A role for sensory nerves in the late asthmatic response

Abstract

Background 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. Method A study was undertaken using ovalbuminsensitised 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. Results 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). Conclusion 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.

Transient Receptor Potential Channels as Drug Targets: From the Science of Basic Research to the Art of Medicine

“…Of note, knocking out TRPV1 did not alter any of these parameters, providing evidence that TRPA1 has a distinct role in this model of allergic disease. The TRPA1 blocker HC-030031 (but not the TRPV1 antagonist JNJ17203212) was also shown to attenuate the late asthmatic response in rodent models of allergic asthma (Raemdonck et al, 2012). TRPA1 has also been implicated in airway neurogenic inflammation caused by the acetaminophen metabolite N-acetyl-p-benzo-quinoneimine in multiple small animal species (Nassini et al, 2010b).…”

The emerging role of transient receptor potential channels in chronic lung disease

“…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. Recent studies suggest that TRPA1 channels activate vagal bronchopulmonary C-fibres in rodent lung, inducing a LAR in sensitised rodents following allergen challenge [67]. The mechanism of action is not completely elucidated, but it is likely that allergens stimulate the channel indirectly via the release of endogenously produced TRPA1 activators ( possibly mast cell products such as tryptase released as a consequence of the EAR), which leads to sensory nerve activation via the TRPA1 channel and central reflex events, ultimately leading to a parasympathetic, cholinergic reflex bronchoconstrictor response (inhibited by LAMAs such as tiotropium and glycopyrrolate) which may be responsible for the LAR seen in this model [67] (figure 1).…”

The G Protein–Coupled Receptor–Transient Receptor Potential Channel Axis: Molecular Insights for Targeting Disorders of Sensation and Inflammation

“…Together, an initial TRPA1 response to respiratory irritants, followed by secondary responses to inflammatory mediators, implicates TRPA1 in sensory processing and augmented dysregulation in airway diseases due to enduring inflammation and lung remodeling (Springer et al, 2007;Li et al, 2008). TRPA1 is also likely to mediate allergen-induced airway inflammation in patients with asthma, as demonstrated using trpa1 2/2 mice or by treatment with the selective TRPA1 inhibitor 2,3,acetamide], which reduces allergen-induced leukocyte infiltration, cytokine and mucus production, and airway hyper-responsiveness Raemdonck et al, 2012). Animal models also show that TRPA1 plays an important role in the early phase of bronchial inflammation to cigarette smoke, causing release of interleukin-8, which is a chemoattractant for neutrophils, T cells, and monocytes (Mukhopadhyay et al, 2011).…”