Published ahead of print on December 12, 2003, doi:10.1165/rcmb.2003-0303OC Am. J. Respir. Cell Mol. Biol., Volume 30, Number 6, June 2004, 793-800 A more recent version of this article appeared on June 1, 2004
Submitted on August 19, 2003 Nerve growth factor and substance P regulation in nasal sensory neurons after TDI exposureErin R Wilfong1 and Richard D Dey2*1 Department of Pharmacology and Toxicology, West Virginia University, Morgantown, WV, USA; Department of Neurobiology and Anatomy, West Virginia University, Morgantown, WV, USA, 2 Department of Neurobiology and Anatomy, West Virginia University, Morgantown, WV, USA; Department of Pharmacology and Toxicology, West Virginia University, Morgantown, WV, USA * To whom correspondence should be addressed. E-mail: rdey{at}hsc.wvu.edu.
Toluene diisocyanate (TDI) exposure produces rhinitis and nasal irritation and increases the synthesis and release of substance P (SP) from airway sensory nerves. The mechanism leading to enhanced SP production following irritant inhalation remains unclear, but may involve actions of nerve growth factor (NGF). NGF binds trkA receptors located on sensory nerve terminals. Activation of trkA receptors initiates kinase-signaling cascades, which ultimately may increase SP. However, the effects of inhaled irritants on NGF release are not known. In this study, NGF levels in nasal lavages were examined following instillation of 10% TDI into both nasal cavities. NGF was significantly increased 2, 6, 12 and 24 hrs after TDI exposure compared to controls. The increase in NGF preceded the neuronal and mucosal increases in SP. Pretreatment with K252a, a non-selective tyrosine-kinase inhibitor prevented the increase in SP-immunoreactivity in TG neurons and epithelial nerve fibers and the inflammatory response to TDI exposure. Since NGF binds to trkA tyrosine-kinase receptors, the NGF released during TDI exposure may mediate SP up-regulation in airway sensory neurons innervating the nasal cavity.
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