Rationale: Cough is the most frequent reason for consultation with a family doctor, or with a general or respiratory physician. Treatment options are limited and one meta-analysis concluded that over-the-counter remedies are ineffective. There is also increasing concern about their use in children. Environmental irritants such as air pollution and cigarette smoke are thought to evoke cough by stimulating airway sensory nerves; however, how this occurs is not fully understood. Objectives: We hypothesized that the TRPA1 (transient receptor potential cation channel, subfamily A, member 1) receptor may have a role as a novel target for tussive agents given that many potential irritants have been shown to activate this channel. Methods: We investigated the effect of TRPA1 ligands on vagal sensory nerve activity in vitro and in guinea pig and human tussive challenge models. Measurements and Main Results: We demonstrated that TRPA1 agonists such as acrolein activate cloned human TRPA1 channels in HEK293 cells and also vagal sensory nerves in murine, guinea pig, and human tissues. A role for TRPA1 was confirmed, using specific inhibitors and tissue from Trpa1^−/− gene–deleted animals. Finally, TRPA1 ligands evoked reproducible tussive responses in both a guinea pig model and normal volunteers. Conclusions: This study identifies the TRPA1 receptor as a promiscuous receptor, activated by a wide range of stimuli, making it a perfect target for triggering cough and as such one of the most promising targets currently identified for the development of antitussive drugs.

Recent studies have suggested that nerve growth factor (NGF) may play a role in inflammation and bronchial hyperresponsiveness in asthma. Neither the types of cells that produce NGF in the human airways nor the effect of inflammation on NGF expression are clear. The two-fold aim of the present study was to determine whether airway smooth muscle produces NGFin vitro, and, if so, whether the pro-inflammatory cytokine interleukin-1β (IL-1β) affects this expression.Human airway smooth muscle cells in culture were incubated in the presence or absence of IL-1β. NGF production was measured by enzyme-linked immunosorbent assay. NGF messenger ribonucleic acid (mRNA) was measured using a specific real-time fluorescent polymerase chain reaction technique, and expressed in relation to glyceraldehyde‐3‐phosphate dehydrogenase (GAPDH) mRNA levels.Human airway smooth muscle cellsin vitroexpressed NGF constitutively (21.4±7.8 pg·mL⁻¹; 14.6±5.4 pg NGF complementary deoxyribonucleic acid (cDNA)·pg GAPDH cDNA⁻¹(mean±sem)). Stimulation with IL–1β (0.1–30 U·mL⁻¹) for 24 h induced a dose-dependent increase in NGF production (22.1 pg·mL⁻¹at 10 U·mL⁻¹; p<0.05). The IL-1β (10 U·mL⁻¹)-induced increase in NGF expression was time-dependent. It was highest for NGF protein at 10 h (1.6-fold increase over control; p<0.001) and for NGF mRNA at 2.5 h (2.4-fold increase over control; p<0.05).In conclusion, the present study clearly shows that the human airway smooth muscle cell is a source of nerve growth factor, the expression of which is upregulated in inflammatory conditions, mimickedin vitroby the addition of interleukin-1β.

Pulmonary hypertension (PH) is characterized by a progressive elevation of pulmonary arterial pressure due to alterations of both pulmonary vascular structure and function. This disease is rare but life-threatening, leading to the development of right heart failure. Current PH treatments, designed to target altered pulmonary vascular reactivity, include vasodilating prostanoids, phosphodiesterase-5 inhibitors and endothelin-1 receptor antagonists. Although managing to slow the progression of the disease, these molecules still do not cure PH. More effective treatments need to be developed, and novel therapeutic strategies, targeting in particular vascular remodelling, are currently under investigation. Reactive oxygen species (ROS) are important physiological messengers in vascular cells. In addition to atherosclerosis and other systemic vascular diseases, emerging evidence also support a role of ROS in PH pathogenesis. ROS production is increased in animal models of PH, associated with NADPH oxidases increased expression, in particular of several Nox enzymes thought to be the major source of ROS in the pulmonary vasculature. These increases have also been observed in vitro and in vivo in humans. Moreover, several studies have shown either the deleterious effect of agents promoting ROS generation on pulmonary vasculature or, conversely, the beneficial effect of antioxidant agents in animal models of PH. In these studies, ROS production has been directly linked to pulmonary vascular remodelling, endothelial dysfunction, altered vasoconstrictive responses, inflammation and modifications of the extracellular matrix, all important features of PH pathophysiology. Altogether, these findings indicate that ROS are interesting therapeutic targets in PH. Blockade of ROS-dependent signalling pathways, or disruption of sources of ROS in the pulmonary vasculature, targeting in particular Nox enzymes, represent promising new therapeutic strategies in this disease.