Role of voltage-gated Ca channels and Ano1 Ca-activated Cl channels in M2 muscarinic receptor-dependent contractions of murine airway smooth muscle.

Cholinergic tone is elevated in obstructive lung conditions such as COPD and asthma, but the cellular mechanisms underlying cholinergic contractions of airway smooth muscle (ASM) are still unclear. Some studies report an important role for L-type Ca channels (LTCC) and Ano1 Ca-activated Cl™ channels (CACC) in these responses, but others dispute their importance. Cholinergic contractions of ASM involve activation of M3Rs, however stimulation of M2Rs exerts a profound hypersensitisation of these responses.

The Clinical Approach to Chronic Cough.

Chronic cough remains a significant clinical challenge, affecting approximately 10% of the population and leading to significant impairment in psychological, social, and physical quality of life. In recent years, efforts have intensified to elucidate the mechanisms underlying chronic cough and to focus on investigating and treating refractory chronic cough (RCC). A "treatable trait" approach, which focuses on identifying and addressing the specific associated causes of chronic cough, has gained traction.

The McMaster Cough Severity Questionnaire (MCSQ): a cough severity instrument for patients with refractory chronic cough.

Background: Cough severity represents an important endpoint to assess the impact of therapies for patients with refractory chronic cough (RCC).

Objective: To develop a new patient-reported outcome measure addressing cough severity in patients with RCC.

Methods: Phase 1 (item generation): A systematic survey, focus groups, and expert consultation generated 51 items.

Body size modulates the extent of seasonal diet switching by large mammalian herbivores in Yellowstone National Park.

Prevailing theories about animal foraging behaviours and the food webs they occupy offer divergent predictions about whether seasonally limited food availability promotes dietary diversification or specialization. Emphasis on how animals compete for food predominates in work on the foraging ecology of large mammalian herbivores, whereas emphasis on how the diversity of available foods generally constrains dietary opportunity predominates work on entire food webs. Reconciling predictions about what promotes dietary diversification is challenging because species' different body sizes and mobilities modulate how they seek and compete for resources-the mechanistic bases of common predictions may not pertain to all species equally.

Neutrophil-Derived Peptidyl Arginine Deiminase Activity Contributes to Pulmonary Emphysema by Enhancing Elastin Degradation.

In chronic obstructive pulmonary disease (COPD), inflammation gives rise to protease-mediated degradation of the key extracellular matrix protein, elastin, which causes irreversible loss of pulmonary function. Intervention against proteolysis has met with limited success in COPD, due in part to our incomplete understanding of the mechanisms that underlie disease pathogenesis. Peptidyl arginine deiminase (PAD) enzymes are a known modifier of proteolytic susceptibility, but their involvement in COPD in the lungs of affected individuals is underexplored.

TRPV2 modulates mechanically Induced ATP Release from Human bronchial epithelial cells.

Repetitive bouts of coughing expose the large airways to significant cycles of shear stress. This leads to the release of alarmins and the tussive agent adenosine triphosphate (ATP) which may be modulated by the activity of ion channels present in the human airway. This study aimed to investigate the role of the transient receptor potential subfamily vanilloid member 2 (TRPV2) channel in mechanically induced ATP release from primary bronchial epithelial cells (PBECs).

Brainstem processing of cough sensory inputs in chronic cough hypersensitivity.

Background: Chronic cough is a prevalent and difficult to treat condition often accompanied by cough hypersensitivity, characterised by cough triggered from exposure to low level sensory stimuli. The mechanisms underlying cough hypersensitivity may involve alterations in airway sensory nerve responsivity to tussive stimuli which would be accompanied by alterations in stimulus-induced brainstem activation, measurable with functional magnetic resonance imaging (fMRI).

Methods: We investigated brainstem responses during inhalation of capsaicin and adenosine triphosphate (ATP) in 29 participants with chronic cough and 29 age- and sex-matched controls.

Structural Predictors of Lung Function Decline in Young Smokers with Normal Spirometry.

Chronic obstructive pulmonary disease (COPD) due to tobacco smoking commonly presents when extensive lung damage has occurred. We hypothesized that structural change would be detected early in the natural history of COPD and would relate to loss of lung function with time. We recruited 431 current smokers (median age, 39 yr; 16 pack-years smoked) and recorded symptoms using the COPD Assessment Test (CAT), spirometry, and quantitative thoracic computed tomography (QCT) scans at study entry.

Consensus goals and standards for specialist cough clinics: the NEUROCOUGH international Delphi study.

Background: Current guidelines on the management of chronic cough do not provide recommendations for the operation of specialist cough clinics. The objective of the present study was to develop expert consensus on goals and standard procedures for specialist cough clinics.

Methods: We undertook a modified Delphi process, whereby initial statements proposed by experts were categorised and presented back to panellists over two ranking rounds using an 11-point Likert scale to identify consensus.

A real world study of cough burden and quality of life of UK patients who have undergone evaluation for chronic cough.

Objective: Treatment options for adults with chronic cough (CC) are limited. This study reports on the health status and experiences of patients with recent healthcare evaluation for CC.

Methods: This prospective, UK, cross-sectional study surveyed adults with a CC evaluation within the previous 12 months.

Modulation of fast sodium current in airway smooth muscle cells by exchange protein directly activated by cAMP.

Airway smooth muscle (ASM) cells from mouse bronchus express a fast sodium current mediated by Na1.7. We present evidence that this current is regulated by cAMP.

Type 1 diabetes contributes to combined pulmonary fibrosis and emphysema in male alpha 1 antitrypsin deficient mice.

Type 1 diabetes (T1D) is a metabolic disease characterized by hyperglycemia and can affect multiple organs, leading to life-threatening complications. Increased prevalence of pulmonary disease is observed in T1D patients, and diabetes is a leading cause of comorbidity in several lung pathologies. A deficiency of alpha-1 antitrypsin (AAT) can lead to the development of emphysema.

Protein Phosphatase 2A as a Therapeutic Target in Pulmonary Diseases.

New disease targets and medicinal chemistry approaches are urgently needed to develop novel therapeutic strategies for treating pulmonary diseases. Emerging evidence suggests that reduced activity of protein phosphatase 2A (PP2A), a complex heterotrimeric enzyme that regulates dephosphorylation of serine and threonine residues from many proteins, is observed in multiple pulmonary diseases, including lung cancer, smoke-induced chronic obstructive pulmonary disease, alpha-1 antitrypsin deficiency, asthma, and idiopathic pulmonary fibrosis. Loss of PP2A responses is linked to many mechanisms associated with disease progressions, such as senescence, proliferation, inflammation, corticosteroid resistance, enhanced protease responses, and mRNA stability.

From bench to bedside: The role of cough hypersensitivity in chronic cough.

Background: Chronic cough is a burdensome condition characterized by persistent cough lasting longer than 8 weeks. Chronic cough can significantly affect quality of life, physical function and productivity, with many people troubled with a cough that lasts for months or even years. People with chronic cough commonly report a persistent urge to cough with frequent bouts of coughing triggered by innocuous stimuli, which has led to the concept of cough hypersensitivity.

Burden of chronic cough in the UK: results from the 2018 National Health and Wellness Survey.

Background: Chronic cough, defined as daily cough for at least 8 weeks, negatively affects quality of life and work productivity and increases healthcare resource utilisation. We aimed to determine the prevalence and burden of chronic cough in the UK.

Methods: Study participants were general population respondents to the 2018 UK National Health and Wellness Survey (NHWS).

Efficacy and Safety of Eliapixant in Refractory Chronic Cough: The Randomized, Placebo-Controlled Phase 2b PAGANINI Study.

Introduction: The PAGANINI study evaluated the efficacy and safety of the selective P2X3 antagonist eliapixant in patients with refractory chronic cough (RCC).

Methods: PAGANINI was a randomized, double-blind, parallel-group, placebo-controlled, multicenter, dose-finding, phase 2b study. Adults with RCC lasting ≥ 12 months and cough severity ≥ 40 mm on a visual analog scale at screening were enrolled.

The P2X3 receptor antagonist filapixant in patients with refractory chronic cough: a randomized controlled trial.

Background: P2X3 receptor antagonists seem to have a promising potential for treating patients with refractory chronic cough. In this double-blind, randomized, placebo-controlled study, we investigated the efficacy, safety, and tolerability of the novel selective P2X3 receptor antagonist filapixant (BAY1902607) in patients with refractory chronic cough.

Methods: Following a crossover design, 23 patients with refractory chronic cough (age: 60.