The role of nitrosative stress in the pathogenesis of unexplained chronic cough with cough hypersensitivity

Am J Rhinol Allergy. 2012 Jan-Feb;26(1):e10-4. doi: 10.2500/ajra.2012.26.3730.


Background: Unexplained chronic cough is a common condition without specific causes. A hyperreactivity of the cough reflex has been suggested as a mechanism for inducing chronic cough. We hypothesized that nitrosative stress in the upper airway might play a role in cough hypersensitivity by causing neurochemical abnormalities.

Methods: Fifty-one patients with unexplained chronic cough and 27 controls were enrolled. A capsaicin cough provocation test was performed to determine cough sensitivity. Nitrosative stress in the upper airway was assessed by quantifying 3-nitrotyrosine (3-NT) immunostaining in nasal epithelial cells (NECs) and measuring nasal nitric oxide (nNO). The effect of NO on airway epithelium was investigated by measuring the levels of substance P (SP) in nasal lavage fluid and evaluating SP expression in airway epithelial cells.

Results: Based on the results of the capsaicin test, patients were divided into two groups: a cough hypersensitivity (CHS) group and a normal cough sensitivity (NCS) group. The levels of 3-NT immunoreactivity in NECs were significantly higher in CHS (49 ± 2.9%) than in NCS (27 ± 3.3%) and controls (12 ± 1.6%), a pattern that was also reflected in the values of nNO (350 ± 43, 215 ± 23, and 138 ± 23 ppb in CHS, NCS, and controls, respectively). SP concentration was also elevated in nasal lavage fluids from CHS (746 ± 28 pg/mL) compared with that from NCS (624 ± 40 pg/mL) and controls (526 ± 41 pg/mL). SP expression in airway epithelial cells was greatly enhanced by exposure to NO donor, which was attenuated by pretreatment with either NO scavenger or NO synthase inhibitor.

Conclusion: Increased nitrosative stress in the upper airway may play a role in the pathogenesis of unexplained chronic cough with CHS through enhanced secretion of SP.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Cells, Cultured
  • Cough / metabolism*
  • Cough / physiopathology
  • Enzyme Inhibitors / pharmacology
  • Free Radical Scavengers / pharmacology
  • Gene Expression Regulation / drug effects
  • Humans
  • Hypersensitivity / metabolism*
  • Hypersensitivity / physiopathology
  • Middle Aged
  • Nasal Mucosa / drug effects
  • Nasal Mucosa / metabolism*
  • Nasal Provocation Tests
  • Nitric Oxide / metabolism*
  • Nitric Oxide Synthase / antagonists & inhibitors
  • Nitrosation
  • Stress, Physiological*
  • Substance P / genetics
  • Substance P / metabolism*
  • Young Adult


  • Enzyme Inhibitors
  • Free Radical Scavengers
  • Nitric Oxide
  • Substance P
  • Nitric Oxide Synthase