Neuroplasticity of bronchopulmonary afferent neurons that respond to mechanical and chemical stimuli may sensitize the cough reflex. Afferent drive in cough is carried by the vagus nerve, and vagal ...afferent nerve terminals have been well defined in animals. Yet, both unmyelinated C fibers and particularly the morphologically distinct, myelinated, nodose-derived mechanoreceptors described in animals are poorly characterized in humans. To date there are no distinctive molecular markers or detailed morphologies available for human bronchopulmonary afferent nerves.
Morphologic and neuromolecular characterization of the afferent nerves that are potentially involved in cough in humans.
A whole-mount immunofluorescence approach, rarely used in human lung tissue, was used with antibodies specific to protein gene product 9.5 (PGP9.5) and, for the first time in human lung tissue, 200-kD neurofilament subunit.
We have developed a robust technique to visualize fibers consistent with autonomic and C fibers and pulmonary neuroendocrine cells. A group of morphologically distinct, 200-kD neurofilament-immunopositive myelinated afferent fibers, a subpopulation of which did not express PGP9.5, was also identified.
PGP9.5-immunonegative nerves are strikingly similar to myelinated airway afferents, the cough receptor, and smooth muscle-associated airway receptors described in rodents. These have never been described in humans. Full description of human airway nerves is critical to the translation of animal studies to the clinical setting.
Towards understanding and managing chronic cough Satia, Imran; Badri, Huda; Al-Sheklly, Bashar ...
Clinical medicine (London, England),
December 2016, 2016-12-00, 20161201, Letnik:
16, Številka:
6
Journal Article
Recenzirano
Odprti dostop
Chronic cough is a common and troublesome condition affecting approximately 12% of the general population. It is associated with poor quality of life with psychological, social and physical ...consequences. Patients typically complain of a dry irritating cough, driven by a strong urge to cough associated with a sensation or irritation located in the throat. Treatment of potential ‘causes’, ie asthma, gastro-oesophageal reflux disease and rhino-sinusitis, may produce a complete or partial response, but the response of some patients to opiates and alpha-2-delta ligand antagonists (gabapentin and pregabalin) supports the concept that this is primarily a neurological disorder, characterised by hyper-responsiveness of the nerves. Novel and highly effective neuronal treatments are in development and offer hope of better symptom control with fewer side effects within a few years. This review focuses on understanding the mechanism of chronic cough, current management approaches and research that may lead to novel therapies.
Background Cough is widely recognized as a key symptom in the diagnosis and the monitoring of asthma, but little is known about how best to assess cough in asthma. Objective To determine how ...objective cough rates correlate with subjective measures of cough in asthma. Methods We studied 56 subjects, median age 42.0 years (range, 28.5-71), 34 (60.7%) female, with asthma. Subjects performed cough reflex sensitivity testing (concentration of citric acid causing 2 and 5 coughs C2 and C5), 24-hour fully ambulatory cough recordings, subjectively scored the severity of their cough (visual analog scales and 0-5 score) and completed a cough-related quality of life questionnaire (Leicester Cough Questionnaire). Ambulatory cough recordings were manually counted and reported in cough seconds per hour (cs/h). Results The median time spent coughing was 2.6 cs/h (range, 0.0-14.2), with subjects spending more time coughing by day (median, 3.9 cs/h 0.0-18.5) than by night (median, 0.3 cs/h 0.0-8.7; P < .001). A weak inverse relationship was seen between day cough rates and log10 C2 ( r = –0.39; P = .03) but not log10 C5 ( r = –0.08; P = .65). Objective time spent coughing was also weak-moderately associated with subjective cough scores and visual analog scales, and most strongly correlated with cough-related quality of life ( r = –0.54; P < .001). Conclusion Subjective measures of cough and cough reflex sensitivity are poor surrogates for objective cough frequency in asthma. When designing studies to assess interventions for cough in asthma, we advocate a combination of both objective measures of cough and cough-related quality of life.
Computational methods involving virtual screening could potentially be employed to discover new biomolecular targets for an individual molecule of interest (MOI). However, existing scoring functions ...may not accurately differentiate proteins to which the MOI binds from a larger set of macromolecules in a protein structural database. An MOI will most likely have varying degrees of predicted binding affinities to many protein targets. However, correctly interpreting a docking score as a hit for the MOI docked to any individual protein can be problematic. In our method, which we term “Virtual Target Screening (VTS)”, a set of small drug-like molecules are docked against each structure in the protein library to produce benchmark statistics. This calibration provides a reference for each protein so that hits can be identified for an MOI. VTS can then be used as tool for: drug repositioning (repurposing), specificity and toxicity testing, identifying potential metabolites, probing protein structures for allosteric sites, and testing focused libraries (collection of MOIs with similar chemotypes) for selectivity. To validate our VTS method, twenty kinase inhibitors were docked to a collection of calibrated protein structures. Here, we report our results where VTS predicted protein kinases as hits in preference to other proteins in our database. Concurrently, a graphical interface for VTS was developed.
Pulmonary function methods which are able to detect small pharmacological effects may be useful for assessing the full dose–response curve of bronchodilatators. We compared the ability of impulse ...oscillometry (R5, R20, X5, RF), plethysmography (sGaw) and spirometry forced expiratory volume in 1 s (FEV1), maximal mid expiratory flow rate (MMEF) to measure the dose–response effects of salbutamol in 12 healthy subjects, 12 mild asthmatics (mean FEV1 96% predicted) and 12 moderate asthmatics (mean FEV1 63% predicted). The techniques were performed twice to assess variability. Then salbutamol 10, 20, 100, 200 and 800 µg was administered. The sensitivity of the methods were compared by determining the lowest dose that caused changes greater than variability. In healthy subjects significant changes (p ≤ 0.05) were observed only in FEV1 (4.1%) and MMEF (14.6%) at 100 µg and sGaw (25.6%) and R20 (8.3%) at 200 µg. In mild asthmatics significant changes were observed in sGaw (15.9%) at 10 µg, X5 (23%), RF (20.3%) and MMEF (15.7%) at 20 µg, R5 (13.9%) and R20 (9.4%) at 100 µg and FEV1 (7.1%) at 200 µg. All measurements except R20 demonstrated significant changes at 10 µg in moderate asthmatics. The most sensitive test for assessing bronchodilatation is different in healthy subjects and asthmatics, and varies with severity of airflow obstruction.
Idiopathic pulmonary fibrosis (IPF) is a clinical syndrome in which the precipitating factors are unclear. An association between Epstein-Barr Virus (EBV) and IPF had previously been suggested using ...serology and immunohistochemistry. This study sought confirmation of the presence of EBV DNA in the lung tissue of patients with IPF. Lung tissue obtained surgically from 27 patients with IPF and 28 control subjects was investigated for the presence of EBV by immunohistochemistry and polymerase chain reaction (PCR) analysis. Immunohistochemistry used antibodies specific for EBV lytic cycle antigens (gp340/220 and VCA). Nested PCR analysis used oligonucleotide primers specific for EBV and was sensitive to one copy of EBV DNA. Twelve of the 27 patients with IPF (44%) and three of the 28 control subjects (10%) were EBV positive by immunohistochemistry (p = 0.005). Thirteen of the patients with IPF (48%) and four of the control subjects (14%) were EBV positive by PCR (p = 0.007). Eleven of the patients with IPF (41%) and none of the control subjects were EBV positive by both immunohistochemistry and PCR (p = < 0.001). These data further suggest an association between EBV and IPF. In addition it defines a novel method for detecting EBV in lung tissue. EBV may be involved in the pathogenesis of the disease; however, further studies are required to establish a causal relationship.
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