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Hyperoxia-induced lung injury is well known in animal and human studies. The respiratory epithelium including sensory nerve endings is a major target for oxidative injury that manifested in lung function changes including cough. On the basis of available information we supposed that hyperoxia alone or in combination with primary lung tissue injury should have a damaging effect on lungs, including the airway nerve endings with the changes in the sensitivity of the central and peripheral neuronal pathways regulating cough. We have previously demonstrated that long-term exposure to 100% oxygen inhibits the cough reflex in cat. This review article summarizes the effect of hyperoxia on the cough reflex in guinea pig model using different concentrations of oxygen and different time of exposure. We also present information on the potential role of antioxidants in reversal of the detrimental effects of hyperoxia on coughing and additional analysis of experiments from previously published studies were obtained and analysed for the cough reflex sensitivity.

The diseases of the esophagus and nose are among the major factors contributing to chronic cough although their role in different patient populations is debated. Studies in animal models and in humans show that afferent C-fiber activators applied on esophageal or nasal mucosa do not initiate cough, but enhance cough induced by inhaled irritants. These results are consistent with the hypothesis that activation of esophageal and nasal C-fibers contribute to cough reflex hypersensitivity observed in chronic cough patients with gastroesophageal reflux disease (GERD) and chronic rhinitis, respectively. The afferent nerves mediating cough sensitization from the esophagus are probably the neural crest-derived vagal jugular C-fibers. In addition to their responsiveness to high concentration of acid typical for gastroesophageal reflux (pH < 5), esophageal C-fibers also express receptors for activation by weakly acidic reflux such as receptors highly sensitive to acid and receptors for bile acids. The nature of sensory pathways from the nose and their activators relevant for cough sensitization are less understood. Increased cough reflex sensitivity was also reported in many patients with GERD or rhinitis who do not complain of cough indicating that additional endogenous or exogenous factors may be required to develop chronic coughing in these diseases.

Cough in respiratory diseases is attributed to the activation of airway C-fibers by inflammation. Inflammatory mediators can act on multiple receptors expressed in airway C-fibers, nonetheless, the action potential initiation in C-fibers depends on a limited number of voltage-gated sodium channel (NaV1) subtypes. We have recently demonstrated that NaV1.8 substantially contributes to the action potential initiation in the airway C-fiber subtype implicated in cough. We therefore hypothesized that the NaV1.8 blocker A-803467 inhibits cough. We evaluated the cough evoked by the inhalation of C-fiber activator capsaicin in awake guinea pigs. Compared to vehicle, intraperitoneal or inhaled A-803467 caused 30-50% inhibition of cough at the doses that did not alter respiratory rate. We conclude that the NaV1.8 blocker A-803467 inhibits cough in a manner consistent with its action on the C-fiber nerve terminals in the airways. Targeting voltage-gated sodium channels mediating action potential initiation in airway C-fibers may offer a means of cough inhibition that is independent of the stimulus.

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

TRPA1 receptor is activated by endogenous inflammatory mediators and exogenous pollutant molecules relevant to respiratory diseases. Previous studies have implicated TRPA1 as a drug target for antitussive therapy. Here we evaluated the relative efficacy of TRPA1 activation to evoke cough. In conscious guinea pigs the TRPA1 agonist allyl-isothiocyanate (AITC) evoked cough with a maximally effective concentration of 10mM that was abolished by the selective TRPA1 antagonist AP-18. AITC (10mM) was approximately 3-times less effective in inducing cough than capsaicin (50 μM). Ex vivo single fiber extracellular recordings revealed that, similarly to capsaicin, AITC evoked activation in airway jugular C-fibers, but not in airway nodose Aδ-fibers. Consistent with the cough studies, AITC was approximately 3-times less effective than capsaicin in evoking sustained activation of the jugular C-fibers. Another TRPA1 agonist, cinnamaldehyde, was approximately twofold more effective than AITC in inducing cough. However, the cinnamaldehyde (10mM)-induced cough was only partially inhibited by the TRPA1 antagonist AP-18, and was abolished by combination of AP-18 and the TRPV1 antagonist I-RTX. We conclude that in naïve guinea pigs, TRPA1 activation initiates cough that is relatively modest compared to the cough initiated by TRPV1, likely due to lower efficacy of TRPA1 stimulation to induce sustained activation of airway C-fibers.

The aim of the study was to investigate the effects of nasal histamine on the intensity of cough reflex and the effects of intensified nasal breathing following the nasal histamine challenge on cough sensitivity (CS) in humans. 20 volunteers (mean age 23, nonsmokers, no history of nasal or respiratory system diseases and atopy) were recruited to the study. Baseline CS was determined in all subjects. 2 days later the subjects (n=20) were challenged with nasal histamine (8 mg/ml, 0.1 ml) and the number of coughs was determined after four consecutive single-breath inhalations of capsaicin C2 concentration during the period of the most intensive nasal symptoms (sneezing, itching of the nose). The same capsaicin C2 challenge was performed after nasal saline challenge two days later. One week later CS was determined after nasal histamine challenge with subsequent 10 min of intensified breathing (5–6 sniff-like aspirations to total lung capacity per minute) through the nose and mouth in randomized order in ten volunteers, and with a two-day interval between the challenges. The same manoeuvres after intranasal saline challenge were performed in volunteers of the control group (n=10). The number of coughs after nasal histamine was significantly higher than that after intranasal saline challenge (8(6–10) vs 5(3–7); p=0.038(. CS was not significantly different between the baseline challenge and challenges after nasal histamine followed by the intensified nasal and mouth breathing ((2.21 (1.8–2.62) vs 2.04 (1.57–2.51) vs 2.05 (1.6–2.5) log10 of capsaicin concentration in μmol.l−1; p=0.09). Conclusions: During the period of maximum nasal symptoms after nasal histamine challenge the cough response to inhaled capsaicin was enhanced. Capsaicin cough sensitivity measured after a 10-min. intensified nasal breathing after nasal histamine challenge, compared to a previous measurement of CS, remain unchanged.

Stimulation of afferent nerves in upper airways may contribute to the pathogenesis of chronic cough in chronic disorders of nose and/or sinuses. We tested the hypothesis that stimulation of the nasal afferent nerves enhances experimentally-induced cough. Intranasal administration of capsaicin (50 microM, 25 microl) did not evoke cough in anaesthetized cats, but enhanced cough induced by mechanical stimulation of the tracheobronchial mucosa (number of coughs, median [IQR]) (6.5 [5.5-8.5] versus 10 [7-14]; P = 0.028, n = 13). In contrast, intranasal histamine (16 mM, 25 microl) had no effect. Intranasal capsaicin (50 microM, 15 microl) did not evoke cough, but enhanced cough evoked by mechanical stimulation of the tracheobronchial mucosa (1 [1-3] versus 3 [2-4]; P = 0.0037, n = 15) in anaesthetized guinea pigs and cough induced by inhalation of citric acid (0.3M, 2 min) in awake guinea pigs (3 [2-5] versus 5 [3-7], P ? 0.0026, n = 23). We conclude that stimulation of nasal afferent nerves with capsaicin enhances experimentally-induced cough. Our results suggest that afferent inputs from the nose interact with the cough reflex pathways in a manner that enhances cough.

isms of any sensitizing or direct action. Methods: Afferent mechanoand chemosensitivity was assessed in mouse colo-rectum In Vitro. High-threshold nociceptive afferents were characterised by responses to mechanical stimuli (3). Cytokine receptor abundance was assessed using PCR of Dorsal Root Ganglia (DRG) (L6-S1) and specifically in laser-captured colonic DRG neurons. Healthy and PIVH (TNBS 130μg/mL with 28 day recovery) mice were compared (3). Results: In healthy mice TNF-α (100ng/mL) induced potent mechanical hypersensitivity (P