Submitted on October 12, 2006
Accepted on January 15, 2007
Role of Transient Receptor Potential Vanilloid 1 receptors in endotoxin-induced airway inflammation in the mouse
Zsuzsanna Helyes1*, Krisztian Elekes1, Jozsef Nemeth2, Gabor Pozsgai2, Katalin Sandor2, Laszlo Kereskai3, Rita Borzsei2, Erika Pinter2, Arpad Szabo2, and Janos Szolcsanyi4
1 Department of Pharmacology and Pharmacotherapy, University of Pécs, Pecs, Hungary
2 Department of Pharmacology and Pharmacotherapy, University of Pécs, Pecs, Hungary; Pecs, Hungary
3 Department of Pathology, University of Pécs, Pecs, Hungary
4 Department of Pharmacology and Pharmacotherapy, University of Pécs, Pecs, Hungary; Neuropharmacology Research Group of the Hungarian Academy of Sciences, Pecs, Hungary
* To whom correspondence should be addressed. E-mail: zsuzsanna.helyes{at}aok.pte.hu.
Airways are densely innervated by capsaicin-sensitive sensory neurons expressing Transient Receptor Potential Vanilloid 1 (TRPV1) receptors/ion channels, which play an important regulatory role in inflammatory processes via the release of sensory neuropeptides. The aim of the present study was to investigate the role of TRPV1 receptors in endotoxin-induced airway inflammation and consequent bronchial hyperreactivity with functional, morphological and biochemical techniques using receptor gene-deficient mice. Inflammation was evoked by intranasal administration of E. coli lipopolysaccharide (60 µl, 167 µg/ml) in TRPV1 knockout (TRPV1-/-) mice and their wild-type counterparts (TRPV1+/+) 24 h before measurement. Airway reactivity was assessed by unrestrained whole body plethysmography and its quantitative indicator, enhanced pause (Penh) was calculated after inhalation of the bronchoconstrictor carbachol. Histological examination and spectrophotometric myeloperoxidase measurement was performed from the lung. Somatostatin concentration was measured in the lung and plasma with radioimmunoassay. Bronchial hyperreactivity, histological lesions (perivascular/peribronchial oedema, neutrophil/macrophage infiltration, goblet cell hyperplasia) and myeloperoxidase activity were significantly greater in TRPV-/- mice. Inflammation markedly elevated lung and plasma somatostatin concentrations in TRPV1+/+, but not in TRPV1-/- animals. In TRPV1-/- mice exogenous administration of somatostatin-14 (4x100 µg/kg i.p.) diminished inflammation and hyperreactivity. Furthermore, in wildtype mice antagonizing somatostatin receptors by cyclo-somatostatin (4x250 µg/kg i.p.) increased these parameters. This study provides the first evidence for a novel counter-regulatory mechanism during endotoxin-induced airway inflammation, which is mediated by somatostatin released from sensory nerve terminals in response to activation of TRPV1 receptors of the lung. It reaches the systemic circulation and inhibits inflammation and consequent bronchial hyperreactivity.
