hc-030031 and Asthma

Topics: Analgesics; Animals; Anti-Inflammatory Agents; Asthma; Humans; Ion Channel Gating; Neurons; Pain; Peripheral Nervous System Diseases; Pulmonary Disease, Chronic Obstructive; Transient Receptor Potential Channels

Studies from epidemiology suggest that ambient temperature is one of the underlying triggers and potential causes of asthma. The aim of this study was to examine the impact and the molecular mechanism of temperature-invoked airway inflammation using an experimental model of asthma in BALB/c mice.. Mice were exposed to different temperature conditions (steady 26°C, 26°C/18°C cycle, 26°C/10°C cycle) and received sensitization and challenge of ovalbumin (OVA) during a 21-day period. HC030031, a selective transient receptor potential A1 (TRPA1) channel blocker, was used to investigate the underlying mechanism of TRPA1 in 'asthmatic' airways. After the final OVA challenge, in vivo lung function was measured, and bronchoalveolar lavage fluid (BALF) and pulmonary inflammation were assessed.. The temperature variations, especially the largest temperature difference (16°C), exacerbated airway inflammation in OVA-induced mice, increasing the levels of serum total-IgE (immunoglobulin E) and IgG1, inflammatory cells and cytokines in BALF. Analysis of histopathological changes and lung function verified that repeated exposure to very cold and changed temperatures aggravated airway hyperresponsiveness (AHR). Significant upregulation of TRPA1 expression was revealed by immunohistochemistry in the presence of the largest temperature variation (26°C/10°C cycle), while administration of HC030031 successfully inhibited TRPA1 expression, thus attenuating the asthma-like pathological features.. Repeated exposure to temperature variation exacerbated experimental 'asthma' and TRPA1 mediated this temperature-dependent inflammatory effect.

Topics: Acetanilides; Animals; Asthma; Bronchoalveolar Lavage Fluid; Cytokines; Disease Models, Animal; Immunoglobulin E; Immunoglobulin G; Inflammation; Male; Mice; Mice, Inbred BALB C; Ovalbumin; Purines; Temperature; TRPA1 Cation Channel

Disruption of epithelial cell-cell junctions is essential for the initiation and perpetuation of airway inflammation in asthma. We've previously reported compromised epithelial barrier integrity in a toluene diisocyanate (TDI)-induced occupational asthma model. This study is aimed to explore the role of transient receptor potential vanilloid 4 (TRPV4) and transient receptor potential ankyrin 1 (TRPA1) in the dysfunction of adherens junctions in TDI-induced asthma. Mice were sensitized and challenged with TDI for a chemical-induced asthma model. Selective blockers of TRPV4 glycogen synthase kinase (GSK)2193874, 5 and 10 mg/kg) and TRPA1 (HC030031, 10 and 20 mg/kg) were intraperitoneally given to the mice. Immunohistochemistry revealed different expression pattern of TRPV4 and TRPA1 in lung. TDI exposure increased TRPV4 expression in the airway, which can be suppressed by GSK2193874, while treatment with neither TDI alone nor TDI together with HC030031 led to changes of TRPA1 expression in the lung. Blocking either TRPV4 or TRPA1 blunted TDI-induced airway hyperreactivity, airway neutrophilia and eosinophilia, as well as Th2 responses in a dose-dependent manner. At the same time, membrane levels of E-cadherin and β-catenin were significantly decreased after TDI inhalation, which were inhibited by GSK2193874 or HC030031. Moreover, GSK2193874 and HC030031 also suppressed serine phosphorylation of glycogen synthase kinase 3β, tyrosine phosphorylation of β-catenin, as well as activation and nuclear transport of β-catenin in mice sensitized and challenged with TDI. Our study suggested that both TRPV4 and TRPA1 contribute critically to E-cadherin and β-catenin dysfunction in TDI-induced asthma, proposing novel therapeutic targets for asthma.

Topics: Acetanilides; Adherens Junctions; Animals; Asthma; beta Catenin; Bronchoalveolar Lavage Fluid; Cadherins; Cytokines; Epithelial Cells; Inflammation; Lung; Mice; Mice, Inbred C57BL; Phosphorylation; Piperidines; Purines; Quinolines; Toluene 2,4-Diisocyanate; Transient Receptor Potential Channels; TRPA1 Cation Channel; TRPV Cation Channels

Asthma is a complex pulmonary inflammatory disease characterized by the hyper-responsiveness, remodeling and inflammation of airways. Formaldehyde is a common indoor air pollutant that can cause asthma in people experiencing long-term exposure. The irritant effect and adjuvant effect are the two possible pathways of formaldehyde promoted asthma.. To explore the neural mechanisms and adjuvant effect of formaldehyde, 48 Balb/c mice in six experimental groups were exposed to (a) vehicle control; (b) ovalbumin; (c) formaldehyde (3.0 mg/m(3)); (d) ovalbumin+formaldehyde (3.0 mg/m(3)); (e) ovalbumin+formaldehyde (3.0 mg/m(3))+HC-030031 (transient receptor potential ankyrin 1 antagonist); (f) ovalbumin+formaldehyde (3.0 mg/m(3))+ capsazepine (transient receptor potential vanilloid 1 antagonist). Experiments were conducted after 4 weeks of combined exposure and 1-week challenge with aerosolized ovalbumin. Airway hyper-responsiveness, pulmonary tissue damage, eosinophil infiltration, and increased levels of interleukin-4, interleukin-6, interleukin-1β, immunoglobulin E, substance P and calcitonin gene-related peptide in lung tissues were found in the ovalbumin+formaldehyde (3.0 mg/m(3)) group compared with the values seen in ovalbumin -only immunized mice. Except for interleukin-1β levels, other changes in the levels of biomarker could be inhibited by HC-030031 and capsazepine.. Formaldehyde might be a key risk factor for the rise in asthma cases. Transient receptor potential ion channels and neuropeptides have important roles in formaldehyde promoted-asthma.

Topics: Acetanilides; Animals; Asthma; Calcitonin Gene-Related Peptide; Capsaicin; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Formaldehyde; Immunoglobulin E; Immunohistochemistry; Interleukin-1beta; Interleukin-4; Interleukin-6; Lung; Male; Mice; Mice, Inbred BALB C; Neuropeptides; Ovalbumin; Purines; Substance P; Transient Receptor Potential Channels

In allergic asthma, exposure to relevant antigens leads to an early asthmatic response (EAR) followed, in certain subjects, by a late asthmatic response (LAR). Although many subjects with asthma consider LAR to be one of the defining symptoms of their disease, and despite its widespread use in the clinical assessment of new therapeutic entities, the mechanism underlying the LAR remains unclear.. A study was undertaken using ovalbumin-sensitised and challenged Brown Norway rat and C57BL/6J mouse models which recapitulate phenotypic features of allergic asthma including the LAR and its susceptibility to clinically effective agents.. In conscious animals an EAR was followed by a LAR. The LAR was subjectively evidenced by audible (wheeze) and visual signs of respiratory distress associated with quantifiable changes in non-invasive lung function assessment. Treatments that attenuated the EAR failed to impact on the LAR and, while anaesthesia did not impact on EAR, it abolished LAR. A key role for airway sensory neuronal reflexes in the LAR was therefore hypothesised, which was confirmed by the blockade observed after administration of ruthenium red (non-selective cation channel blocker), HC-030031 (TRPA1 inhibitor) and tiotropium bromide (anticholinergic) but not JNJ-17203212 (TRPV1 inhibitor).. These results suggest that LAR involves the following processes: allergen challenge triggering airway sensory nerves via the activation of TRPA1 channels which initiates a central reflex event leading to a parasympathetic cholinergic constrictor response. These data are supported by recent clinical trials suggesting that an anticholinergic agent improved symptoms and lung function in patients with asthma.

Topics: Acetanilides; Animals; Asthma; Bronchi; Bronchoconstriction; Disease Models, Animal; Disease Progression; Male; Mice; Mice, Inbred C57BL; Ovalbumin; Parasympathetic Nervous System; Purines; Rats; Rats, Inbred BN; Ruthenium Red; Sensory Receptor Cells; Transient Receptor Potential Channels