Tracheal tuft cells release ATP and link innate to adaptive immunity in pneumonia.

Tracheal tuft cells shape immune responses in the airways. While some of these effects have been attributed to differential release of either acetylcholine, leukotriene C4 and/or interleukin-25 depending on the activating stimuli, tuft cell-dependent mechanisms underlying the recruitment and activation of immune cells are incompletely understood. Here we show that Pseudomonas aeruginosa infection activates mouse tuft cells, which release ATP via pannexin 1 channels.

Coxsackievirus A6 U.K. Genetic and Clinical Epidemiology Pre- and Post-SARS-CoV-2 Emergence.

Coxsackievirus A6 (CVA6) has become increasingly clinically relevant as a cause of Hand, Foot and Mouth Disease (HFMD) globally since 2008. However, most laboratories do not routinely determine the enteroviral type of positive samples. The non-pharmaceutical measures introduced to curb transmission during the COVID-19 pandemic may also have perturbed CVA6 epidemiology.

Efficacy and tolerability of zinc acetate for treatment of chronic refractory cough: pilot randomised futility trial.

Background: Cough is the most reported symptom in the United States, with chronic refractory cough representing significant morbidity to patients. Zinc acetate may have beneficial effects in the cough reflex pathway. We sought to assess the safety and efficacy of zinc acetate in the management of chronic refractory cough.

Case report: Clearance of longstanding, immune-deficiency-associated, vaccine-derived polio virus infection following remdesivir therapy for chronic SARS-CoV-2 infection.

The global polio eradication campaign has had remarkable success in reducing wild-type poliovirus infection, largely built upon the live attenuated Sabin oral poliovirus vaccine. Whilst rare, vaccine poliovirus strains may cause infection and subsequently revert to a neurovirulent type, termed vaccine-derived poliovirus (VDPV). Persistent, vaccine derived infection may occur in an immunocompromised host (iVDPV), where it is a recognised complication following receipt of the Sabin vaccine.

Cough hypersensitivity and chronic cough.

Chronic cough is globally prevalent across all age groups. This disorder is challenging to treat because many pulmonary and extrapulmonary conditions can present with chronic cough, and cough can also be present without any identifiable underlying cause or be refractory to therapies that improve associated conditions. Most patients with chronic cough have cough hypersensitivity, which is characterized by increased neural responsivity to a range of stimuli that affect the airways and lungs, and other tissues innervated by common nerve supplies.

A double-blind randomised placebo-controlled trial investigating the effects of lesogaberan on the objective cough frequency and capsaicin-evoked coughs in patients with refractory chronic cough.

Objective: Baclofen is a centrally acting γ-aminobutyric acid type B (GABA) receptor agonist which reduces gastro-oesophageal reflux and suppresses the cough reflex; however, central nervous system side-effects limit its use. Lesogaberan is a novel peripherally acting GABA agonist, but its effects on refractory chronic cough are unknown.

Design: We performed a single-centre, placebo-controlled, double-blind randomised crossover study in patients with chronic cough, refractory to the treatment of underlying conditions.

Evidence for Alpha Nicotinic Receptor Activation During the Cough Suppressing Effects Induced by Nicotine and Identification of ATA-101 as a Potential Novel Therapy for the Treatment of Chronic Cough.

Studies performed in healthy smokers have documented a diminished responsiveness to tussive challenges, and several lines of experimental evidence implicate nicotine as an antitussive component in both cigarette smoke and the vapors generated by electronic cigarettes (eCigs). We set out to identify the nicotinic receptor subtype involved in the antitussive actions of nicotine and to further evaluate the potential of nicotinic receptor-selective agonists as cough-suppressing therapeutics. We confirmed an antitussive effect of nicotine in guinea pigs.

Effect of centrally and peripherally acting GABA agonism on the healthy human cough reflex.

Background: Currently there are no effective licensed anti-tussive therapies. Understanding how the neuronal mechanisms mediating the cough reflex in animal models translate to humans is important for the development of effective therapies. Pre-clinical studies suggest that the activation of GABA receptors in both the peripheral and central nervous systems inhibit cough.

Antitussive effects of Na 1.7 blockade in Guinea pigs.

Our previous studies implicated the voltage-gated sodium channel subtype Na 1.7 in the transmission of action potentials by the vagal afferent nerves regulating cough and thus identified this channel as a rational therapeutic target for antitussive therapy. But it is presently unclear whether a systemically administered small molecule inhibitor of Na 1.

Acute activation of bronchopulmonary vagal nociceptors by type I interferons.

Type I interferon receptors are expressed by the majority of vagal C-fibre neurons innervating the respiratory tract Interferon alpha and beta acutely and directly activate vagal C-fibers in the airways. The interferon-induced activation of C-fibers occurs secondary to stimulation of type 1 interferon receptors Type 1 interferons may contribute to the symptoms as well as the spread of respiratory viral infections by causing coughing and other defensive reflexes associated with vagal C-fibre activation ABSTRACT: We evaluated the ability of type I interferons to acutely activate airway vagal afferent nerve terminals in mouse lungs. Using single cell RT-PCR of lung-specific vagal neurons we found that IFNAR1 and IFNAR2 were expressed in 70% of the TRPV1-positive neurons (a marker for vagal C-fibre neurons) and 44% of TRPV1-negative neurons.

P2X3-Receptor Antagonists as Potential Antitussives: Summary of Current Clinical Trials in Chronic Cough.

Cough is among the most common complaints for which patients worldwide seek medical attention. In a majority of patients with chronic cough (defined as cough of greater than 8 weeks' duration), successful management results from a thorough evaluation and treatment of underlying causes. In a subgroup of patients, however, cough proves refractory to therapeutic trials aimed at known reversible causes of chronic cough.

Back to the future: re-establishing guinea pig in vivo asthma models.

Research using animal models of asthma is currently dominated by mouse models. This has been driven by the comprehensive knowledge on inflammatory and immune reactions in mice, as well as tools to produce genetically modified mice. Many of the identified therapeutic targets influencing airway hyper-responsiveness and inflammation in mouse models, have however been disappointing when tested clinically in asthma.

Thermonuclease test accuracy is preserved in methicillin-resistant isolates.

The gene encodes a thermonuclease which is present in but not in coagulase-negative staphylococci (CoNS) and is the target of the rapid phenotypic thermonuclease test. The effect of gene variation in methicillin-resistant (MRSA) on the performance of PCR testing has been noted, although there are no reports about the effect of MRSA on the activity of the thermonuclease enzyme. Our goals were to examine the sensitivity and specificity of the thermonuclease test used to distinguish from CoNS cultured from blood.

Tracheal brush cells release acetylcholine in response to bitter tastants for paracrine and autocrine signaling.

For protection from inhaled pathogens many strategies have evolved in the airways such as mucociliary clearance and cough. We have previously shown that protective respiratory reflexes to locally released bacterial bitter "taste" substances are most probably initiated by tracheal brush cells (BC). Our single-cell RNA-seq analysis of murine BC revealed high expression levels of cholinergic and bitter taste signaling transcripts (Tas2r108, Gnat3, Trpm5).

Nicotinic receptor dependent regulation of cough and other airway defensive reflexes.

Nicotinic receptor activation in the airways evokes airway defensive reflexes including cough. These reflexes are the direct result of bronchopulmonary afferent nerve activation, which may occur directly, through activation of nicotinic receptors expressed on the terminals of airway sensory nerves, or indirectly, secondary to the end organ effects associated with autonomic nerve stimulation. The irritating effects of nicotine delivered topically to the airways are counterbalanced by an inhibitory effect of nicotinic receptor activation in the central nervous system.

Severe gangrene in a patient with anti-RNP positive limited cutaneous systemic sclerosis/rheumatoid arthritis overlap syndrome caused by vasculopathy and vasculitis.

In this paper, we describe a case of a male patient with anti-U1RNP positive limited cutaneous systemic sclerosis/rheumatoid arthritis overlap syndrome, who presented acutely with rapidly progressive digital ischemia, which lead to extensive gangrene. Management with conventional vasodilator therapy was unsuccessful. There were constitutional symptoms and a marked inflammatory response in the absence of evidence of infection, implying a component of vasculitis underlying the presentation.

Mrgprs on vagal sensory neurons contribute to bronchoconstriction and airway hyper-responsiveness.

Asthma, accompanied by lung inflammation, bronchoconstriction and airway hyper-responsiveness, is a significant public health burden. Here we report that Mas-related G protein-coupled receptors (Mrgprs) are expressed in a subset of vagal sensory neurons innervating the airway and mediates cholinergic bronchoconstriction and airway hyper-responsiveness. These findings provide insights into the neural mechanisms underlying the pathogenesis of asthma.

Opposing effects of bronchopulmonary C-fiber subtypes on cough in guinea pigs.

We have addressed the hypothesis that the opposing effects of bronchopulmonary C-fiber activation on cough are attributable to the activation of C-fiber subtypes. Coughing was evoked in anesthetized guinea pigs by citric acid (0.001-2 M) applied topically in 100-µl aliquots to the tracheal mucosa.

Evidence for autocrine and paracrine regulation of allergen-induced mast cell mediator release in the guinea pig airways.

Mast cells play an essential role in immediate type hypersensitivity reactions and in chronic allergic diseases of the airways, including asthma. Mast cell mediator release can be modulated by locally released autacoids and circulating hormones, but surprisingly little is known about the autocrine effects of mediators released upon mast cell activation. We thus set out to characterize the autocrine and paracrine effects of mast cell mediators on mast cell activation in the guinea pig airways.

Central inhibition of initiation of swallowing by systemic administration of diazepam and baclofen in anaesthetized rats.

Dysphagia is caused not only by neurological and/or structural damage but also by medication. We hypothesized memantine, dextromethorphan, diazepam, and baclofen, all commonly used drugs with central sites of action, may regulate swallowing function. Swallows were evoked by upper airway (UA)/pharyngeal distension, punctate mechanical stimulation using a von Frey filament, capsaicin or distilled water (DW) applied topically to the vocal folds, and electrical stimulation of a superior laryngeal nerve (SLN) in anesthetized rats and were documented by recording electromyographic activation of the suprahyoid and thyrohyoid muscles and by visualizing laryngeal elevation.

Control of Neurotransmission by NaV1.7 in Human, Guinea Pig, and Mouse Airway Parasympathetic Nerves.

Little is known about the neuronal voltage-gated sodium channels (NaVs) that control neurotransmission in the parasympathetic nervous system. We evaluated the expression of the subunits of each of the nine NaVs in human, guinea pig, and mouse airway parasympathetic ganglia. We combined this information with a pharmacological analysis of selective NaV blockers on parasympathetic contractions of isolated airway smooth muscle.

Parainfluenza 3-Induced Cough Hypersensitivity in the Guinea Pig Airways.

The effect of respiratory tract viral infection on evoked cough in guinea pigs was evaluated. Guinea pigs were inoculated intranasally with either parainfluenza type 3 (PIV3) and cough was quantified in conscious animals. The guinea pigs infected with PIV3 (day 4) coughed nearly three times more than those treated with the viral growth medium in response to capsaicin, citric acid, and bradykinin.

Pharmacology of Bradykinin-Evoked Coughing in Guinea Pigs.

Bradykinin has been implicated as a mediator of the acute pathophysiological and inflammatory consequences of respiratory tract infections and in exacerbations of chronic diseases such as asthma. Bradykinin may also be a trigger for the coughing associated with these and other conditions. We have thus set out to evaluate the pharmacology of bradykinin-evoked coughing in guinea pigs.

Eight International London Cough Symposium 2014: Cough hypersensitivity syndrome as the basis for chronic cough.

At the Eighth International London Cough Conference held in London in July 2014, the focus was on the relatively novel concept of cough hypersensitivity syndrome (CHS) as forming the basis of chronic cough. This concept has been formulated following understanding of the neuronal pathways for cough and a realisation that not all chronic cough is usually associated with a cause. The CHS is defined by troublesome coughing triggered by low level of thermal, mechanical or chemical exposure.