PURPOSE: An enhanced reactivity of cough reflex manifested as increased cough sensitivity(ICS) to inhaled capsaicin has been suggested to be important mechanism inducing chronic cough. Reactive oxygen species(ROS), which can lead to nitrosative stress through interacting with nitric oxide(NO), was reported to stimulate capsaicin-sensitive nerves. We hypothesized that nitrosative stress may play a role in the pathogenesis of enhancing cough sensitivity of chronic cough by causing neurochemical abnormalities in the upper airway.
METHODS: 51 patients with prolonged nonproductive cough as a sole clinical manifestation and 27 control subjects were enrolled to this study. A capsaicin cough provocation test was performed to determine cough sensitivity. To assess a presence of nitrosative stress,immunostaining of 3-nitrotyrosine(3-NT) in nasal epithelial cells was quantified and nasal nitric oxide(nNO) was also measured. The relationship between cough sensitivity and nitrosative stress was analyzed. To investigate the function of nitrosative stress on airway epithelium, the levels of Substance P(SP)were firstly measured in nasal lavage fluid(NFL) and then expression levels of SP were evaluated after treatment of NO and nitric oxide synthase inhibitors in primary human nasal epithelial cells(HNECs) and BEAS-2B human bronchial epithelial cells(BECs).
RESULTS: The patients were divided into 2 groups according to the results of the capsaicin cough provocation test: an increased cough sensitivity group(ICS,C5< 32umol/L) and a normal cough sensitivity group(NCS). The levels of immunoreactivity for 3-NT in nasal brush cells and the values of nNO were significantly higher in subjects with ICS than those in NCS and control subjects. Patients with ICS showed elevated SP concentrations in NLFs compared with those of NCS and control subjects. The intracellular expression of SP was greatly enhanced in HNECs and BECs exposed to PAPA-NONOate, which was suppressed with the pre-treatment of L-NAME.
CONCLUSION: Increased nitrosative stress in the upper airway may play an important role in the pathogenesis of chronic dry cough with ICS via enhanced secretion of SP from airway epithelial cells.
CLINICAL IMPLICATIONS: Therapeutic strategy reducing nitrosative stress may be beneficial for management of chronic dry cough.
DISCLOSURE: Yun-Jeong Bae, No Financial Disclosure Information; No Product/Research Disclosure Information