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Introduction: Over the past 50 years, the prevalence of allergic respiratory diseases has been increasing. The Hygiene hypothesis explains this progression by the decrease in the bio-diversity of early microbial exposure. This study aims to evaluate the effect of early-life farm exposure on airway hyperresponsiveness and cough hypersensitivity in an allergic airway inflammation rabbit model., Method: A specific environment was applied to pregnant rabbits and their offspring until six weeks after birth. Rabbits were housed in a pathogen-free zone for the control group and a calf barn for the farm group. At the end of the specific environmental exposure, both groups were then housed in a conventional zone and then sensitized to ovalbumin. Ten days after sensitization, the rabbit pups received ovalbumin aerosols to provoke airway inflammation. Sensitization to ovalbumin was assessed by specific IgE assay. Cough sensitivity was assessed by mechanical stimulation of the trachea, and bronchial reactivity was assessed by methacholine challenge. The farm environment was characterized by endotoxin measurement., Results: A total of 38 rabbit pups were included (18 in the farm group). Endotoxin levels in the farm environment varied from 30 to 1854 EU.m-3. There was no significant difference in specific IgE values to ovalbumin (p = 0.826) between the two groups. The mechanical threshold to elicit a cough did not differ between the two groups (p = 0.492). There was no difference in the number of cough (p = 0.270) or the intensity of ventilatory responses (p = 0.735). After adjusting for age and weight, there was no difference in respiratory resistance before and after methacholine challenge., Conclusion: Early exposure to the calf barn did not affect cough sensitivity or bronchial reactivity in ovalbumin-sensitized rabbits. These results suggest that not all farm environments protect against asthma and atopy. Continuous exposure to several sources of microbial diversity is probably needed., Competing Interests: A.D-C. reports support from ARAIRLOR for the present manuscript; a contract with the French Public Agency ANSES as an expert in allergy and pediatric; consulting fees for expertise in pediatric allergy for Stallergens, Aimmune Therapeutics and ALK; and support for attending meetings from Mead Johnson, Nutricia, Aimmune Therapeutics and Novartis Pharma SAS. F.M. reports a grant from the French public agency ANSES and participation on a Data Safety Monitoring Board for the clinical “Propila-Rifax”. All other authors have no conflict of interest in relation to this work., (Copyright: © 2023 Divaret-Chauveau et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

In order to clear airways and lungs defensive reflexes are provoked rather by the dynamic phase of mechanical stimulus. It is speculated that provocation of defensive response depends not only on stimulus duration but also on stimulus velocity. Fourteen adult rabbits were anaesthetized and tracheotomized. Mechanical stimulus was provoked by a mechanical probe introduced through the tracheotomy and rotated by a small electrical motor using a rotational velocity of 40 rpm/s and 20 rpm/s. Threshold, incidence and intensity of cough reflex (CR) were analyzed for each animal. Statistical comparisons between two velocities were performed using Friedman nonparametric test for repeated measurements. Results are median (25-75 %). The threshold of CR was significantly increased (p=0.005) from 350 ms (300-500 ms) to 550 ms (350-1150 ms) and the incidence of cough reflex was significantly reduced (p=0.002) from 50 % (19 50 %) to 0 % (0-25 %) when the rotational velocity of the mechanical probe was reduced by half. The findings of this study are of interest as they show that protective reflex cough, an important mechanism that allows clearing airways even during sleep or anesthesia, is tuned by mechanical stimulus velocity.

Chronic irritating cough in patients with allergic disorders may reflect behavioral or reflex response that is inappropriately matched to the stimulus present in the respiratory tract. Such dysregulated response is likely caused by sensory nerve damage driven by allergic mediators leading to cough hypersensitivity. Some indirect findings suggest that even acid-sensitive, capsaicin-insensitive A-δ fibers called "cough receptors" that are likely responsible for protective reflex cough may be modulated through immune driven inflammation. The aim of this study was to find out whether protective reflex cough is altered during acute allergic airway inflammation in rabbits sensitized to ovalbumin. In order to evaluate the effect of such inflammation exclusively on protective reflex cough, C-fiber mediated cough was silenced using general anesthesia. Cough provocation using citric acid inhalation and mechanical stimulation of trachea was realized in 16 ovalbumin (OVA) sensitized, anesthetized and tracheotomised rabbits 24h after OVA (OVA group, n = 9) or saline challenge (control group, n = 7). Number of coughs provoked by citric acid inhalation did not differ between OVA and control group (12,2 ±6,1 vs. 17,9 ± 6,9; p = 0.5). Allergic airway inflammation induced significant modulation of cough threshold (CT) to mechanical stimulus. Mechanically induced cough reflex in OVA group was either up-regulated (subgroup named "responders" CT: 50 msec (50-50); n = 5 p = 0.003) or down-regulated (subgroup named "non responders", CT: 1200 msec (1200-1200); n = 4 p = 0.001) when compared to control group (CT: 150 msec (75-525)). These results advocate that allergen may induce longer lasting changes of reflex cough pathway, leading to its up- or down-regulation. These findings may be of interest as they suggest that effective therapies for chronic cough in allergic patients should target sensitized component of both, reflex and behavioral cough., Competing Interests: The authors have declared that no competing interests exist.

Lung hyperinflation may alter the pattern of ventilatory reflexes in chronic respiratory disorders. The aim of the study was to test the effect of continuous positive airway pressure (CPAP) on ventilatory responses to mechanical stimulation of the trachea., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Introduction: Cough is a major symptom of asthma frequently experienced during exercise but little is known about interactions between cough and exercise. The goal of our study was to clarify the potential modulation of the cough reflex (CR) by exercise in a spontaneously breathing anaesthetized animal model of airway eosinophilic inflammation., Materials & Methods: Ten ovalbumin (OVA) sensitized adult rabbits and 8 controls were studied. The ventilatory response to direct tracheal stimulation, performed both at rest and during exercise was determined to quantify the incidence and the sensitivity of the CR. Broncho-alveolar lavages (BAL) and cell counts were performed to assess the level of the airway inflammation following OVA-induced sensitization. Exercise was mimicked by Electrically induced hindlimb Muscular Contractions (EMC)., Results: Among 494 tracheal stimulations, 261 were performed at rest and 233 at exercise. OVA challenges in sensitized rabbits caused a significant increase in the percentage of eosinophils (p = 0.008) in BAL. EMC increased minute ventilation by 36% and 35% in OVA and control rabbits respectively, compared to rest values. The sensitivity of the CR decreased during exercise compared to baseline in control rabbits (p = 0.0313) while it remained unchanged in OVA rabbits., Conclusion: The desensitization of the CR during exercise in control rabbits was abolished in OVA rabbits. The precise role of airway inflammation in this lack of CR desensitization needs to be further investigated but it might contribute to the exercise-induced cough in asthmatics., Competing Interests: The authors have declared that no competing interests exist.

A link between cough in childhood and neonatal exposure to hyperoxia following preterm birth has been suggested. The hypothesis is tested that neonatal exposure to hyperoxia is associated with long term up regulation of cough. Airway hyperresponsiveness is also investigated because it is a frequent finding in children born preterm and may be linked to cough. Thirty nine young rabbits survived a 48 h neonatal exposure to 93% oxygen (H, n=26) or continued room air (A, n=13). Cough response to mechanical tracheal stimulation and airway responses to a mock exercise and to methacholine were studied under anaesthesia. Larger incidence of coughs and increased sensitivity to tracheal stimulation occurred in H vs A (p<0.01), while bronchial responses to exercise or methacholine were similar in both groups. Neonatal hyperoxia is associated with up regulation of cough in young rabbits. The lack of a parallel increase in airway responsiveness suggests up regulation may be of central origin., (Copyright © 2015 Elsevier B.V. All rights reserved.)

The 'cough network' exhibits plasticity at the sensor and integration levels leading to modulation of the strength or pattern of the cough reflex. Little is known about the interactions between cough and human activities, especially during exercise. The present study was designed to determine whether exercise, mimicked by electrically induced muscle contractions, can modify the incidence and/or strength of cough following mechanical stimulation of the trachea in anesthetized rabbits. Thirteen anesthetized, tracheotomized rabbits were studied by a total of 311 tracheal stimulations: 196 at rest and 115 during exercise. During muscle contractions, the incidence of the cough reflex (CR) decreased and the expiration reflex (ER) increased (p < 0.0001). The sensitivity of the CR and ER both decreased during exercise compared to the sensitivity of the CR at rest (p < 0.02), while the strength of the expulsive response remained unchanged. These results indicate that adjustments occurring during muscle contractions likely downregulate tracheal defensive reflexes in anesthetized rabbits., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

The 'cough center' can be tuned by various afferent inputs, suggesting possible interactions at a central level of neural pathways originating from distant anatomical sites. The present study was designed to determine whether brief mechanical stimulation of the trachea can trigger cough during apnea elicited by nasal instillation of water. Twelve anesthetized, tracheotomized rabbits were studied. Mechanical stimulation of the trachea was performed under 3 conditions: baseline control, after instillation of saline into the nose and during apnea following instillation of water. The baseline breathing pattern did not differ between the 3 conditions. In a series of 171 stimulations, expiration reflex occurred in 81% of stimulations during apnea with a significantly (p<0.0001) lower peak expiratory flow than at baseline or during saline instillation. The incidence of responses comprising a cough reflex was also lower during water instillation than at either baseline or with saline (p<0.0001). These results indicate that stimulation of nasal afferents with distilled water likely down-regulates cough., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Expiration reflex and cough may have distinct afferent pathways and/or central integrative mechanisms that may both result in different stimulus response latencies. A newly described method that uses a punctuate mechanical tracheal stimulus to provoke defensive ventilatory reflexes should allow the stimulus response latency to be calculated with reasonable accuracy. The aim of the study was to test whether cough and expiration reflex have different stimulus response latencies. Four hundred and sixty one mechanical tracheal stimulations (50-300 msec) were performed in 21 anesthetized, tracheotomized rabbits. Twenty three percent stimulations (108) provoked a cough reflex and 37% an expiration reflex (171). The individual mean stimulus response latency was computed for each reflex, calculated from stimulus onset to earliest detectable change in ventilatory flow. Cough reflex latency was significantly shorter in inspiration compared to expiration (257±19 msec vs 391±61 msec; p=0.01). In contrast, the expiration reflex latency was significantly shorter in expiration compared to inspiration (210±11 msec vs 329±29 msec, p=0.003). It is concluded that the within breath dependence of the difference in stimulus response latency between cough and expiration reflex is more likely to express different brainstem mechanisms but difference in afferent fibres may not be excluded., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Objectives: The aim of the study was to characterise mechanically induced cough threshold and reactivity by exposing the trachea to stimuli of variable duration in rabbit., Background: Long lasting mechanical stimulation is widely used in experimental protocols studying cough reflex. The cough threshold and reactivity to chemical agents is known to change due to e.g. airway inflammation but similar evidence for mechanical stimulation has not been reported., Methods: The tracheal provocation was realized in two anesthetized tracheotomized rabbits with a rotating probe actuated by a small electrical motor with mechanical stimulus times (ST) lasting 50, 150, 300 and 600 ms. Cough reflex was evaluated from tidal volume and airflow signals., Results: The incidence of cough reflex (single or multiple) increased from 8% (ST 50 ms) to 84% (ST 600 ms). With the lengthening of stimulus, the rate of multiple responses increases., Conclusion: The technique developed here may prove useful to standardize the protocols of mechanical cough in the experimental animal using an approach similar to chemical tussigenic agents. The cough threshold could be defined as minimal ST (STmin) capable to elicit 1 cough and cough reactivity obtained by interpolation as ST that provokes 50 % of cough responses (STso) (Tab. 1, Fig. 3, Ref. 27).