Nerve growth factor enhances cough and airway obstruction via TrkA receptor- and TRPV1-dependent mechanisms

Abstract

Background: Nerve growth factor (NGF) is an important mediator of airway hyper-responsiveness and hyperalgesia but its role in cough is unknown. Objectives: In this study the effects of NGF on the cough reflex and airway calibre were investigated in guinea pigs. The involvement of the tropomyosin-related kinase A (TrkA) receptor and transient receptor potential vanilloid-1 (TRPV1), and the p38 mitogen-activated protein kinase (MAPK)-dependent pathway in any NGF-induced effects on cough and airway obstruction was also assessed. Methods: Guinea pigs were placed in a transparent whole-body plethysmograph box. Cough was assessed visually, acoustically and by analysis of the airflow signal. Airway obstruction was measured using enhanced pause (Penh) as an index. Results: Exposure of guinea pigs to NGF did not induce a cough response nor a significant airway obstruction. However, exposure of guinea pigs to NGF immediately before citric acid inhalation resulted in a significant increase in the citric acid-induced cough and airway obstruction compared with vehicle-treated animals. Pretreatment with the TrkA receptor antagonist, K252a, or the TRPV1 antagonist, iodoresiniferatoxin, significantly inhibited the NGF-enhanced cough and airway obstruction. Exposure to NGF also increased p38 MAPK phosphorylation, but pretreatment with the p38 MAPK inhibitor, SB203580, did not affect either the NGFenhanced cough or airway obstruction despite preventing the NGF-induced elevation in p38 MAPK phosphorylation. Conclusions: The data show that NGF can enhance both cough and airway obstruction via a mechanism that involves the activation of the TrkA receptor and TRPV1 but not the p38 MAPK-dependent pathway.Cough has a high prevalence rate and is one of the most common symptoms for which sufferers seek medical help from primary care physicians and pulmonologists.

Acid-sensing by airway afferent nerves

“…Recent studies have shown that TRPV1 expression is up-regulated in the sensory nerves innervating the lung and airways during chronic allergic airway inflammation [60] and the laryngeal mucosa in patients with laryngopharyngeal reflux [61]. Furthermore, the responses of isolated pulmonary sensory neurons to acid are enhanced by certain inflammatory mediators [62], such as tryptase [56,63], human eosinophil-derived cationic proteins [64], tumor nacrosis factor α [65], and nerve growth factor [66]. These positive interactions may have important clinical implications because tissue acidification and endogenous release of these chemical mediators often occur concurrently during airway inflammatory reaction [62].…”

Anti-tussive and bronchodilator mechanisms of action for the enaminone E121

“…A measure of airway function, enhanced pause (Penh) and cough were measured simultaneously in response to inhaled citric acid, in conscious unrestrained guinea pigs, using whole body plethysmography (Buxco, Troy, NY, USA), a well characterized and validated method (Chong et al, 1998;El-Hashim et al, 2002;El-Hashim and Jaffal., 2009). In brief, Penh is a dimensionless value that reflects changes in the waveform of the box pressure signal from both inspiration and expiration and combines it with the timing comparison of early and late expiration (Pause).…”

“…Our understanding of the pharmacological mechanisms underlying cough has been increasing substantially as evidenced by the identification of several receptors and channels that have been reported to be involved in modulating the cough response such as sigma-1, NOP-1, cannabinoid-2 (CB2), neurokinin-1 (NK1), neurokinin-2 (NK2), TRPA1 channels and TrkA receptors (Belvisi et al, 2008;Birrell et al, 2009;El-Hashim et al, 2004b;El-Hashim and Jaffal, 2009;Brown et al, 2004). Additionally, there is strong evidence from preclinical studies showing that K ATP channels can modulate the cough response.…”

Small Interfering RNA Targeting Nerve Growth Factor Alleviates Allergic Airway Hyperresponsiveness

“…3,4 NGF contributed to the sensitivity of nerves 5,6 and enhanced expressions of neuropeptides (such as substance P (SP)) which were stored in the terminals of sensory afferent nerves and induced neurogenic inflammatory responses after allergen exposure. 7,8 In contrast, overwhelming evidences suggested that NGF is increased in inflamed airway 9,10 and involved in airway inflammation 11 and remodeling.…”