Role of transient receptor potential vanilloid 1 receptors in endotoxin-induced airway inflammation in the mouse

1 Department of Pharmacology and Pharmacotherapy, 2 Neuropharmacology Research Group of the Hungarian Academy of Sciences, and 3 Department of Pathology, Faculty of Medicine, University of Pécs, Pécs, Hungary Submitted 12 October 2006 ; accepted in final form 15 January 2007 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 Escherichia 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 edema, 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 TRPV1 –/– animals. In TRPV1 –/– mice, exogenous administration of somatostatin-14 (4 x 100 µg/kg ip) diminished inflammation and hyperreactivity. Furthermore, in wild-type mice, antagonizing somatostatin receptors by cyclo-somatostatin (4 x 250 µg/kg ip) increased these parameters. This study provides the first evidence for a novel counterregulatory 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. capsaicin-sensitive afferents; inflammatory airway hyperreactivity; lipopolysaccharide; myeloperoxidase activity; somatostatin Address for repri