Dataset Information

TRPA1 agonists evoke coughing in guinea pig and human volunteers.

ABSTRACT:

Rationale

Cough is the most frequent reason for consultation with a family doctor, or with a general or respiratory physician. Treatment options are limited and one meta-analysis concluded that over-the-counter remedies are ineffective. There is also increasing concern about their use in children. Environmental irritants such as air pollution and cigarette smoke are thought to evoke cough by stimulating airway sensory nerves; however, how this occurs is not fully understood.

Objectives

We hypothesized that the TRPA1 (transient receptor potential cation channel, subfamily A, member 1) receptor may have a role as a novel target for tussive agents given that many potential irritants have been shown to activate this channel.

Methods

We investigated the effect of TRPA1 ligands on vagal sensory nerve activity in vitro and in guinea pig and human tussive challenge models.

Measurements and main results

We demonstrated that TRPA1 agonists such as acrolein activate cloned human TRPA1 channels in HEK293 cells and also vagal sensory nerves in murine, guinea pig, and human tissues. A role for TRPA1 was confirmed, using specific inhibitors and tissue from Trpa1(-/-) gene-deleted animals. Finally, TRPA1 ligands evoked reproducible tussive responses in both a guinea pig model and normal volunteers.

Conclusions

This study identifies the TRPA1 receptor as a promiscuous receptor, activated by a wide range of stimuli, making it a perfect target for triggering cough and as such one of the most promising targets currently identified for the development of antitussive drugs.

SUBMITTER: Birrell MA

PROVIDER: S-EPMC2784411 | biostudies-literature | 2009 Dec

REPOSITORIES: biostudies-literature

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Publications

TRPA1 agonists evoke coughing in guinea pig and human volunteers.

Birrell Mark A MA Belvisi Maria G MG Grace Megan M Sadofsky Laura L Faruqi Shoaib S Hele David J DJ Maher Sarah A SA Freund-Michel Véronique V Morice Alyn H AH

American journal of respiratory and critical care medicine 20090903 11

<h4>Rationale</h4>Cough is the most frequent reason for consultation with a family doctor, or with a general or respiratory physician. Treatment options are limited and one meta-analysis concluded that over-the-counter remedies are ineffective. There is also increasing concern about their use in children. Environmental irritants such as air pollution and cigarette smoke are thought to evoke cough by stimulating airway sensory nerves; however, how this occurs is not fully understood.<h4>Objective ...[more]

PMID: 19729665

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Project description:Cough airflow dynamics have been previously studied using a variety of experimental methods. In this study, real-time, non-invasive shadowgraph imaging was applied to obtain additional analyses of cough airflows produced by healthy volunteers. Twenty healthy volunteers (10 women, mean age 32.2±12.9 years; 10 men, mean age 25.3±2.5 years) were asked to cough freely, then into their sleeves (as per current US CDC recommendations) in this study to analyze cough airflow dynamics. For the 10 females (cases 1-10), their maximum detectable cough propagation distances ranged from 0.16-0.55 m, with maximum derived velocities of 2.2-5.0 m/s, and their maximum detectable 2-D projected areas ranged from 0.010-0.11 m(2), with maximum derived expansion rates of 0.15-0.55 m(2)/s. For the 10 males (cases 11-20), their maximum detectable cough propagation distances ranged from 0.31-0.64 m, with maximum derived velocities of 3.2-14 m/s, and their maximum detectable 2-D projected areas ranged from 0.04-0.14 m(2), with maximum derived expansion rates of 0.25-1.4 m(2)/s. These peak velocities were measured when the visibility of the exhaled airflows was optimal and compare favorably with those reported previously using other methods, and may be seen as a validation of these previous approaches in a more natural setting. However, the propagation distances can only represent a lower limit due to the inability of the shadowgraph method to visualize these cough airflows once their temperature cools to that of the ambient air, which is an important limitation of this methodology. The qualitative high-speed video footage of these volunteers coughing into their sleeves demonstrates that although this method rarely completely blocks the cough airflow, it decelerates, splits and redirects the airflow, eventually reducing its propagation. The effectiveness of this intervention depends on optimum positioning of the arm over the nose and mouth during coughing, though unsightly stains on sleeves may make it unacceptable to some.

Project description:BackgroundToxoplasma gondii is an obligate intracellular parasite with a worldwide distribution. Congenital infection in humans and animals may lead to severe symptoms in the offspring, especially in the brain. A suitable animal model for human congenital toxoplasmosis is currently lacking. The aim of this study is to establish and validate the guinea pig as a model for human congenital toxoplasmosis by investigating the impact of the T. gondii infection dose, the duration of infection and the gestational stage at infection on the seroconversion, survival rate of dams, fate of the offspring, T. gondii DNA loads in various offspring tissues and organs and the integrity of the offspring brain.MethodsPregnant guinea pigs were infected with three different doses (10, 100, 500 oocysts) of T. gondii strain ME49 at three different time points during gestation (15, 30, 48 days post-conception). Serum of dams was tested for the presence of T. gondii antibodies using immunoblotting. T. gondii DNA levels in the dam and offspring were determined by qPCR. Offspring brains were examined histologically.ResultsWe found the survival rate of dams and fate of the offspring to be highly dependent on the T. gondii infection dose with an inoculation of 500 oocysts ending lethally for all respective offspring. Moreover, both parameters differ depending on the gestational stage at infection with infection in the first and third trimester of gestation resulting in a high offspring mortality rate. The duration of infection was found to substantially impact the seroconversion rate of dams with the probability of seroconversion exceeding 50% after day 20 post-infection. Furthermore, the infection duration of dams influenced the T. gondii DNA loads in the offspring and the integrity of offspring brain. Highest DNA levels were found in the offspring brain of dams infected for ≥ 34 days.ConclusionThis study contributes to establishing the guinea pig as a suitable model for human congenital toxoplasmosis and thus lays the foundation for using the guinea pig as a suitable animal model to study scientific questions of high topicality and clinical significance, which address the pathogenesis, diagnosis, therapy and prognosis of congenital toxoplasmosis.

Dataset Information

TRPA1 agonists evoke coughing in guinea pig and human volunteers.

Rationale

Objectives

Methods

Measurements and main results

Conclusions

Publications

TRPA1 agonists evoke coughing in guinea pig and human volunteers.

Similar Datasets

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