimoto M, Sharma TS, Manzi S. 35 - Lupus and the Cardiopulmonary System. In: Wallace DJ, Hahn BH, eds. Dubois' Lupus Erythematosus and Related Syndromes (Ninth Edition). Content Repository Only!; 2019:418-433. https://doi.org/10.1016/B978-0-323-47927-1.00035-9 Reference #3: Cojocaru M, Cojocaru IM, Silosi I, Vrabie CD. Manifestations of systemic lupus erythematosus. Maedica (Buchar). 2011;6(4):330-336. DISCLOSURES: No relevant relationships by dan grinnan, source=Web Response No relevant relationships by Meagan Shinbashi, source=Web Response

Observational studies assessing the pharmacological treatment of obstructive lung disease: strengths, challenges and considerations for study design.

Randomised controlled trials (RCTs) are the gold standard for evaluating treatment efficacy in patients with obstructive lung disease. However, due to strict inclusion criteria and the conditions required for ascertaining statistical significance, the patients included typically represent as little as 5% of the general obstructive lung disease population. Thus, studies in broader patient populations are becoming increasingly important. These can be randomised effectiveness trials or observational studies providing data on real-world treatment effectiveness and safety data that complement efficacy RCTs.In this review we describe the features associated with the diagnosis of asthma and chronic obstructive pulmonary disease (COPD) in the real-world clinical practice setting. We also discuss how RCTs and observational studies have reported opposing outcomes with several treatments and inhaler devices due to differences in study design and the variations in patients recruited by different study types. Whilst observational studies are not without weaknesses, we outline recently developed tools for defining markers of quality of observational studies. We also examine how observational studies are capable of providing valuable insights into disease mechanisms and management and how they are a vital component of research into obstructive lung disease.As we move into an era of personalised medicine, recent observational studies, such as the NOVEL observational longiTudinal studY (NOVELTY), have the capacity to provide a greater understanding of the value of a personalised healthcare approach in patients in clinical practice by focussing on standardised outcome measures of patient-reported outcomes, physician assessments, airway physiology, and blood and airway biomarkers across both primary and specialist care.

Azithromycin Inhibits Constitutive Airway Epithelial Sodium Channel Activation in Vitro and Modulates Downstream Pathogenesis in Vivo.

Epithelial sodium channel (ENaC) is an amiloride-sensitive sodium ion channel that is expressed in epithelial tissues. ENaC overexpression and/or hyperactivation in airway epithelial cells cause sodium over-absorption and dysregulated ciliary movement for mucus clearance; however, the agents that suppress constitutive airway ENaC activation are yet to be clinically available. Here, we focused on macrolides, which are widely used antibiotics that have many potential immunomodulatory effects. We examined whether macrolides could modulate constitutive ENaC activity and downstream events that typify cystic fibrosis (CF) and chronic obstructive pulmonary diseases (COPD) in in vitro and in vivo models of ENaC overexpression. Treatment of ENaC-overexpressing human bronchial epithelial cells (β/γENaC-16HBE14o- cells) with three macrolides (erythromycin, clarithromycin, azithromycin) confirmed dose-dependent suppression of ENaC function. For in vivo studies, mice harboring airway specific βENaC overexpression (C57BL/6J-βENaC-transgenic mice) were treated orally with azithromycin, a well-established antimicrobial agent that has been widely prescribed. Azithromycin treatment modulated pulmonary mechanics, emphysematous phenotype and pulmonary dysfunction. Notably, a lower dose (3 mg kg-1) of azithromycin significantly increased forced expiratory volume in 0.1 s (FEV0.1), an inverse indicator of bronchoconstriction. Although not statistically significant, improvement of pulmonary obstructive parameters such as emphysema and lung dysfunction (FEV0.1%) was observed. Our results demonstrate that macrolides directly attenuate constitutive ENaC function in vitro and may be promising for the treatment of obstructive lung diseases with defective mucociliary clearance, possibly by targeting ENaC hyperactivation.

Exploring Patient's Perspectives and Experiences After Start with Inhalation Maintenance Therapy: A Qualitative Theory-Based Study.

BackgroundTreatment of obstructive lung disease with inhalation therapy needs changes in patient behavior. Shortly after the start with inhaled corticosteroids (ICS) maintenance therapy, patients might be in need of additional pharmaceutical care, tailored to their individual needs. This study aimed to provide insight into patient behavior, goals and perceptions regarding their medical treatment at start with ICS therapy, by telephone interviews with ICS starters. Besides, this study investigated pharmacists’ and patients’ experiences with these interviews and opinions on the utility of this type of consultation for daily practice. MethodsSemi-structured telephone interviews were conducted by pharmacists with adult patients 2–3 weeks after starting ICS. The Theoretical Domain Framework (TDF) was used for data analysis and coding. Afterward, the patients and pharmacists were questioned about their experiences with the interview.ResultsFive pharmacists conducted interviews with 23 ICS starters. Except the domains “environmental context and resources”, “optimism”, and “reinforcement”, the remaining 11 domains in the TDF were addressed in the interviews. The majority of patients defined personal goals, which mainly addressed disease or symptom control (clinical goals). Some patients showed a lack of knowledge regarding the clinical indication or therapy duration. Views on beneficial medication effects differed between patients. Some patients specifically mentioned concerns or anxiety about side effects. The interviewees described different perceptions on the necessity of a personalized routine for regular medication use. Patients and pharmacists both felt positive about an added value of these interviews for daily practice.ConclusionPatient interviews shortly after start with ICS therapy revealed various perceptions and beliefs that might influence medication use and achievement of individual treatment goals. The patients appreciated the opportunity to ask questions and share their perspectives and needs with their pharmacist, and the pharmacists experienced that the interviews had added value.

Synthesis and Evaluation of Dendrimers for Autophagy Augmentation and Alleviation of Obstructive Lung Diseases.

Preservation of cellular homeostasis requires constant synthesis of fresh proteins and cellular organelles and efficient degradation or removal of damaged proteins and cellular components. This involves two cellular degradation processes or molecular mechanisms: the ubiquitin-proteasome and autophagy-lysosomal systems. Impairment of these catabolic processes has been linked to pathogenesis of a variety of chronic obstructive lung diseases such as COPD (chronic obstructive pulmonary disease) and CF (cystic fibrosis). Proteosomal and autophagic functions (proteostasis) are known to decline with advancing age leading to accumulation of cellular debris and proteins, initiating cellular senescence or death and accelerating lung aging. Obstructive lung diseases associated with airway hyperinflammation and mucus obstruction provide major challenges to the delivery and therapeutic efficacy of nanotherapeutics systems as they need to bypass the airway defense. Targeted autophagy augmentation has emerged, as a promising therapeutic utility for alleviating obstructive lung diseases, and promoting healthy aging. A targeted dendrimer-based approach has been designed to penetrate the airway obstruction and allow the selective correction of proteostasis/autophagy in the diseased cells while circumventing the side effects. This report describes methods for synthesis and therapeutic evaluation of autophagy augmenting dendrimers in the treatment of obstructive lung disease(s). The formulations and methods of autophagy augmentation described here are currently under clinical development in our laboratory for alleviating pathogenesis and progression of chronic obstructive lung diseases, and promoting healthy aging.

Voice changes associated with inhaled steroids 1n obstructive lung disease patients

Background/Aims: The widespread use of inhaled corticosteroids (ICS) for the treatment of obstructive lung disease may be associated with both systemic and local side effects. These local side effects; including voice problems, oropharyngeal candidiasis, throat clearing, sense of fullness, pharyngitis, and cough, are generally viewed as minor complications of therapy in what is called steroid inhaler laryngitis (SIL). Few studies have been performed to specifically evaluate local side effects of ICS. However, they can be clinically significant, affect patient's quality of life, hinder compliance with therapy, and mask symptoms of more serious disease. The aim of this study is to examine the effect of ICS on the larynx and subsequent voice changes, and highlighting if these voice problems related to the type of inhaled corticosteroids in order to determine the importance of regular laryngeal examination in those patients. Methods: 40patients with bronchial asthma and 40 patients with COPD admitted to Chest department in Menoufia and Zagazig University Hospitals during the period from March 2017 to March 2019 were included in the study. They were divided according to the type of cortisone used into four groups; group (I): beclomethasone dipropionate (BDP) users, group (II): budesonide (BUD) users, group (III): Ciclesonide users and group (IV): fluticasone propionate (FP) users. They were evaluated as regards videolaryngoscopic examination and acoustic analysis Results: The age of the patients with bronchial asthma ranged from 29 to 42years and the age of the patients with COPD ranged from 31 to 43years. There was a statistically significant difference among the four groups of cortisone inhalation regarding laryngoscopic findings; as presence of congestion (diffuse and local), mucus spills on VF and glottis gap were all higher in frequency among the group of patients used fluticasone FP, while least signs found among ciclesonide users. Also, average pitch, Jitter, H/N ratio and MPT were more worsen in fluticasone group when compared with Ciclesonide group. Conclusion: obstructive lung disease patients may suffer from voice problems related to the type of inhaled corticosteroids that could be fade when therapy is stopped. So, regular laryngeal examination in those patients is important.

Prévalence et retentissement sur la qualité de vie de l’incontinence urinaire dans une population adulte atteinte de troubles ventilatoires obstructifs, revue de littérature

Patients with obstructive lung diseases (OLD) are at-risk population for urinary incontinence (UI) with high frequency of increased intra-abdominal pressure because of chronic cough symptoms. This review is aimed at determining the prevalence of UI and its impact on quality of life, patient healthcare research, diagnosis and treatment of UI among this population. Literature review from January 2001 to 2018 on Medline (PubMed) using keywords urinary incontinence, chronic obstructive pulmonary disease (COPD), asthma, cystic fibrosis, quality of life. The largest study showed that in a population of 14,828 people, whose 995 were diagnosed COPD, UI prevalence was 34.9% in people with COPD, versus 27.3% among the general population of the study (P=0.0048). Results in the other studies of the review were similar. UI was more severe in OLD patients and occurred on young subjects. Stress urinary incontinence symptoms were predominant, during cough but also during spirometry and chest rehabilitation sessions. Despite an impact on quality of life and treatment of OLD, UI was neglected. UI prevalence seemed higher on population with OLD, to a greater degree of severity. Quality of life self-evaluation was further decreased when UI was associated with pulmonary disease.

Clinical Pharmacology of Oral Maintenance Therapies for Obstructive Lung Diseases.

Although inhaled therapies are typically preferred for the maintenance treatment of obstructive lung diseases, oral drug therapies can also play valuable roles. The most commonly used oral agents are phosphodiesterase inhibitors, theophylline, macrolides, leukotriene modifiers, and mucoactive agents. Advantages of these oral agents include the unique pharmacologic mechanisms of action, the avoidance of the challenges of proper inhalational lung administration, and, in most instances, relative drug cost. For many of these agents, anti-inflammatory or immunomodulatory effects are the predominant pharmacologic mechanism that each provides clinical benefit, with the exception of guaifenesin. In addition, theophylline, leukotriene modifiers, chronic macrolides, phosphodiesterase inhibitors, and N-acetylcysteine have been shown to decrease exacerbations in obstructive lung disease. Fairly rapid bronchodilation occurs with the phosphodiesterase inhibitors, theophylline, and leukotriene modifiers, although less than that achieved with inhaled therapies. The clinical roles of phosphodiesterase inhibitors, specifically roflumilast, and macrolides continues to be defined today, whereas the roles theophylline and leukotriene modifiers have probably been largely delineated. Azithromycin is the principal macrolide used chronically for obstructive lung diseases, especially COPD. Although guaifenesin is used widely, its effectiveness is unclear, whereas N-acetylcysteine currently has strong evidence supporting a decreased risk of COPD exacerbations. Mucolytic agents like N-acetylcysteine are used more widely outside the United States in obstructive lung diseases.

Pulmonary arterial stiffening in COPD and its implications for right ventricular remodelling

BackgroundPulmonary pulse wave velocity (PWV) allows the non-invasive measurement of pulmonary arterial stiffening, but has not previously been assessed in COPD. The aim of the current study was to assess PWV in COPD and its association with right ventricular (RV) remodelling.MethodsFifty-eight participants with COPD underwent pulmonary function tests, 6-min walk test and cardiac MRI, while 21 healthy controls (HCs) underwent cardiac MRI. Thirty-two COPD patients underwent a follow-up MRI to assess for longitudinal changes in RV metrics. Cardiac MRI was used to quantify RV mass, volumes and PWV. Differences in continuous variables between the COPD and HC groups was tested using an independent t-test, and associations between PWV and right ventricular parameters was examined using Pearson’s correlation coefficient.ResultsThose with COPD had reduced pulsatility (COPD (mean±SD):24.88±8.84% vs. HC:30.55±11.28%, p=0.021), pulmonary acceleration time (COPD:104.0±22.9ms vs. HC: 128.1±32.2ms, p<0.001), higher PWV (COPD:2.62±1.29ms-1 vs. HC:1.78±0.72ms-1, p=0.001), lower RV end diastolic volume (COPD:53.6±11.1ml vs. HC:59.9±13.0ml, p=0.037) and RV stroke volume (COPD:31.9±6.9ml/m2 vs. HC:37.1±6.2ml/m2, p=0.003) with no difference in mass (p=0.53). PWV was not associated with right ventricular parameters.ConclusionsWhile pulmonary vascular remodelling is present in COPD, cardiac remodelling favours reduced filling rather than increased afterload. Treatment of obstructive lung disease may have greater effect on cardiac function than treatment of pulmonary vascular disease in most COPD patientsKey Points• Pulmonary pulse wave velocity (PWV) is elevated in COPD.• Pulmonary PWV is not associated with right ventricular remodelling.• Right ventricular remodelling is more in keeping with that of reduced filling.

Overexpression of GLP-1 receptors suppresses proliferation and cytokine release by airway smooth muscle cells of patients with chronic obstructive pulmonary disease via activation of ABCA1

Glucagon-like peptide-1 (GLP‑1) is an important insulin secretagogue that possesses anti‑inflammatory effects. GLP‑1 receptor (GLP‑1R) agonists have been demonstrated to serve a pivotal role in the treatment of obstructive lung diseases, including chronic obstructive pulmonary disease (COPD). However, the specific function and underlying mechanisms of GLP‑1R in COPD remain uncertain. The aim of the present study was to investigate the action and underlying mechanisms of GLP‑1R in airway smooth muscle (ASM) cells from COPD patients. GLP‑1R expression levels were markedly decreased in ASM cells from COPD patients compared with those from healthy controls. ASM cell proliferation and migration, and the levels of the inflammatory cytokines interleukin (IL)‑1β, IL‑4, tumor necrosis factor (TNF)‑α, and granulocyte‑macrophage colony‑stimulating factor (GM‑CSF) were measured. Transfection of pcDNA3.1‑GLP‑1R had inhibitory effects on ASM cell proliferation and migration, whereas GLP‑1R small interfering (si)RNA reversed these effects. Furthermore, the present study demonstrated that GLP‑1R overexpression markedly suppressed IL‑1β, IL‑4, TNF‑α and GM‑CSF levels. GLP‑1R overexpression upregulated the expression levels of adenosine triphosphate‑binding cassette, subfamily A, member 1 (ABCA1) in ASM cells, and the effects of GLP‑1R on cell proliferation and migration, and inflammatory cytokine expression in ASM cells was abolished by siRNA‑mediated silencing of ABCA1. The results of the present study suggested that GLP‑1R contributes to COPD pathology, potentially via an ABCA1‑mediated pathway.

A novel inhaled phosphodiesterase 4 inhibitor (CHF6001) reduces the allergen challenge response in asthmatic patients

CHF6001 is an inhaled phosphodiesterase 4 (PDE4) inhibitor in development for the treatment of obstructive lung diseases. The efficacy and safety of CHF6001 were investigated in a double blind, placebo controlled, 3-way cross-over study using the allergen challenge model.Thirty-six atopic asthmatics who were not taking inhaled corticosteroids and who demonstrated a late asthmatic response (LAR) to inhaled allergen at screening were randomised to receive CHF6001 400 μg or 1200 μg or placebo administered once a day using a dry powder inhaler. The three treatment periods were 9 days; allergen challenges were performed on day 9 and induced sputum was obtained after 10 h from challenge. Washout periods between treatments were up to 5 weeks.Both CHF6001 doses significantly attenuated the LAR; the primary endpoint analysis showed that CHF6001 400 μg and 1200 μg caused reductions of 19.7% (p = 0.015) and 28.2% (p < 0.001) respectively of the weighted FEV1 AUC4–10h compared with placebo. The difference between the CHF6001 doses was not statistically significant (p = 0.223). Compared with placebo, CHF6001 caused greater reduction in sputum eosinophil counts, although these changes were not statistically significant. CHF6001 was well tolerated, with similar numbers of adverse events in each treatment period.This inhaled PDE4 inhibitor has the potential to provide clinical benefits in patients with atopic asthma.

Antimitogenic effect of bitter taste receptor agonists on airway smooth muscle cells

Airway remodeling is a hallmark feature of asthma and chronic obstructive pulmonary disease. Clinical studies and animal models have demonstrated increased airway smooth muscle (ASM) mass, and ASM thickness is correlated with severity of the disease. Current medications control inflammation and reverse airway obstruction effectively but have limited effect on remodeling. Recently we identified the expression of bitter taste receptors (TAS2R) on ASM cells, and activation with known TAS2R agonists resulted in ASM relaxation and bronchodilation. These studies suggest that TAS2R can be used as new therapeutic targets in the treatment of obstructive lung diseases. To further establish their effectiveness, in this study we aimed to determine the effects of TAS2R agonists on ASM growth and promitogenic signaling. Pretreatment of healthy and asthmatic human ASM cells with TAS2R agonists resulted in a dose-dependent inhibition of ASM proliferation. The antimitogenic effect of TAS2R ligands was not dependent on activation of protein kinase A, protein kinase C, or high/intermediate-conductance calcium-activated K(+) channels. Immunoblot analyses revealed that TAS2R agonists inhibit growth factor-activated protein kinase B phosphorylation without affecting the availability of phosphatidylinositol 3,4,5-trisphosphate, suggesting TAS2R agonists block signaling downstream of phosphatidylinositol 3-kinase. Furthermore, the antimitogenic effect of TAS2R agonists involved inhibition of induced transcription factors (activator protein-1, signal transducer and activator of transcription-3, E2 factor, nuclear factor of activated T cells) and inhibition of expression of multiple cell cycle regulatory genes, suggesting a direct inhibition of cell cycle progression. Collectively, these findings establish the antimitogenic effect of TAS2R agonists and identify a novel class of receptors and signaling pathways that can be targeted to reduce or prevent airway remodeling as well as bronchoconstriction in obstructive airway disease.

Budesonide Inhibits Intracellular Infection with Non-Typeable Haemophilus influenzae despite Its Anti-Inflammatory Effects in Respiratory Cells and Human Lung Tissue: A Role for p38 MAP Kinase

Background: Inhaled corticosteroids (ICS) are widely used in the treatment of obstructive lung diseases. Recent data suggest a higher pneumonia risk in chronic obstructive pulmonary disease (COPD) patients treated with ICS. Objective: Since non-typeable Haemophilus influenzae (NTHi) is the most common pathogen associated with acute exacerbations of COPD, we investigated the effects of budesonide (BUD) on NTHi-induced inflammation and invasive infection. Methods: The alveolar epithelial cell line A549 and specimens of human lung tissue (HLT) were used in our experiments. Intracellular infection was determined by a lysis/culture assay of infected cells. Activated p38 mitogen-associated protein kinase (MAPK) was assessed using Western blotting and immunohistochemistry, expression of toll-like receptor 2 (TLR2) was determined by PCR, and CXCL-8 levels were measured using ELISA. Immunohistochemistry was used for detection of CXCL-8, platelet-activating factor receptor (PAF-R) and NTHi. Results: BUD significantly reduced CXCL-8 secretion in A549 cells and lung tissue infected with NTHi. Furthermore, BUD decreased the expression of PAF-R in HLT and A549 cells. In A549 cells and HLT, BUD inhibited intracellular infection and - synergistically with NTHi - increased the expression of TLR2 (in A549 cells). TLR2 stimulation did not influence the intracellular infection of A549 cells, but p38 MAPK inhibition resulted in a significant reduction of infection. Conclusion: The present study adds new insights into the effects of glucocorticoids on pulmonary host defence after NTHi infection. Although the inflammatory response to infection is suppressed by BUD, interestingly, the intracellular infection is also inhibited. This effect seems to depend on the inhibition of p38 MAPK - a key enzyme in many pro-inflammatory pathways - as well as of PAF-R expression.

Regional ventilation changes in severe asthma after bronchial thermoplasty with (3)He MR imaging and CT.

To quantify regional lung ventilation in healthy volunteers and patients with severe asthma (both before and after thermoplasty) by using a combination of helium 3 ((3)He) magnetic resonance (MR) imaging and computed tomography (CT), with the intention of developing more effective image-guided treatments for obstructive lung diseases. With approval of the local institutional review board, informed consent, and an Investigational New Drug Exemption, six healthy volunteers and 10 patients with severe asthma were imaged in compliance with HIPAA regulations by using both multidetector CT and (3)He MR imaging. Individual bronchopulmonary segments were labeled voxel by voxel from the CT images and then registered to the (3)He MR images by using custom software. The (3)He signal intensity was then analyzed by evaluating the volume-weighted fraction of total-lung signal intensity present in each segment (segmental ventilation percentage [ SVP segmental ventilation percentage ]) and by identifying the whole-lung defect percentage and the segmental defect percentage. Of the 10 patients with asthma, seven received treatment with bronchial thermoplasty and were imaged with (3)He MR a second time. Changes in segmental defect percentages and whole-lung defect percentages are presented. Ventilation measures for healthy volunteers yielded smaller segment-to-segment variation (mean SVP segmental ventilation percentage , 100% ± 18 [standard deviation]) than did the measures for patients with severe asthma (mean SVP segmental ventilation percentage , 97% ± 23). Patients with asthma also demonstrated larger segmental defect percentages (median, 13.5%; interquartile range, 8.9%-17.8%) than healthy volunteers (median, 6%; interquartile range, 5.6%-6.3%). These quantitative results confirm what is visually observed on the (3)He images. A Spearman correlation of r = -0.82 was found between the change in whole-lung defect percentage and the number of days between final treatment and second (3)He imaging. Regional quantification of lung ventilation is indeed feasible and may be a useful technique for image-guided treatment of obstructive lung diseases, such as bronchial thermoplasty for severe asthma. In these patients, ventilation defects decreased as a function of time after treatment.

Bitter Taste Receptor Function in Asthmatic and Nonasthmatic Human Airway Smooth Muscle Cells

Bitter taste receptors (TAS2Rs) have recently been found to be expressed on human airway smooth muscle (HASM), and their activation results in marked relaxation. These agents have been proposed as a new class of bronchodilators in the treatment of obstructive lung diseases because they act via a different mechanism than β-agonists. The TAS2R signal transduction pathway in HASM has multiple elements that are potentially subject to regulation by inflammatory, genetic, and epigenetic mechanisms associated with asthma. To address this, expression, signaling, and physiologic functions of the three major TAS2Rs (subtypes 10, 14, and 31) on HASM were studied. Transcript expression of these TAS2Rs was not decreased in HASM cells derived from donors with asthma compared with those without asthma (n = 6 from each group). In addition, intracellular calcium ([Ca(2+)]i) signaling using TAS2R subtype-specific agonists (diphenhydramine, chloroquine, saccharin, and flufenamic acid) was not impaired in the cells derived from donors with asthma, nor was the response to quinine, which activates all three subtypes. HASM cell mechanics measured by magnetic twisting cytometry revealed equivalent TAS2R-mediated relaxation of methacholine-treated cells between the two groups. Human precision-cut lung slices treated with IL-13 caused a decrease in β-agonist (formoterol)-mediated relaxation of carbachol-contracted airways compared with control slices. In contrast, TAS2R-mediated relaxation was unaffected by IL-13. We conclude that TAS2R expression or function is unaffected in HASM cells derived from patients with asthma or the IL-13 inflammatory environment.