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.

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.

History of Histamine-Releasing Factor (HRF)/Translationally Controlled Tumor Protein (TCTP) Including a Potential Therapeutic Target in Asthma and Allergy.

Histamine-releasing factor (HRF) also known as translationally controlled tumor protein (TCTP) is a highly conserved, ubiquitous protein that has both intracellular and extracellular functions. Here we will highlight the subcloning of the molecule, its clinical implications, as well as an inducible-transgenic mouse. Particular attention will be paid to its extracellular functioning and its potential role as a therapeutic target in asthma and allergy.

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.

Regulation of cough by neuronal Na(+)-K(+) ATPases.

The Na(+)-K(+) ATPases play an essential role in establishing the sodium gradients in excitable cells. Multiple isoforms of the sodium pumps have been identified, with tissue and cell specific expression patterns. Because the vagal afferent nerves regulating cough must be activated at sustained high frequencies of action potential patterning to achieve cough initiation thresholds, it is a certainty that sodium pump function is essential to maintaining cough reflex sensitivities in health and in disease.

Genetics of allergic diseases.

Genome-wide association studies (GWAS) have been employed in the field of allergic disease, and significant associations have been published for nearly 100 asthma genes/loci. An outcome of GWAS in allergic disease has been the formation of national and international collaborations leading to consortia meta-analyses, and an appreciation for the specificity of genetic associations to sub-phenotypes of allergic disease. Molecular genetics has undergone a technological revolution, leading to next-generation sequencing strategies that are increasingly employed to hone in on the causal variants associated with allergic diseases.

Potential role of histamine releasing factor (HRF) as a therapeutic target for treating asthma and allergy.

Histamine releasing factor (HRF), also known as translationally controlled tumor protein (TCTP), is a highly conserved, ubiquitous protein that has both intracellular and extracellular functions. Here, we will highlight the history of the molecule, its clinical implications with a focus on its extracellular functioning, and its potential role as a therapeutic target in asthma and allergy. The cells and cytokines produced when stimulated or primed by HRF/TCTP are detailed as well as the downstream signaling pathway that HRF/TCTP elicits.

A role for ATP in bronchoconstriction-induced activation of guinea pig vagal intrapulmonary C-fibres.

Activation of vagal afferent sensory C-fibres in the lungs leads to reflex responses that produce many of the symptoms associated with airway allergy. There are two subtypes of respiratory C-fibres whose cell bodies reside within two distinct ganglia, the nodose and jugular, and whose properties allow for differing responses to stimuli. We here used extracellular recording of action potentials in an ex vivo isolated, perfused lung-nerve preparation to study the electrical activity of nodose C-fibres in response to bronchoconstriction.

A critical role for the protein apoptosis repressor with caspase recruitment domain in hypoxia-induced pulmonary hypertension.

Background: Pulmonary hypertension (PH) is a lethal syndrome associated with the pathogenic remodeling of the pulmonary vasculature and the emergence of apoptosis-resistant cells. Apoptosis repressor with caspase recruitment domain (ARC) is an inhibitor of multiple forms of cell death known to be abundantly expressed in striated muscle. We show for the first time that ARC is expressed in arterial smooth muscle cells of the pulmonary vasculature and is markedly upregulated in several experimental models of PH.

Enhancement of myofilament calcium sensitivity by acute hypoxia in rat distal pulmonary arteries.

Hypoxic contraction of pulmonary arterial smooth muscle is thought to require increases in both intracellular Ca(2+) concentration ([Ca(2+)](i)) and myofilament Ca(2+) sensitivity, which may or may not be endothelium-dependent. To examine the effects of hypoxia and endothelium on Ca(2+) sensitivity in pulmonary arterial smooth muscle, we measured the relation between [Ca(2+)](i) and isometric force at 37°C during normoxia (21% O(2)-5% CO(2)) and after 30 min of hypoxia (1% O(2)-5% CO(2)) in endothelium-intact (E+) and -denuded (E-) rat distal intrapulmonary arteries (IPA) permeabilized with staphylococcal α-toxin. Endothelial denudation enhanced Ca(2+) sensitivity during normoxia but did not alter the effects of hypoxia, which shifted the [Ca(2+)](i)-force relation to higher force in E+ and E- IPA.

Role of SHIP-1 in the adaptive immune responses to aeroallergen in the airway.

Background: Th2-dominated inflammatory response in the airway is an integral component in the pathogenesis of allergic asthma. Accumulating evidence supports the notion that the phosphoinositide 3-kinase (PI3K) pathway is involved in the process. We previously reported that SHIP-1, a negative regulator of the PI3K pathway, is essential in maintaining lung immunohomeostasis, potentially through regulation of innate immune cells.

The human glucocorticoid receptor as an RNA-binding protein: global analysis of glucocorticoid receptor-associated transcripts and identification of a target RNA motif.

Posttranscriptional regulation is emerging as a key factor in glucocorticoid (GC)-mediated gene regulation. We investigated the role of the human GC receptor (GR) as an RNA-binding protein and its effect on mRNA turnover in human airway epithelial cells. Cell treatment with the potent GC budesonide accelerated the decay of CCL2 mRNA (t(1/2) = 8 ± 1 min versus 62 ± 17 min in DMSO-treated cells) and CCL7 mRNA (t(1/2) = 15 ± 4 min versus 114 ± 37 min), but not that of CCL5 mRNA (t(1/2)=231 ± 8 min versus 266 ± 5 min) in the BEAS-2B cell line.

Decreases in human dendritic cell-dependent T(H)2-like responses after acute in vivo IgE neutralization.

Background: Dendritic cells (DCs) and other professional antigen-presenting cells express a variant of the high-affinity IgE receptor known as alphagamma(2), which, on the basis of in vitro findings, has long been implicated to function in facilitating allergen uptake and presentation to T(H) cells.

Objectives: To use omalizumab as an in vivo tool to neutralize IgE binding to circulating dendritic cells and to assess whether this results in altered DC-dependent T-cell responsiveness to allergen ex vivo.

Methods: Subjects with cat allergy were enrolled in a 3.

Synaptic and membrane properties of parasympathetic ganglionic neurons innervating mouse trachea and bronchi.

The pathophysiology of airway diseases, such as asthma, is increasingly studied using transgenic mice and other mouse models of airway inflammation where allergen-induced changes in airway smooth muscle tone and mucous secretion is due, in part, to activation of preganglionic airway parasympathetic nerves. Ganglionic parasympathetic neurons located in the airways in several species, including humans, have anatomical and electrophysiological properties that limit transmission of preganglionic synaptic input. In this study, intracellular recordings were made from neurons in parasympathetic ganglia located on the trachea and bronchi of adult mice to determine electrophysiological properties associated with regulation of transmission of preganglionic input.

SHP-1 deficient mast cells are hyperresponsive to stimulation and critical in initiating allergic inflammation in the lung.

Phosphatase Src homology region 2 domain-containing phosphatase 1 (SHP-1)-deficient mice display an allergic asthma phenotype that is largely IL-13 and STAT6 dependent. The cell types responsible for the Th2 phenotype have not been identified. We hypothesized that SHP-1 deficiency leads to mast cell dysregulation and increased production and release of mediators and Th2 cytokines, leading to the allergic asthma phenotype.

Basophils beyond effector cells of allergic inflammation.

Despite being first described in humans nearly 130 years ago, the basophil granulocyte has received little recognition other than being the least common leukocyte circulating in blood. Even after its identity as the source of histamine released by blood cells in response to reaginic IgE, its role in allergic disease has largely been viewed as redundant to that of the tissue mast cell. This line of thought, however, is changing with evidence that has emerged during the last 15 years.

Recent advances in genetic predisposition to clinical acute lung injury.

It has been well established that acute lung injury (ALI), and the more severe presentation of acute respiratory distress syndrome (ARDS), constitute complex traits characterized by a multigenic and multifactorial etiology. Identification and validation of genetic variants contributing to disease susceptibility and severity has been hampered by the profound heterogeneity of the clinical phenotype and the role of environmental factors, which includes treatment, on outcome. The critical nature of ALI and ARDS, compounded by the impact of phenotypic heterogeneity, has rendered the amassing of sufficiently powered studies especially challenging.

Distinct characteristics of signal transduction events by histamine-releasing factor/translationally controlled tumor protein (HRF/TCTP)-induced priming and activation of human basophils.

We previously identified a negative correlation between histamine release to histamine releasing factor/translationally controlled tumor protein (HRF/TCTP) and protein levels of the Src homology 2 domain-containing inositol 5' phosphatase (SHIP) in basophils. We have also demonstrated that HRF/TCTP primes basophils to release mediators. The purpose of this study was to begin characterization of signal transduction events directly induced by HRF/TCTP and to investigate these events when HRF/TCTP is used as a priming agent for human basophil histamine release.

Inhibition of FcepsilonRI-dependent mediator release and calcium flux from human mast cells by sialic acid-binding immunoglobulin-like lectin 8 engagement.

Background: Sialic acid-binding immunoglobulin-like lectins (Siglecs) are a family of glycan-binding inhibitory receptors, and among them, Siglec-8 is selectively expressed on human eosinophils, basophils, and mast cells. On eosinophils, Siglec-8 engagement induces apoptosis, but its function on mast cells is unknown.

Objective: We sought to study the effect of Siglec-8 engagement on human mast cell survival and mediator release responses.

Ca2+ signaling in hypoxic pulmonary vasoconstriction: effects of myosin light chain and Rho kinase antagonists.

Antagonists of myosin light chain (MLC) kinase (MLCK) and Rho kinase (ROK) are thought to inhibit hypoxic pulmonary vasoconstriction (HPV) by decreasing the concentration of phosphorylated MLC at any intracellular Ca(2+) concentration ([Ca(2+)](i)) in pulmonary arterial smooth muscle cells (PASMC); however, these antagonists can also decrease [Ca(2+)](i). To determine whether MLCK and ROK antagonists alter Ca(2+) signaling in HPV, we measured the effects of ML-9, ML-7, Y-27632, and HA-1077 on [Ca(2+)](i), Ca(2+) entry, and Ca(2+) release in rat distal PASMC exposed to hypoxia or depolarizing concentrations of KCl. We performed parallel experiments in isolated rat lungs to confirm the inhibitory effects of these agents on pulmonary vasoconstriction.

Mechanistic studies of acid-evoked coughing in anesthetized guinea pigs.

Experiments carried out in conscious guinea pigs suggest that citric acid-evoked coughing is partly mediated by transient receptor potential vanilloid type 1 (TRPV1) receptor-dependent activation of tachykinin-containing, capsaicin-sensitive C fibers. In vitro electrophysiological analyses indicate, however, that acid also activates capsaicin-sensitive and -insensitive vagal afferent nerves by a TRPV1-independent mechanism, and studies in anesthetized guinea pigs show that coughing evoked by acid is mediated by activation of capsaicin-insensitive vagal afferent nerves. In the present study, we have characterized the mechanisms of citric acid-evoked coughing in anesthetized guinea pigs.

Atopic dermatitis or hyper-IgE syndrome?

A case of atopic dermatitis (AD), recurrent infections, and elevated immunoglobulin E (IgE) level is presented. Clinical characteristics, pathophysiology, diagnosis, and management in this patient are reviewed. Clinical pearls and pitfalls include the following: (1) deep-seeded Staphylococcus aureus infections occur rarely in AD and should raise the possibility of immunodeficiency syndromes such as hyper-IgE syndrome (HIES); (2) HIES is characterized by a clinical triad consisting of elevated serum IgE levels, recurrent staphylococcal skin abscesses, and pneumonia with pneumatocele formation; (3) although serum IgE levels in AD have been noted to be as high as 10,000 IU/mL, severe cases of AD such as that presented here can exceed this range; (4) the efficacy of anti-IgE therapy in AD or HIES is unknown and may be limited by dosing requirements.

Transduction mechanisms in airway sensory nerves.

The induction of action potentials in airway sensory nerves relies on events leading to the opening of cation channels in the nerve terminal membrane and subsequent membrane depolarization. If the membrane depolarization is of sufficient rate and amplitude, action potential initiation will occur. The action potentials are then conducted to the central nervous system, leading to the initiation of various sensations and cardiorespiratory reflexes.

Genetic epidemiology of health disparities in allergy and clinical immunology.

The striking racial and ethnic disparities in disease prevalence for common disorders, such as allergic asthma, cannot be explained entirely by environmental, social, cultural, or economic factors, and genetic factors should not be ignored. Unfortunately, genetic studies in underserved minorities are hampered by disagreements over the biologic construct of race and logistic issues, including admixture of different races and ethnicities. Current observations suggest that the frequency of high-risk variants in candidate genes can differ between African Americans, Puerto Ricans, and Mexican Americans, and this might contribute to the differences in disease prevalence.