PI3Kγδ inhibition suppresses key disease features in a rat model of asthma.

Background: Two isoforms of Phosphoinositide 3-kinase (PI3K), p110γ and p110δ, are predominantly expressed in leukocytes and represent attractive therapeutic targets for the treatment of allergic asthma. The study aim was to assess the impact of administration of an inhaled PI3Kγδ inhibitor (AZD8154) in a rat model of asthma.

Methods: Firstly, we checked that the tool compound, AZD8154, inhibited rat PI3K γ & δ kinases using rat cell-based assays.

Novel airway smooth muscle-mast cell interactions and a role for the TRPV4-ATP axis in non-atopic asthma.

Mast cell-airway smooth muscle (ASM) interactions play a major role in the immunoglobulin (Ig)E- dependent bronchoconstriction seen in asthma but less is known about IgE-independent mechanisms of mast cell activation. Transient receptor potential cation channel, subfamily V, member 4 (TRPV4) activation causes contraction of human ASM the release of cysteinyl leukotrienes (cysLTs) but the mechanism is unknown. The objective of the present study was to investigate a role for IgE-independent, mast cell-ASM interaction in TRPV4-induced bronchospasm.

ERS International Congress, Madrid, 2019: highlights from the Airway Diseases, Asthma and COPD Assembly.

The European Respiratory Society (ERS) International Congress 2019 in Madrid, Spain, was a platform for scientific discussion of the highest quality scientific research, cutting-edge techniques and innovative new therapies within the respiratory field. This article discusses some of the high-quality research studies presented at that Congress, with a focus on airway diseases, including asthma, COPD, small airways, bronchiectasis and cough, presented through the Airway Diseases, Asthma and COPD Assembly (Assembly 5) of the ERS. The authors establish the key take-home messages of these studies, compare their findings and place them into context of current understanding.

Research highlights from the 2018 European Respiratory Society International Congress: airway disease.

The annual European Respiratory Society (ERS) International Congress (held in Paris in 2018) was once again a platform for discussion of the highest-quality scientific research, cutting-edge techniques and innovative new therapies within the respiratory field. This article discusses only some of the high-quality research studies presented at this year's Congress, with a particular focus on airway diseases including asthma, chronic obstructive pulmonary disease (COPD), bronchiectasis and cough, as presented through Assembly 5 of the ERS (Airway Diseases: Asthma and COPD). The authors establish the key take-home messages of these studies, compare their findings and place them in the context of current understanding.

Research highlights from the 2017 ERS International Congress: airway diseases in focus.

For another year, high-quality research studies from around the world transformed the annual ERS International Congress into a vivid platform to discuss trending research topics, to produce new research questions and to further push the boundaries of respiratory medicine and science. This article reviews only some of the high-quality research studies on asthma, chronic obstructive pulmonary disease (COPD), bronchiectasis and chronic cough that were presented during the congress through the Airway Diseases Assembly (ERS Assembly 5) and places them into the context of current knowledge and research challenges.

Targeting fatty acid amide hydrolase as a therapeutic strategy for antitussive therapy.

Cough is the most common reason to visit a primary care physician, yet it remains an unmet medical need. Fatty acid amide hydrolase (FAAH) is an enzyme that breaks down endocannabinoids, and inhibition of FAAH produces analgesic and anti-inflammatory effects. Cannabinoids inhibit vagal sensory nerve activation and the cough reflex, so it was hypothesised that FAAH inhibition would produce antitussive activity elevation of endocannabinoids.

Cough and airway disease: The role of ion channels.

Cough is the most common reason for patients to visit a primary care physician, yet it remains an unmet medical need. It can be idiopathic in nature but can also be a troublesome symptom across chronic lung diseases such as asthma, COPD and idiopathic pulmonary fibrosis (IPF). Chronic cough affects up to 12% of the population and yet there are no safe and effective therapies.

Mechanistic link between diesel exhaust particles and respiratory reflexes.

Background: Diesel exhaust particles (DEPs) are a major component of particulate matter in Europe's largest cities, and epidemiologic evidence links exposure with respiratory symptoms and asthma exacerbations. Respiratory reflexes are responsible for symptoms and are regulated by vagal afferent nerves, which innervate the airway. It is not known how DEP exposure activates airway afferents to elicit symptoms, such as cough and bronchospasm.

Modulation of the TRPV4 ion channel as a therapeutic target for disease.

Transient Receptor Potential Vanilloid 4 (TRPV4) is a broadly expressed, polymodally gated ion channel that plays an important role in many physiological and pathophysiological processes. TRPV4 knockout mice and several synthetic pharmacological compounds that selectively target TRPV4 are now available, which has allowed detailed investigation in to the therapeutic potential of this ion channel. Results from animal studies suggest that TRPV4 antagonism has therapeutic potential in oedema, pain, gastrointestinal disorders, and lung diseases such as cough, bronchoconstriction, pulmonary hypertension, and acute lung injury.

Transient receptor potential cation channel, subfamily V, member 4 and airway sensory afferent activation: Role of adenosine triphosphate.

Background: Sensory nerves innervating the airways play an important role in regulating various cardiopulmonary functions, maintaining homeostasis under healthy conditions and contributing to pathophysiology in disease states. Hypo-osmotic solutions elicit sensory reflexes, including cough, and are a potent stimulus for airway narrowing in asthmatic patients, but the mechanisms involved are not known. Transient receptor potential cation channel, subfamily V, member 4 (TRPV4) is widely expressed in the respiratory tract, but its role as a peripheral nociceptor has not been explored.

Neurophenotypes in Airway Diseases. Insights from Translational Cough Studies.

Rationale: Most airway diseases, including chronic obstructive pulmonary disease (COPD), are associated with excessive coughing. The extent to which this may be a consequence of increased activation of vagal afferents by pathology in the airways (e.g.

Targeting TRP channels for chronic cough: from bench to bedside.

Cough is currently the most common reason for patients to visit a primary care physician in the UK, yet it remains an unmet medical need. Current therapies have limited efficacy or have potentially dangerous side effects. Under normal circumstances, cough is a protective reflex to clear the lungs of harmful particles; however, in disease, cough can become excessive, dramatically impacting patients' lives.

Prostaglandin D2 and the role of the DP1, DP2 and TP receptors in the control of airway reflex events.

Prostaglandin D2 (PGD2) causes cough and levels are increased in asthma suggesting that it may contribute to symptoms. Although the prostaglandin D2 receptor 2 (DP2) is a target for numerous drug discovery programmes little is known about the actions of PGD2 on sensory nerves and cough. We used human and guinea pig bioassays, in vivo electrophysiology and a guinea pig conscious cough model to assess the effect of prostaglandin D2 receptor (DP1), DP2 and thromboxane receptor antagonism on PGD2 responses.

The role of adenylyl cyclase isoform 6 in β-adrenoceptor signalling in murine airways.

Background And Purpose: Adenylyl cyclase (AC) is a key signalling enzyme for many GPCRs and catalyses the conversion of ATP to cAMP which, in turn, is a crucial determinant of many biological responses. β-Adrenoceptor agonists are prescribed as bronchodilators for asthma and chronic obstructive pulmonary disease, and it is commonly assumed that they elicit their actions via AC-dependent production of cAMP. However, empirical evidence in support of this is lacking and the exact mechanism by which these drugs acts remains elusive.

The peroxisome proliferator-activated receptor β/δ agonist GW0742 has direct protective effects on right heart hypertrophy.

Pulmonary hypertension is a debilitating disease with no cure. We have previously shown that peroxisome proliferator-activated receptor (PPAR) β/δ agonists protect the right heart in hypoxia-driven pulmonary hypertension without affecting vascular remodeling. PPARβ/δ is an important receptor in lipid metabolism, athletic performance, and the sensing of prostacyclin.

Novel drug targets for asthma and COPD: lessons learned from in vitro and in vivo models.

Asthma and chronic obstructive pulmonary disease (COPD) are highly prevalent respiratory diseases characterized by airway inflammation, airway obstruction and airway hyperresponsiveness. Whilst current therapies, such as β-agonists and glucocorticoids, may be effective at reducing symptoms, they do not reduce disease progression. Thus, there is a need to identify new therapeutic targets.

Tiotropium modulates transient receptor potential V1 (TRPV1) in airway sensory nerves: A beneficial off-target effect?

Background: Recent studies have suggested that the long-acting muscarinic receptor antagonist tiotropium, a drug widely prescribed for its bronchodilator activity in patients with chronic obstructive pulmonary disease and asthma, improves symptoms and attenuates cough in preclinical and clinical tussive agent challenge studies. The mechanism by which tiotropium modifies tussive responses is not clear, but an inhibition of vagal tone and a consequent reduction in mucus production from submucosal glands and bronchodilation have been proposed.

Objective: The aim of this study was to investigate whether tiotropium can directly modulate airway sensory nerve activity and thereby the cough reflex.

Selectivity profiling of the novel EP2 receptor antagonist, PF-04418948, in functional bioassay systems: atypical affinity at the guinea pig EP2 receptor.

Background And Purpose: Understanding the role of the EP(2) receptor has been hampered by the lack of a selective antagonist. Recently, a selective EP(2) receptor antagonist, PF-04418948, has been discovered. The aim of this study was to demonstrate the selectivity profile of PF-04418948 for the EP(2) receptor over other EP receptors using a range of isolated tissue systems.