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TRPV1 antagonists attenuate antigen-provoked cough in ovalbumin sensitized guinea pigs.

ABSTRACT: We examined the molecular pharmacology and in vivo effects of a TRPV1 receptor antagonist, N-(4-Tertiarybutylphenyl)-4(3-cholorphyridin-2-yl)-tetrahydro-pyrazine1(2H) - carboxamide (BCTC) on the guinea pig TRPV1 cation channel. BCTC antagonized capsaicin-induced activation and PMA-mediated activation of guinea pig TRPV1 with IC50 values of 12.2 +/- 5.2 nM, and 0.85 +/- 0.10 nM, respectively. In addition, BCTC (100 nM) completely blocked the ability of heterologously expressed gpTRPV1 to respond to decreases in pH. Thus, BCTC is able to block polymodal activation of gpTRPV1. Furthermore, in nodose ganglia cells, capsaicin induced Ca2+ influx through TRPV1 channel was inhibited via BCTC in a concentration dependent manner. In in vivo studies capsaicin (10 - 300 muM) delivered by aerosol to the pulmonary system of non-sensitized guinea pigs produced an increase in cough frequency. In these studies, the tussigenic effects of capsaicin (300 muM) were blocked in a dose dependent fashion when BCTC (0.01-3.0 mg/kg, i.p.) was administered 30 minutes before challenge. The high dose of BCTC (3.0 mg/kg, i.p) produced a maximum inhibition of capsaicin-induced cough of 65%. We also studied the effects of BCTC (0.03 and 3.0) when administered 60 minutes before capsaicin. Under these conditions, BCTC (3.0 mg/kg, i.p) produced a maximum decrease in capsaicin-induced cough of 31%. In ovalbumin passively sensitized guinea pigs, we found that BCTC (1 and 3 mg/kg, i.p.) attenuated antigen ovalbumin (0.3%) cough responses by 27% and 60%, respectively. We conclude that TRPV1 channel activation may play role in cough mediated by antigen in sensitized guinea pigs. Our results supports increasing evidence that TRPV1 may play a role in the generation of the cough response.

SUBMITTER: McLeod RL

PROVIDER: S-EPMC1764418 | biostudies-literature | 2006 Dec

REPOSITORIES: biostudies-literature

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TRPV1 antagonists attenuate antigen-provoked cough in ovalbumin sensitized guinea pigs.

McLeod Robbie L RL Fernandez Xiomara X Correll Craig C CC Phelps Tara P TP Jia Yanlin Y Wang Xin X Hey John A JA

Cough (London, England) 20061215

We examined the molecular pharmacology and in vivo effects of a TRPV1 receptor antagonist, N-(4-Tertiarybutylphenyl)-4(3-cholorphyridin-2-yl)-tetrahydro-pyrazine1(2H) - carboxamide (BCTC) on the guinea pig TRPV1 cation channel. BCTC antagonized capsaicin-induced activation and PMA-mediated activation of guinea pig TRPV1 with IC50 values of 12.2 +/- 5.2 nM, and 0.85 +/- 0.10 nM, respectively. In addition, BCTC (100 nM) completely blocked the ability of heterologously expressed gpTRPV1 to respond ...[more]

PMID: 17173683

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Project description:BackgroundAcupuncture has achieved good results in the treatment of cough, asthma, chronic obstructive pulmonary disease (COPD) and other lung diseases, but the mechanism associated with acupuncture in the treatment of chronic cough induced by lung surgery is unknown. We investigated whether acupuncture therapy could improve the symptoms of chronic cough after lung surgery through cyclic-AMp dependent protein kinase A (PKA)/cyclic-AMp dependent protein kinase C (PKC) regulation of the transient receptor potential vanilloid-1 (TRPV1) signaling pathway.MethodsThe guinea pigs were divided into 5 groups: the Sham operation Group (Sham), the Model Group (Model), the Electroacupuncture + Model Group (EA + M), the H89 + Model Group (H89 + M) and the Go6983 + Model Group (Go6983 + M). The effect of treatment was determined by measuring cough symptoms (number of coughs/cough incubation period) as the outcome criterion. The levels of inflammatory cytokines in bronchoalveolar lavage fluid (BALF) and blood were determined by enzyme-linked immunosorbent assays (ELISA). Lung tissue was stained with hematoxylin and eosin (H&E). The expression of p-PKA, p-PKC and p-TRPV1 proteins was measured by Western blotting. The mRNA levels of TRPV1, Substance P (SP), calcitonin gene-related peptide (CGRP) and neurokinin-1R (NK1R) were measured by real-time polymerase chain reaction (RT-PCR).ResultsAcupuncture significantly reduced the cough frequency and prolonged the cough latency of chronic cough in guinea pigs after lung surgery. In addition, acupuncture reduced the damage to lung tissue. The levels of inflammatory cytokines decreased in all treatment groups, the expression levels of p-PKA, p-PKC and p-TRPV1 were significantly inhibited and the mRNA levels of TRPV1, SP, CGRP and NK1R decreased significantly after acupuncture treatment.ConclusionsAcupuncture therapy ameliorated chronic cough in guinea pigs after lung surgery by regulating the TRPV1 signaling pathway via PKA/PKC. Our results showed that acupuncture may be an effective treatment of chronic cough after lung surgery, and also clarified the potential mechanism, which provides a theoretical basis for the clinical treatment of patients with chronic cough after lung surgery.

Project description:Allergy is a major public health concern, the main treatment for which is symptomatic relief with anti-inflammatory drugs. A key clinical challenge is to induce specific tolerance in order to control allergen-specific memory B and T cells, and specifically block effector cell responses. Our lab recently developed antigen-specific regulatory T-cell (Treg) therapies as a treatment for adverse responses. Recently, we created a chimeric antigen receptor (CAR) approach in which we engineered a target protein antigen, ovalbumin (OVA), linked with the transmembrane and signal transduction domains, CD28-CD3? to directly target B cells and sensitized mast cells in an allergy model. We named this receptor "BAR" for B-cell Antibody Receptor. Murine or human Tregs, transduced with a BAR containing OVA or control Tregs expressing an unrelated antigen, were successfully expanded in vitro and tested in the murine OVA-alum allergy model with measurable titers of anti-OVA IgE. Because BAR Tregs express the target antigen and could interact with specific IgE on sensitized mast cells, we first demonstrated that intravenously injected OVA-BAR Tregs did not directly lead to a drop in temperature or release of mediators in plasma indicative of anaphylaxis. Forty-eight hours later, mice were challenged intraperitoneally with 200??g OVA to induce an anaphylactic reaction, and temperature immediately measured for 30?min. We found that OVA-BAR Tregs protected mice from hypothermia, whereas mice given control BARs (expressing an unrelated antigen) or PBS showed substantial temperature drops indicative of anaphylaxis when systemically challenged with OVA. Importantly, this effect was also demonstrated in a passive anaphylaxis model in which mice that received anti-OVA IgE antibody were protected from hypothermia when treated with OVA-BAR Tregs prior to systemic OVA challenge. These results provide proof of principle that engineered allergen-specific T-regulatory cells can provide clinical protection against severe allergic reactions in individuals already IgE-sensitized to an allergen.

Project description:BackgroundThe differential sensitivity of cough to antitussive therapies implies the existence of heterogeneity in cough hypersensitivity, but how such heterogeneity is expressed across individual patients is poorly understood. We investigated the phenotypes of cough hypersensitivity by examining transient receptor potential ankyrin 1 (TRPA1)- and transient receptor potential vanilloid 1 (TRPV1)-mediated cough sensitivity in patients with chronic refractory cough.MethodsUsing a selective TRPA1 agonist, allyl isothiocyanate (AITC), we established an AITC cough challenge as a measure of TRPA1-mediated cough sensitivity. The AITC cough challenge and the widely used capsaicin (a selective TRPV1 agonist) cough challenge were performed with 250 patients with chronic refractory cough and 56 healthy subjects. The concentration of AITC or capsaicin solution causing at least two (C2) and five coughs (C5) was recorded. Cough sensitivity was expressed as the mean (95% confidence interval) of log C5, and cough hypersensitivity was defined as a log C5 value lower than that of healthy subjects.ResultsA distinct concentration-response effect of inhaled AITC was identified both in patients with chronic refractory cough and in healthy subjects. Cough sensitivity to AITC and capsaicin was significantly higher in patients than in healthy subjects (AITC: 2.42 [2.37-2.48] vs 2.72 [2.66-2.78] mM, p = 0.001; capsaicin: 1.87 [1.75-1.98] vs 2.53 [2.36-2.70] μM, p = 0.001) and was higher in females than in males for both healthy subjects and patients (all p < 0.05). Among the 234 patients who completed both challenges, 25 (10.7%) exhibited hypersensitivity to both AITC and capsaicin, 44 (18.8%) showed hypersensitivity to AITC only, 28 (11.9%) showed hypersensitivity to capsaicin only, and 137 (58.6%) exhibited hypersensitivity to neither. Those with TRPA1- and/or TRPV1-mediated hypersensitivity were predominantly female, while those without TRPA1- and TRPV1-mediated hypersensitivity were mainly male.ConclusionsFour phenotypes of cough hypersensitivity were identified by the activation of TRPV1 and TRPA1 channels, which supports the existence of heterogeneity in cough pathways and provides a new direction for personalized management of chronic refractory cough.Trial registrationClinicalTrials.gov NCT02591550 .

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TRPV1 antagonists attenuate antigen-provoked cough in ovalbumin sensitized guinea pigs.

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TRPV1 antagonists attenuate antigen-provoked cough in ovalbumin sensitized guinea pigs.

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