The Effects of Inhaled KP-496, a Novel Dual Antagonist for Cysteinyl Leukotriene Receptor and Thromboxane A&lt;sub&gt;2&lt;/sub&gt; Receptor, on Allergic Asthmatic Responses in Guinea Pigs

Suda, Masashi; Okuda, Toshiaki; Ishimura, Masakazu; Kurokawa, Shigeo; Tokuoka, Shota; Nakamura, Tsutomu; Takahashi, Yoshimasa; Tanaka, Hiroyuki; Nagai, Hiroichi

doi:10.1159/000241724

Cited by 5 publications

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“…Also, the EAR bronchoconstriction is pronounced and mediated by histamine, cysteinyl leukotrienes and prostaglandins in both species, contrasting with mice where the EAR bronchoconstriction is minimal and mediated by 5-HT ( Fernandez-Rodriguez, Ford, Broadley, & Kidd, 2008; Moffatt, Cocks, & Page, 2004; Ressmeyer et al, 2006; Zosky et al, 2008 ). Several groups have demonstrated isolated characteristics of asthma such as AHR, EAR and LAR in guinea-pigs ( Riley et al, 2013; Suda et al, 2009 ). However, most studies do not assess all of these characteristics in the same model together with inflammatory cell recruitment, which has potential limitations for using them to assess drug efficacy of novel treatments ( Stevenson & Birrell, 2011 ).…”

Section: Introductionmentioning

confidence: 99%

Adjustment of sensitisation and challenge protocols restores functional and inflammatory responses to ovalbumin in guinea-pigs

Lowe

Broadley

Nials

et al. 2015

Journal of Pharmacological and Toxicological Methods

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IntroductionInhalation of antigen in atopic asthma induces early (EAR) and late asthmatic responses (LARs), inflammatory cell infiltration and airways hyperresponsiveness (AHR). Previously, we have established a protocol of sensitisation and subsequent ovalbumin (Ova) inhalation challenge in guinea-pigs which induced these 4 features (Smith & Broadley, 2007). However, the responses of guinea-pigs to Ova challenge have recently declined, producing no LAR or AHR and diminished EAR and cells. By making cumulative modifications to the protocol, we sought to restore these features.MethodsGuinea-pigs were sensitised with Ova (i.p. 100 or 150 μg) on days 1 and 5 or days 1, 4 and 7 and challenged with nebulised Ova (100 or 300 μg/ml, 1 h) on day 15. Airway function was measured in conscious guinea-pigs by whole-body plethysmography to record specific airway conductance (sGaw). Airway responsiveness to aerosolized histamine (0.3 mM) was determined before and 24 h after Ova challenge. Bronchoalveolar lavage was performed for total and differential inflammatory cell counts. Lung sections were stained for counting of eosinophils.ResultsLack of AHR and LAR with the original protocol was confirmed. Increasing the Ova challenge concentration from 100 to 300 μg/ml restored AHR and eosinophils and increased the peak of the EAR. Increasing the number of sensitisation injections from 2 to 3 did not alter the responses. Increasing the Ova sensitisation concentration from 100 to 150 μg significantly increased total cells, particularly eosinophils. A LAR was revealed and lymphocytes and eosinophils increased when either the Al(OH)3 concentration was increased or the duration between the final sensitisation injection and Ova challenge was extended from 15 to 21 days.DiscussionThis study has shown that declining allergic responses to Ova in guinea-pigs could be restored by increasing the sensitisation and challenge conditions. It has also demonstrated an important dissociation between EAR, LAR, AHR and inflammation.

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Section: Introductionmentioning

confidence: 99%