Nerve growth factor enhances cough and airway obstruction via TrkA receptor- and TRPV1-dependent mechanisms.
BACKGROUND
Nerve growth factor (NGF) is an important mediator of airway hyper-responsiveness and hyperalgesia but its role in cough is unknown.


OBJECTIVE
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 NGF-enhanced 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.
El-Hashim
A Z
AZ
Department of Applied Therapeutics, Faculty of Pharmacy, Kuwait University, Safat 13110, Kuwait. ahmed.elhashim@hsc.edu.kw
Jaffal
S M
SM
D000402:Airway Obstruction / Q000139:chemically induced / Q000378:metabolism*; D000818:Animals; D002227:Carbazoles / Q000494:pharmacology; D019343:Citric Acid; D003371:Cough / Q000139:chemically induced / Q000378:metabolism*; D004224:Diterpenes / Q000493:pharmacokinetics; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006168:Guinea Pigs; D007093:Imidazoles / Q000494:pharmacology; D026121:Indole Alkaloids / Q000494:pharmacology; D008297:Male; D009414:Nerve Growth Factors / Q000494:pharmacology*; D010766:Phosphorylation; D011725:Pyridines / Q000494:pharmacology; D020917:Receptor, trkA / Q000037:antagonists & inhibitors / Q000187:drug effects* / Q000378:metabolism; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors / Q000187:drug effects* / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
D002227:Carbazoles; D004224:Diterpenes; D004791:Enzyme Inhibitors; D007093:Imidazoles; D026121:Indole Alkaloids; D009414:Nerve Growth Factors; D011725:Pyridines; D050916:TRPV Cation Channels; C494484:TRPV1 receptor; C468130:iodoresiniferatoxin; D019343:Citric Acid; C049985:staurosporine aglycone; D020917:Receptor, trkA; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580