V. Calkovsky

Modulation of cough response by sensory inputs from the nose - role of trigeminal TRPA1 versus TRPM8 channels.

BackgroundCough, the most important airways defensive mechanism is modulated by many afferent inputs either from respiratory tussigenic areas, but also by afferent drive from other organs. In animal models, modulation of cough by nasal afferent inputs can either facilitate or inhibit the cough response, depending on the type of trigeminal afferents stimulated.MethodsIn this study we addressed the question of possible bidirectional modulation of cough response in human healthy volunteers by nasal challenges with TRPA1 and TRPM8 agonists respectively. After nasal challenges with isocyanate (AITC), cinnamaldehyde, (−) menthol and (+) menthol (all 10-3 M) nasal symptom score, cough threshold (C2), urge to cough (Cu) and cumulative cough response were measured).ResultsNasal challenges with TRPA1 relevant agonists induced considerable nasal symptoms, significantly enhanced urge to cough (p<0.05) but no statistically significant modulation of the C2 and cumulative cough response. In contrast, both TRPM8 agonists administered to the nose significantly modulated all parameters including C2 (p<0.05), Cu (p<0.01) and cumulative cough response (p <0.01) documenting strong anti irritating potential of menthol isomers.ConclusionsIn addition to trigeminal afferents expressing TRP channels, olfactory nerve endings, trigemino – olfactoric relationships, the smell perception process and other supramedullar influences should be considered as potential modulators of the cough response in humans.

Antitussive effects of nasal thymol challenges in healthy volunteers.

Eighteen healthy volunteers with normal lung function were tested for cough. Before and after nasal administration of thymol (0.025 ml, 10(-3) M) into both nostrils, urge-to-cough, cough threshold, cumulative and total count of coughs per provocation were estimated during standardized and validated capsaicin cough challenge. Nasal thymol challenges induced pleasant olfactory sensation and in 6 out of the 18 subjects also mild cooling sensation. Cough threshold was not influenced when compared with intranasal saline and vehicle challenges (12.5 vs. 13.2 vs. 10.2 μM of capsaicin to induce two or more coughs (C2), respectively), but the total count of coughs after nasal thymol challenge was significantly lower than that obtained after saline or vehicle (19 vs. 20 vs. 14 coughs/provocation, respectively; p<0.05). Importantly, subjects did not report the urge to cough, which appeared to correspond to C2. We conclude that the modulation of cough by thymol is mostly of olfactory origin.

Pulmonary surfactant in the airway physiology: a direct relaxing effect on the smooth muscle.

Beside alveoli, surface active material plays an important role in the airway physiology. In the upper airways it primarily serves in local defense. Lower airway surfactant stabilizes peripheral airways, provides the transport and defense, has barrier and anti-edematous functions, and possesses direct relaxant effect on the smooth muscle. We tested in vitro the effect of two surfactant preparations Curosurf® and Alveofact® on the precontracted smooth muscle of intra- and extra-pulmonary airways. Relaxation was more pronounced for lung tissue strip containing bronchial smooth muscle as the primary site of surfactant effect. The study does not confirm the participation of ATP-dependent potassium channels and cAMP-regulated epithelial chloride channels known as CFTR chloride channels, or nitric oxide involvement in contractile response of smooth muscle to surfactant.By controlling wall thickness and airway diameter, pulmonary surfactant is an important component of airway physiology. Thus, surfactant dysfunction may be included in pathophysiology of asthma, COPD, or other diseases with bronchial obstruction.

Sensitivity of airway cough-related afferents is influenced by female sex hormones

Chronic hypersensitivity cough syndrome affects mainly postmenopausal women; however, the pathogenesis of cough hypersensitivity in this demographic is not entirely understood. The role of sex hormones in cough has never been studied in detail; however, sex hormones seem to play an important role in the lung health of women. Our study was aimed to analyse the effect of female sex hormones (oestrogen - E2 and progesterone - Pg) on cough sensitivity measured by inhalation of capsaicin in follicular and luteal phases of menstrual cycle, characterized by significantly different concentrations of sex hormones. These data were compared with a matched group of women taking oral contraceptives. Cough sensitivity to capsaicin increased in luteal phase in subjects with normal menstrual cycle, and this functional change was not present in group with contraceptive pills. The cough sensitivity correlates with the Pg/E2 ratio, and relative lack of oestrogen in luteal phase is associated with higher cough sensitivity to capsaicin.

The Nose as a Target of Air Pollution, Physiological Aspects and Clinical Relevance of Nasal Trpa1 (Transient Receptor Potential A1) Receptors

The Nose as a Target of Air Pollution, Physiological Aspects and Clinical Relevance of Nasal Trpa1 (Transient Receptor Potential A1) Receptors Worldwide more than several hundred million humans are exposed to severe air pollution, and a significant part of them also smoke. The effect of air pollution on human health has been recognized for many years. The nose, as the first portal of entry to the respiratory system is constantly exposed to a large volumes of air, which is composed of a mixture of gases, particulate matter and infectious agent, and any material other than physiological amount of oxygen, nitrogen, carbon dioxide and water is considered as pollutant. Being exposed to critical amount of air pollutants, nasal cavity shares sophisticated system of protective and defensive mechanisms regarding the lower airways and lungs, however the highest risk of direct exposure to relevant air pollutants is just within the nose. Air pollution is considered to be responsible for some of the pathological processes affecting airways prone to allergic reactions in predisposed subjects, onset of nasal sensorineural hyperresponsiveness, non-specific inflammation, sinonasal cancer and definitely, the risk is not limited just to the nasal mucosa, but can proceed toward the lower airways. The broad spectrum of irritants probably shares very similar molecular background of action. They are capable to activate the cation channenl tranisient receptor potential A1-TRPA1 by covalent modification of the channel protein, because many of them are highly reactive and nonstable molecules with possibilities for various chemical reactions. Activation of this channel is responsible for nociceptive reactions mediated by stimulation of afferent trigeminal nerves, retrograde release of tachykinins, activation of parasympathetic afferent drive leading to increase of mucus output and decrease of nasal patency, with subsequent alteration of nasal functions. Based on the recently described neuro-immune bidirectional relationships, air pollutants may be responsible for recruitment of immune cells with infiltration of the nasal mucosa possibly leading to the inflammatory processes and allergies. Our paper is discussing the nose as the target for air pollution, and focuses on the relevance of TRPA1 channel on trigeminal afferents in pollution mediated responses.

Lung surfactant alterations in pulmonary thromboembolism.

Beside neonatal respiratory distress syndrome, secondary surfactant deficiency may occur in patients with mature lungs. Recent studies revealed quantitative and qualitative changes of lung surfactant in pulmonary thromboembolism (PTE) concerning the total phospholipids content in BAL fluid, alterations in surfactant phospholipids classes and a large-to-small aggregates ratio. Reduced expression of surfactant protein A (SP-A) mRNA and SP-A in lung tissue after pulmonary embolism was found. Serum levels of SP-A were significantly higher in patients with PTE than in other lung diseases, except COPD. Surfactant changes in PTE may result from damage of type II cells by hypoxia, leakage of plasma proteins into the airspaces and/or by reactive oxygen species. They can contribute to lung atelectasis and edema, and a further reduction in oxygen saturation as seen in clinical picture of PTE. Surfactant changes are reliable marker of lung injury that might become a prognostic indicator in patients with pulmonary thromboembolism.

Upper Airway Control in Airway Defense

Abstract Upper airways (UA) are an organic component of the respiratory tract, they serve to respiration, respiratory tract protection and defense, phonation, deglutition, etc. The functions of UA are regulated by motor control of the oral, pharyngeal, and laryngeal muscles. UA typically stiffen and widen during inspiration mainly due to the activation of the alae nasi, genioglossus m., pharyngeal dilators, and laryngeal abductors. These and other UA muscles (e.g. laryngeal and pharyngeal constrictors) may express varoius activity patterns, actively shaping UA depending on species, arousal, respiratory drive, and behavior being executed. E.g. during coughing and sneezing laryngeal movement consists of abductions in inspiration and expiration and adductions in compression and subsequent constriction phase. The cricopharyngeus m., in cough expiration the superior pharyngeal constrictor and in the sneeze expiration the styloglossus and levator veli palatini m. are activated. Unlike in breathing or coughing, where UA serve to respiration-protection-defense, the pharyngeal phase of swallowing is essentially made by the coordinated action of a number of UA muscles. Motoneurons driving the UA muscles are located primarily in the hypoglossal and ambigual nuclei. Motor pattern of individual motoneuronal pools is determined by activation-inhibition-modulation from pre-motoneurons and other upstream neurons of the reflex circuits. Laryngeal and hypoglossal nerve activity is during breathing under command of respiratory central pattern generator. UA muscles are driven in inspiration primarily from augmenting, less from decrementing and constant inspiratory neurons. Number of additional inputs is involved in UA regulation during expirations and other motor behaviors. Anatomical and functional studies pointed out number of brainstem areas, such as the regions of solitary tract nucleus, hypoglossal ncl., trigeminal ncl., lateral tegmental field, raphé, the ventral and ventrolateral medulla, pontine parabrachial region, etc. with neurons related to UA motor control. Abundant connectivity of the neuronal network that controls UA patency employs almost all kind of receptors and neurotransmitter/neuromodulator systems. Among large number of diseases and disorders that relate to UA, primarily cholinergic, norepinephrine, and serotonergic tonic drives are implicated in those resulted from the reduced UA tone. Pharmacological and frequently simple surgical interventions may improve these conditions (snore, obturation) in patients. Recently, besides medicinal treatment, conditional procedures incorporating an exercise and practice, stimulation of appropriate afferent pathways, and combining reflex responses may offer promising therapies.

Laryngeal Cancer: 12-Year Experience of a Single Center

Laryngeal cancer is about the twentieth most common cancer in the world and more than 150,000 new cases are diagnosed annually. The aim of the study was to evaluate the history, diagnostics, treatment outcomes, and prognosis in patients with laryngeal cancer in Northern Slovakia. We analyzed retrospectively 227 patients (207 males, 20 females) with laryngeal carcinoma treated in the period 2003-2014 at the Clinic of Otorhinolaryngology and Head and Neck Surgery of the Jessenius Faculty of Medicine and Martin University Hospital in Martin, Slovakia. The majority of patients were in the sixth (38.0 %) and seventh decade of life (30.8 %). Two hundred and seventeen patients (95.6 %) were smokers or ex-smokers. Sixty-six percent of patients were diagnosed with glottic or transglottic carcinoma, related probably to the anatomical structure of the larynx and exposure to inhalation pollutants. It is alarming that the majority of patients with malignant laryngeal disease were admitted to the hospital in advanced stages. In 151 (66.5 %) of patients, the extent of infiltration was T3 or T4, and 156 (68 %) patients were in disease stage III and IV. The incidence and mortality of laryngeal cancer suggest the need to intensify the prevention and to search for an early clinical stage of laryngeal cancer using a targeted screening.

Castleman's Disease Mimicking Carotid Body Tumor

Castlemans Disease Mimicking Carotid Body Tumor The authors present a case of 41-year-old patient with unicentric type of Castlemans disease in the neck imitating carotid glomus tumor. This rare condition can affect any lymph-node in the body and neck localization occurs only in 14% of cases. The case when Castlemans disease simulating chemodectoma have not been described yet in the literature. The authors give details on the course of the disease, its diagnosis and treatment and the discussion focuses on the reasons why the auxiliary imaging methods have led to the clinical diagnosis of carotid glomus tumor, and why the treatment was chosen.