Senolytics dasatinib and quercetin in idiopathic pulmonary fibrosis: results of a phase I, single-blind, single-center, randomized, placebo-controlled pilot trial on feasibility and tolerability.

Background: Idiopathic pulmonary fibrosis (IPF) is an age-related, chronic, irreversible fibrotic lung disease. IPF is associated with increased senescent cells burden, which may be alleviated with administration of senescent cell targeting drugs termed 'senolytics'. We previously conducted an open-label single-arm pilot study of the senolytic combination of dasatinib and quercetin (D + Q) in patients with IPF but lack of control group limited interpretation and next-stage trial planning.

Pulmonary Rehabilitation in the Management of Chronic Lung Disease.

Pulmonary rehabilitation is a core component of management of patients with chronic lung disease that have exercise or functional limitations. Causes of these limitations are manifold but include loss of skeletal muscle mass, power and endurance, diminished respiratory capacity owing to respiratory muscle weakness, inefficient gas exchange, and increased work of breathing, and impaired cardiovascular functioning. Besides physical limitations, patients with chronic lung disease have high rates of depression and anxiety leading to social isolation and increased health care use.

Senolytics in idiopathic pulmonary fibrosis: Results from a first-in-human, open-label, pilot study.

Background: Cellular senescence is a key mechanism that drives age-related diseases, but has yet to be targeted therapeutically in humans. Idiopathic pulmonary fibrosis (IPF) is a progressive, fatal cellular senescence-associated disease. Selectively ablating senescent cells using dasatinib plus quercetin (DQ) alleviates IPF-related dysfunction in bleomycin-administered mice.

Effects of bronchoscopy on lung function in asthmatics.

Background: To better understand the changes in pulmonary physiology related to asthma severity following bronchoscopy, we performed scheduled pre- and post-procedure spirometry on subjects undergoing bronchoscopy in our research program.

Methods: Control subjects and asthma subjects were recruited for bronchoscopy. On the day of bronchoscopy, subjects underwent spirometry pre-bronchoscopy and then up to three sets within 2 hour following the completion of bronchoscopy.

Predictors of response to tiotropium versus salmeterol in asthmatic adults.

Background: Tiotropium has activity as an asthma controller. However, predictors of a positive response to tiotropium have not been described.

Objective: We sought to describe individual and differential responses of asthmatic patients to salmeterol and tiotropium when added to an inhaled corticosteroid, as well as predictors of a positive clinical response.

Biomarker surrogates do not accurately predict sputum eosinophil and neutrophil percentages in asthmatic subjects.

Background: Sputum eosinophil percentages are a strong predictor of airway inflammation and exacerbations and aid asthma management, whereas sputum neutrophil percentages indicate a different severe asthma phenotype that is potentially less responsive to TH2-targeted therapy. Variables, such as blood eosinophil counts, total IgE levels, fraction of exhaled nitric oxide (Feno) levels, or FEV1 percent predicted, might predict airway eosinophil percentages, whereas age, FEV1 percent predicted, or blood neutrophil counts might predict sputum neutrophil percentages. Availability and ease of measurement are useful characteristics, but accuracy in predicting airway eosinophil and neutrophil percentages either individually or combined is not established.

Comparison of physician-, biomarker-, and symptom-based strategies for adjustment of inhaled corticosteroid therapy in adults with asthma: the BASALT randomized controlled trial.

Context: No consensus exists for adjusting inhaled corticosteroid therapy in patients with asthma. Approaches include adjustment at outpatient visits guided by physician assessment of asthma control (symptoms, rescue therapy, pulmonary function), based on exhaled nitric oxide, or on a day-to-day basis guided by symptoms.

Objective: To determine if adjustment of inhaled corticosteroid therapy based on exhaled nitric oxide or day-to-day symptoms is superior to guideline-informed, physician assessment-based adjustment in preventing treatment failure in adults with mild to moderate asthma.

Asthma.

Asthma is a common disease encountered in internal medicine practice. In most cases, the diagnosis and management of asthma is straightforward; however, the management of severe asthma may require subspecialty consultation. Abnormal responses of resident cells to infections and antigens may cause asthma in early life and may chronically perpetuate asthma.

Safety of investigative bronchoscopy in the Severe Asthma Research Program.

Background: Investigative bronchoscopy was performed in a subset of participants in the Severe Asthma Research Program to gain insights into the pathobiology of severe disease. We evaluated the safety aspects of this procedure in this cohort with specific focus on patients with severe asthma.

Objective: To evaluate prospectively changes in lung function and the frequency of adverse events related to investigative bronchoscopy.

Tiotropium bromide step-up therapy for adults with uncontrolled asthma.

Background: Long-acting beta-agonist (LABA) therapy improves symptoms in patients whose asthma is poorly controlled by an inhaled glucocorticoid alone. Alternative treatments for adults with uncontrolled asthma are needed.

Methods: In a three-way, double-blind, triple-dummy crossover trial involving 210 patients with asthma, we evaluated the addition of tiotropium bromide (a long-acting anticholinergic agent approved for the treatment of chronic obstructive pulmonary disease but not asthma) to an inhaled glucocorticoid, as compared with a doubling of the dose of the inhaled glucocorticoid (primary superiority comparison) or the addition of the LABA salmeterol (secondary noninferiority comparison).

Anti-mitogenic effects of β-agonists and PGE2 on airway smooth muscle are PKA dependent.

Inhaled β-agonists are effective airway smooth muscle (ASM)-relaxing agents that help reverse bronchoconstriction in asthma, but their ability to affect the aberrant ASM growth that also occurs with asthma is poorly understood. β-Agonists exhibit PKA-dependent antimitogenic effects in several cell types. However, recent studies suggest that Epac, and not PKA, mediates the antimitogenic effect of cAMP in both ASM and fibroblasts.

Pharmacogenetics of asthma.

Current asthma treatments are effective for most but not all patients. Asthma is classified as a complex genetic disease with its pathogenesis and expression (severity) determined by the interaction of many genes and environmental factors. Asthma is characterized by its heterogeneity in terms of its clinical and inflammatory phenotypes and their responses to therapy.

The irreversible component of persistent asthma.

Irreversible airflow obstruction or limitation occurs in some patients with asthma, can develop early in life, and becomes more common as asthma becomes more severe. Efforts to understand irreversible airflow obstruction or limitation have been hampered by the lack of a standardized definition of the phenotype and by the lack of appropriate research models. Unfortunately, it appears that currently available asthma treatments do not prevent this important asthma complication.

Glucocorticoid- and protein kinase A-dependent transcriptome regulation in airway smooth muscle.

Glucocorticoids (GCs) and protein kinase A (PKA)-activating agents (beta-adrenergic receptor agonists) are mainstream asthma therapies based on their ability to prevent or reverse excessive airway smooth muscle (ASM) constriction. Their abilities to regulate another important feature of asthma--excessive ASM growth--are poorly understood. Recent studies have suggested that GCs render agents of inflammation such as IL-1 beta and TNF-alpha mitogenic to ASM, via suppression of (antimitogenic) induced cyclooxygenase-2-dependent PKA activity.

Endogenous Gs-coupled receptors in smooth muscle exhibit differential susceptibility to GRK2/3-mediated desensitization.

Although G protein-coupled receptor (GPCR) kinases (GRKs) have been shown to mediate desensitization of numerous GPCRs in studies using cellular expression systems, their function under physiological conditions is less well understood. In the current study, we employed various strategies to assess the effect of inhibiting endogenous GRK2/3 on signaling and function of endogenously expressed G s-coupled receptors in human airway smooth muscle (ASM) cells. GRK2/3 inhibition by expression of a Gbetagamma sequestrant, a GRK2/3 dominant-negative mutant, or siRNA-mediated knockdown increased intracellular cAMP accumulation mediated via beta-agonist stimulation of the beta-2-adrenergic receptor (beta 2AR).

Mitogenic effects of cytokines on smooth muscle are critically dependent on protein kinase A and are unmasked by steroids and cyclooxygenase inhibitors.

Excessive smooth muscle growth occurs within the context of inflammation associated with certain vascular and airway diseases. The inflammatory cytokines interleukin (IL)-1beta and tumor necrosis factor-alpha (TNF-alpha) have been shown previously to inhibit mitogen-stimulated smooth muscle growth through a mechanism presumed to be dependent on the induction of cyclooxygenase-2, prostaglandins, and activation of the cAMP-dependent protein kinase (PKA). Using both molecular and pharmacological strategies, we demonstrate that the mitogenic effects of IL-1beta and TNF-alpha on cultured human airway smooth muscle (ASM) cells are tightly regulated by PKA activity.

PKC-dependent regulation of the receptor locus dominates functional consequences of cysteinyl leukotriene type 1 receptor activation.

Leukotrienes are important lipid mediators of asthma that contribute to airway inflammation and bronchoconstriction. Critical mechanisms for physiological regulation of the main G protein-coupled receptor (GPCR) mediating the leukotriene responses in asthma, cysteinyl leukotriene type 1 receptor (CysLT1R), have not been delineated. Although desensitization of GPCRs is a well-established phenomenon, studies demonstrating its physiological relevance are lacking.

Regulatory features of interleukin-1beta-mediated prostaglandin E2 synthesis in airway smooth muscle.

Exposure of airway smooth muscle (ASM) cells to the cytokine IL-1beta results in an induction of PGE2 synthesis that affects numerous cell functions. Current dogma posits induction of COX-2 protein as the critical, obligatory event in cytokine-induced PGE2 production, although PGE2 induction can be inhibited without a concomitant inhibition of COX-2. To explore other putative regulatory features we examined the role of phospholipase A2 (PLA2) and PGE synthase (PGES) enzymes in IL-1beta-induced PGE2 production.

Cytokines regulate beta-2-adrenergic receptor responsiveness in airway smooth muscle via multiple PKA- and EP2 receptor-dependent mechanisms.

Beta2AR desensitization in airway smooth muscle (ASM) mediated by airway inflammation has been proposed to contribute to asthma pathogenesis and diminished efficacy of beta-agonist therapy. Mechanistic insight into this phenomenon is largely conceptual and lacks direct empirical evidence. Here, we employ molecular and genetic strategies to reveal mechanisms mediating cytokine effects on ASM beta2AR responsiveness.

Airway remodeling contributes to the progressive loss of lung function in asthma: an overview.

Airway inflammation, airflow obstruction, and bronchial hyperresponsiveness are characteristic phenotypic features of asthma. Clinically, airflow obstruction in asthma often is not fully reversible, and many asthmatic subjects experience an accelerated and progressive loss of lung function over time. Histopathologic studies of the asthmatic airway have demonstrated stereotypic changes that might explain the loss of lung function that many patients with asthma experience.

Contemporary issues in the care of patients with chronic obstructive pulmonary disease.

Objective: Chronic obstructive pulmonary disease (COPD) is the fourth leading cause of death in the United States and is estimated to be responsible for 119,000 deaths in the year 2000 alone. Additionally, COPD places a tremendous burden on the health care system, with estimated annual costs of US 24 billion dollars in 2000, and it is generally expected that costs will continue to rise as more individuals are diagnosed. COPD was responsible for approximately 8 million physician outpatient visits, 1.

Regulation of cysteinyl leukotriene type 1 receptor internalization and signaling.

Cysteinyl leukotrienes activate the cysteinyl leukotriene type 1 receptor (CysLT1R) to regulate numerous cell functions important in inflammatory processes and diseases such as asthma. Despite its physiologic importance, no studies to date have examined the regulation of CysLT1R signaling or trafficking. We have established model systems for analyzing recombinant human CysLT1R and found regulation of internalization and signaling of the CysLT1R to be unique among G protein-coupled receptors.

Differential expression of TRAIL and TRAIL receptors in allergic asthmatics following segmental antigen challenge: evidence for a role of TRAIL in eosinophil survival.

Asthma is a chronic lung disease exhibiting airway obstruction, hyperresponsiveness, and inflammation, characterized by the infiltration of eosinophils into the airways and the underlying tissue. Prolonged eosinophilic inflammation depends on the balance between the cell's inherent tendency to undergo apoptosis and the local eosinophil-viability enhancing activity. TRAIL, a member of the TNF family, induces apoptosis in most transformed cells; however, its role in health and disease remains unknown.