Airway responsiveness in an allergic rabbit model

Keir, Sandra; Spina, Domenico; Douglas, Garry J.; Herd, Caroline M.; Page, C. P.

doi:10.1016/j.vascn.2011.08.003

Cited by 10 publications

(8 citation statements)

References 33 publications

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“…Moreover, our findings regarding the Gβγ-regulated mechanism underlying the effects of IL-13 on ASM responsiveness are consistent with those in previous reports demonstrating that IL-13 evokes downstream ERK1/2-dependent changes in HASM contractility [58] and intracellular calcium mobilization [59] , as well as pulmonary inflammation [60] . Regarding the latter, it should be noted that our in vivo observations in rabbits,concur with those in previous reports that also demonstrated a predominant neutrophilic pulmonary inflammatory response initially (i.e., up to 24 hours) following antigen challenge in sensitized mice [61] – [63] and rabbits [64] , as well as the reported predominant neutrophilic inflammatory response detected in BAL samples obtained hours following airway antigen challenge in allergic asthmatic individuals [65] . In this regard, however, it is important to note that, given the frequent observance of eosinophilic infiltration at 24 hours after allergen challenge in other studies in OVA-sensitized mice, consideration must be given to other factors that may also contribute to our observed neutrophilic response, including LPS contamination of the administered OVA preparation.…”

Section: Discussionsupporting

confidence: 92%

G Protein βγ-Subunit Signaling Mediates Airway Hyperresponsiveness and Inflammation in Allergic Asthma

Niño

Grunstein

et al. 2012

PLoS ONE

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Since the Gβγ subunit of Gi protein has been importantly implicated in regulating immune and inflammatory responses, this study investigated the potential role and mechanism of action of Gβγ signaling in regulating the induction of airway hyperresponsiveness (AHR) in a rabbit model of allergic asthma. Relative to non-sensitized animals, OVA-sensitized rabbits challenged with inhaled OVA exhibited AHR, lung inflammation, elevated BAL levels of IL-13, and increased airway phosphodiesterase-4 (PDE4) activity. These proasthmatic responses were suppressed by pretreatment with an inhaled membrane-permeable anti-Gβγ blocking peptide, similar to the suppressive effect of glucocorticoid pretreatment. Extended mechanistic studies demonstrated that: 1) corresponding proasthmatic changes in contractility exhibited in isolated airway smooth muscle (ASM) sensitized with serum from OVA-sensitized+challenged rabbits or IL-13 were also Gβγ-dependent and mediated by MAPK-upregulated PDE4 activity; and 2) the latter was attributed to Gβγ-induced direct stimulation of the non-receptor tyrosine kinase, c-Src, resulting in downstream activation of ERK1/2 and its consequent transcriptional upregulation of PDE4. Collectively, these data are the first to identify that a mechanism involving Gβγ-induced direct activation of c-Src, leading to ERK1/2-mediated upregulation of PDE4 activity, plays a decisive role in regulating the induction of AHR and inflammation in a rabbit model of allergic airway disease.

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Section: Discussionsupporting

confidence: 92%

G Protein βγ-Subunit Signaling Mediates Airway Hyperresponsiveness and Inflammation in Allergic Asthma

Niño

Grunstein

et al. 2012

PLoS ONE

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“…Rabbits were anesthetized with a mixture of ketamine (34 mg/kg; Vetalar, 100 mg/ml; Animal Health, Pfizer Ltd, Sandwich, UK), and xylazine (20 mg/kg; Rompun, 23.32 mg/ml, 2%, Animal Health Division, Bayer plc, Newbury UK) administered intramuscularly and, if required, maintenance anesthesia (50% then 25% at 20-minute intervals) until adequate anesthesia was obtained. This anesthetic regimen was chosen so that total lung resistance (R L ) and dynamic lung compliance (Cdyn) could be monitored noninvasively and repeatedly in rabbits without the need for artificial ventilation ( Keir et al, 2011 ).…”

Section: Methodsmentioning

confidence: 99%

Ozone-Induced Hypertussive Responses in Rabbits and Guinea Pigs

Clay¹,

Patacchini²,

Trevisani³

et al. 2016

Journal of Pharmacology and Experimental Therapeutics

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Cough remains a major unmet clinical need, and preclinical animal models are not predictive for new antitussive agents. We have investigated the mechanisms and pharmacological sensitivity of ozone-induced hypertussive responses in rabbits and guinea pigs. Ozone induced a significant increase in cough frequency and a decrease in time to first cough to inhaled citric acid in both conscious guinea pigs and rabbits. This response was inhibited by the established antitussive drugs codeine and levodropropizine. In contrast to the guinea pig, hypertussive responses in the rabbit were not inhibited by bronchodilator drugs (β2 agonists or muscarinic receptor antagonists), suggesting that the observed hypertussive state was not secondary to bronchoconstriction in this species. The ozone-induced hypertussive response in the rabbit was inhibited by chronic pretreatment with capsaicin, suggestive of a sensitization of airway sensory nerve fibers. However, we could find no evidence for a role of TRPA1 in this response, suggesting that ozone was not sensitizing airway sensory nerves via activation of this receptor. Whereas the ozone-induced hypertussive response was accompanied by a significant influx of neutrophils into the airway, the hypertussive response was not inhibited by the anti-inflammatory phosphodiesterase 4 inhibitor roflumilast at a dose that clearly exhibited anti-inflammatory activity. In summary, our results suggest that ozone-induced hypertussive responses to citric acid may provide a useful model for the investigation of novel drugs for the treatment of cough, but some important differences were noted between the two species with respect to sensitivity to bronchodilator drugs.

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“…Page showed how his group used rabbits and guinea-pigs, rather than just relying on mice, over several decades to investigate the mechanisms of bronchial hyperresponsiveness. 52-54 He first pointed the value of the rabbit in this context as it is of a size that allows minimally invasive lung function recordings to be made in the same animals over time. 52,53 More recently, Pr.…”

Section: Session 7: Relevance Of Animal Modelsmentioning

confidence: 99%

“… 52-54 He first pointed the value of the rabbit in this context as it is of a size that allows minimally invasive lung function recordings to be made in the same animals over time. 52,53 More recently, Pr. Page's group used the guinea pig to aid in the development of a novel class of inhaled bifunctional drug for the treatment of asthma and COPD, the dual phosphodiesterase (PDE) 3/4 inhibitor RPL554, 55 where animal studies predicted the clinical efficacy of this drug in man.…”

Section: Session 7: Relevance Of Animal Modelsmentioning

confidence: 99%

Therapeutic monoclonal antibodies for respiratory diseases: Current challenges and perspectives, March 31 – April 1, 2016, Tours, France

Désoubeaux

Reichert²,

Sleeman³

et al. 2016

mAbs

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Monoclonal antibody (mAb) therapeutics have tremendous potential to benefit patients with lung diseases, for which there remains substantial unmet medical need. To capture the current state of mAb research and development in the area of respiratory diseases, the Research Center of Respiratory Diseases (CEPR-INSERM U1100), the Laboratory of Excellence “MAbImprove,” the GDR 3260 “Antibodies and therapeutic targeting,” and the Grant Research program ARD2020 “Biotherapeutics” invited speakers from industry, academic and government organizations to present their recent research results at the Therapeutic Monoclonal Antibodies for Respiratory Diseases: Current challenges and perspectives congress held March 31 – April 1, 2016 in Tours, France.

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Airway responsiveness in an allergic rabbit model

Cited by 10 publications

References 33 publications

G Protein βγ-Subunit Signaling Mediates Airway Hyperresponsiveness and Inflammation in Allergic Asthma

G Protein βγ-Subunit Signaling Mediates Airway Hyperresponsiveness and Inflammation in Allergic Asthma

Ozone-Induced Hypertussive Responses in Rabbits and Guinea Pigs

Therapeutic monoclonal antibodies for respiratory diseases: Current challenges and perspectives, March 31 – April 1, 2016, Tours, France

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