An overview of the sensory receptors regulating cough

The cough reflex represents a primary defensive mechanism for airway protection in a variety of mammalian species. However, excessive and inappropriate coughing can emerge as a primary presenting symptom of many airway diseases. Cough disorders are characterized by a reduction in the threshold for reflex initiation and, as a consequence, the occurrence of cough in response to stimuli that are normally innocuous in nature. The current therapeutic strategies for the treatment of cough disorders are only moderately effective. This undoubtedly relates in part to limitations in our understanding of the neural components comprising the cough reflex pathway. The aim of this review is to provide an overview of current concepts relating to the sensory innervation to the mammalian airways, focusing particularly on the sensory receptors that regulate cough. In addition, the review will highlight particular areas and issues relating to cough neurobiology that are creating controversy in the field

Characterization of the Vagal Motor Neurons Projecting to the Guinea Pig Airways and Esophagus

Distinct parasympathetic postganglionic neurons mediate contractions and relaxations of the guinea pig airways. We set out to characterize the vagal inputs that regulate contractile and relaxant airway parasympathetic postganglionic neurons. Single and dual retrograde neuronal tracing from the airways and esophagus revealed that distinct, but intermingled, subsets of neurons in the compact formation of the nucleus ambiguus (nAmb) innervate these two tissues. Tracheal and esophageal neurons identified in the nAmb were cholinergic. Esophageal projecting neurons also preferentially (greater than 70%) expressed the neuropeptide CGRP, but could not otherwise be distinguished immunohistochemically from tracheal projecting preganglionic neurons. Few tracheal or esophageal neurons were located in the dorsal motor nucleus of the vagus. Electrical stimulation of the vagi in vitro elicited stimulus dependent tracheal and esophageal contractions and tracheal relaxations. The voltage required to evoke tracheal smooth muscle relaxation was significantly higher than that required for evoking either tracheal contractions or esophageal longitudinal striated muscle contractions. Together our data support the hypothesis that distinct vagal preganglionic pathways regulate airway contractile and relaxant postganglionic neurons. The relaxant preganglionic neurons can also be differentiated from the vagal motor neurons that innervate the esophageal striated muscle

Immunohistochemical characterization of nodose cough receptor neurons projecting to the trachea of guinea pigs

Cough in guinea pigs is mediated in part by capsaicin-insensitive low threshold mechanoreceptors (cough receptors). Functional studies suggest that cough receptors represent a homogeneous population of nodose ganglia-derived sensory neurons. In the present study we set out to characterize the neurochemical profile of cough receptor neurons in the nodose ganglia.Nodose neurons projecting to the guinea pig trachea were retrogradely labeled with fluorogold and processed immunohistochemically for the expression of a variety of transporters (Na+/K+/2C1- co-transporter (NKCC1), alpha1 and alpha3 Na+/K+ ATPase, vesicular glutamate transporters (vGlut)1 and vGlut2), neurotransmitters (substance P, calcitonin gene-related peptide (CGRP), somatostatin, neuronal nitric oxide synthase (nNOS)) and cytosolic proteins (neurofilament, calretinin, calbindin, parvalbumin).Fluorogold labeled ~3 per cent of neurons in the nodose ganglia with an average somal perimeter of 137 +/- 6.2 mum (range 90-200 microm). All traced neurons (and seemingly all nodose neurons) were immunoreactive for NKCC1. Many (> 90 per cent) were also immunoreactive for vGlut2 and neurofilament and between 50 and 85 per cent expressed alpha1 ATPase, alpha3 ATPase or vGlut1. Cough receptor neurons that did not express the above markers could not be differentiated based on somal size, with the exception of neurofilament negative neurons which were significantly smaller (P < 0.05). Less than 10 per cent of fluorogold labeled neurons expressed substance P or CGRP (and these had somal perimeters less than 110 microm) and none expressed somatostatin, calretinin, calbindin or parvalbumin. Two distinct patterns of nNOS labeling was observed in the general population of nodose neurons: most neurons contained cytosolic clusters of moderately intense immunoreactivity whereas less than 10 per cent of neurons displayed uniform intensely fluorescent somal labeling. Less than 3 per cent of the retrogradely traced neurons were intensely fluorescent for nNOS (most showed clusters of nNOS immunoreactivity) and nNOS immunoreactivity was not expressed by cough receptor nerve terminals in the tracheal wall.These data provide further insights into the neurochemistry of nodose cough receptors and suggest that despite their high degree of functional homogeneity, nodose cough receptors subtypes may eventually be distinguished based on neurochemical profile

Defining Feedback: Understanding Students’ Perceptions of Feedback in the Introductory Communication Course

Feedback is an essential part of the teaching/learning processes. This statement is especially true in the introductory communication course where students receive feedback throughout the presentational speaking process. This paper explores how students define useful feedback based on 1,600 qualitative questionnaires that asked students about their perceptions of feedback. A thematic analysis of a randomly selected subset of 163 responses uncovered two themes: (1) feedback content characteristics (e.g., specific, constructive, praiseworthy, and purposive) and (2) process of instructor-provided feedback (e.g., iterative, timely). Based on these findings, a set of best practices for providing feedback is offered as a means to improve teaching/learning in the introductory communication course

Investigation of the neural control of cough and cough suppression in humans using functional brain imaging

Excessive coughing is one of the mostcommonreasons for seeking medical advice, yet the available therapies for treating cough disorders are inadequate. Humans can voluntarily cough, choose to suppress their cough, and are acutely aware of an irritation that is present in their airways. This indicates a significant level of behavioral and conscious control over the basic cough reflex pathway. However, very little is known about the neural basis for higher brain regulation of coughing. The aim of the present study was to use functional brain imaging in healthy humans to describe the supramedullary control of cough and cough suppression. Our data show that the brain circuitry activated during coughing in response to capsaicin-evoked airways irritation is not simply a function of voluntarily initiated coughing and the perception of airways irritation. Rather, activations in several brain regions, including the posterior insula and posterior cingulate cortex, define the unique attributes of an evoked cough. Furthermore, the active suppression of irritant-evoked coughing is also associated with a unique pattern of brain activity, including an involvement of the anterior insula, anterior mid-cingulate cortex, and inferior frontal gyrus. These data demonstrate for the first time that evoked cough is not solely a brainstem-mediated reflex response to irritation of the airways, but rather requires active facilitation by cortical regions, and is further regulated by distinct higher order inhibitory processes. Copyright © 2011 the authors

Selective expression of a sodium pump isozyme by cough receptors and evidence for its essential role in regulating cough

We have identified a distinct subtype of airway vagal afferent nerve that plays an essential role in regulating the cough reflex. These afferents are exquisitely sensitive to punctate mechanical stimuli, acid, and decreases in extracellular chloride concentrations, but are insensitive to capsaicin, bradykinin, histamine, adenosine, serotonin, or changes in airway intraluminal pressures. In this study we used intravital imaging, retrograde neuronal tracing, and electrophysiological analyses to characterize the structural basis for their peculiar mechanical sensitivity and to further characterize the regulation of their excitability. In completing these experiments, we uncovered evidence for an essential role of an isozyme of Na(+)-K(+) ATPase in regulating cough. These vagal sensory neurons arise bilaterally from the nodose ganglia and are selectively and brilliantly stained intravitally with the styryl dye FM2-10. Cough receptor terminations are confined and adherent to the extracellular matrix separating the airway epithelium and smooth muscle layers, a site of extensive remodeling in asthma and chronic obstructive pulmonary disease. The cough receptor terminals uniquely express the alpha(3) subunit of Na(+)-K(+) ATPase. Intravital staining of cough receptors by FM2-10, cough receptor excitability in vitro, and coughing in vivo are potently and selectively inhibited by the sodium pump inhibitor ouabain. These data provide the first detailed morphological description of the peripheral terminals of the sensory nerves regulating cough and identify a selective molecular target for their modulation

Crystal structure and phonon softening in Ca3Ir4Sn13

We investigated the crystal structure and lattice excitations of the ternary intermetallic stannide Ca3Ir4Sn13 using neutron and x-ray scattering techniques. For T > T* ~ 38 K the x-ray diffraction data can be satisfactorily refined using the space group Pm-3n. Below T* the crystal structure is modulated with a propagation vector of q = (1/2, 1/2, 0). This may arise from a merohedral twinning in which three tetragonal domains overlap to mimic a higher symmetry, or from a doubling of the cubic unit cell. Neutron diffraction and neutron spectroscopy results show that the structural transition at T* is of a second-order, and that it is well described by mean-field theory. Inelastic neutron scattering data point towards a displacive structural transition at T* arising from the softening of a low-energy phonon mode with an energy gap of Delta(120 K) = 1.05 meV. Using density functional theory the soft phonon mode is identified as a 'breathing' mode of the Sn12 icosahedra and is consistent with the thermal ellipsoids of the Sn2 atoms found by single crystal diffraction data

Relation of Abdominal Fat Depots to Systemic Markers of Inflammation in Type 2 Diabetes

OBJECTIVE: Both visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) have been linked to systemic inflammation in nondiabetic cohorts. We examined the relationships between VAT and SAT and systemic inflammatory markers in a large well-characterized cohort of subjects with type 2 diabetes. RESEARCH DESIGN AND METHODS: Three hundred eighty-two subjects with type 2 diabetes in the CHICAGO (Carotid Intima-Media Thickness in Atherosclerosis Using Pioglitazone) study cohort underwent abdominal computed tomography to determine SAT and VAT distribution. Fasting blood was obtained for measurement of inflammatory markers. The relationships between inflammatory markers and BMI, SAT, and VAT were examined using regression models adjusted for age, sex, diabetes treatment, duration of diabetes, smoking, statin use, and A1C. RESULTS: VAT was positively related to CRP, monocyte chemoattractant protein (MCP), intracellular adhesion molecule (ICAM)-1, and plasminogen activator inhibitor type 1 (PAI-1) antigen before adjustment for BMI. After adjustment for BMI, the relationship to CRP was lost but positive associations with MCP (P < 0.01), PAI-1 (P < 0.0001), ICAM-1 (P < 0.01), and vascular cell adhesion molecule (P = 0.01) were evident. BMI was positively related to CRP (P < 0.0001) and IL-6 (P < 0.01) even after adjustment for VAT and SAT. SAT was not related to any inflammatory marker after adjustment for BMI. CONCLUSIONS: In this large group of subjects with type 2 diabetes, BMI was most strongly associated with CRP and IL-6 levels. SAT was not associated with markers of systemic inflammation. The size of the VAT depot provided information additional to that provided by BMI regarding inflammatory markers that are strongly related to vascular wall remodeling and coagulation. Our findings suggest that adipose tissue distribution remains an important determinant of systemic inflammation in type 2 diabetes.National Institutes of Health (DK-71711); University of Illinois at Chicag

Hypertriglyceridemic Waist Phenotype Predicts Increased Visceral Fat in Subjects With Type 2 Diabetes

OBJECTIVE: Greater accumulation of visceral fat is strongly linked to risk of cardiovascular disease. However, elevated waist circumference by itself does not always identify individuals with increased visceral fat. RESEARCH DESIGN AND METHODS: We examined 375 subjects with type 2 diabetes from the CHICAGO cohort for presence of hypertriglyceridemic waist phenotype (waist circumference >90 cm in men or >85 cm in women, in conjunction with a plasma triglyceride concentration of ≥177 mg/dl) to determine its usefulness for identifying subjects with increased amounts of visceral fat. We divided subjects into three groups: group 1 (low waist circumference and low triglycerides; waist circumference ≤90 cm in men or ≤85 cm in women and triglyceride <177 mg/dl, n = 18), group 2 (high waist circumference and low triglycerides; waist circumference >90 cm in men or >85 cm in women and triglycerides <177 mg/dl, n = 230), and group 3 (high waist circumference and high triglycerides; waist circumference >90 cm in men or >85 cm in women and triglycerides ≥177 mg/dl, n = 127). RESULTS: Subjects in group 3 had significantly higher visceral fat (P < 0.0001), A1C (P < 0.01), and coronary artery calcium (P < 0.05) compared with group 2, despite similar age, BMI, and waist circumference. The relationship of the phenotype to atherosclerosis, however, was attenuated by adjustment for HDL cholesterol, triglyceride-rich lipoprotein cholesterol, apolipoprotein B, or LDL particle number. CONCLUSIONS: The presence of hypertriglyceridemic waist phenotype in subjects with type 2 diabetes identifies a subset with greater degree of visceral adiposity. This subset also has greater degree of subclinical atherosclerosis that may be related to the proatherogenic lipoprotein changes.Takeda Global Research and Development; National Institutes of Health (DK 71711); University of Illinois at Chicag