Pulmonary chemoreflex responses are potentiated by tumor necrosis factor-alpha in mice

Ruei Lung Lin, Yu Jung Lin, Marcus J. Geer, Richard Kryscio, Lu Yuan Lee

Research output: Contribution to journalArticlepeer-review

13 Scopus citations


Inhalation of tumor necrosis factor-alpha (TNF-a), a proinflammatory cytokine, induces airway hyperresponsiveness, and the underlying mechanism is not fully understood. Hypersensitivity of vagal bronchopulmonary C-fiber afferents is known to contribute to the airway hyperresponsiveness during an airway inflammatory reaction. Because activation of these afferents can elicit pulmonary chemoreflexes, this study was designed to determine if a pretreatment with TNF-α induced airway inflammation and enhanced the pulmonary chemoreflex sensitivity in anesthetized mice; and if so, whether the effect was mediated through activation of either or both of the TNF receptors, p55 and p75. Our results showed that TNF-α instilled into the lung caused an increased sensitivity of pulmonary chemoreflex responses to various chemical stimulants of the vagal bronchopulmonary C-fiber afferents. The increased sensitivity was found 24 h later, persisted at 48 h, and then gradually declined after several days. The TNF-α-induced airway hypersensitivity was accompanied by airway inflammation as shown by a striking elevation of the levels of eosinophils and neutrophils, several potent bronchoactive inflammatory mediators, and proinflammatory cytokines in the bronchoalveolar lavage fluid. Furthermore, the increase in pulmonary chemoreflex response caused by TNF-α was partially abrogated in both p55-null and p75-null mice, but completely abolished in p55/p75-null mice. In conclusion, TNF-α pretreatment induced airway inflammation and a sustained elevation of pulmonary chemoreflex sensitivity, which was mediated through an activation of both types of TNF receptors.

Original languageEnglish
Pages (from-to)1536-1543
Number of pages8
JournalJournal of Applied Physiology
Issue number11
StatePublished - Jun 1 2013


  • Airway inflammation
  • Airway reflex
  • Asthma
  • C-fibers
  • Transient receptor potential vanilloid type 1

ASJC Scopus subject areas

  • General Medicine


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