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 l, 167 g/ml) in TRPV1 knockout (TRPV1 Ϫ/Ϫ ) mice and their wild-type counterparts (TRPV1 ϩ/ϩ ) 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 Ϫ/Ϫ mice. Inflammation markedly elevated lung and plasma somatostatin concentrations in TRPV1 ϩ/ϩ but not TRPV1 Ϫ/Ϫ animals. In TRPV1 Ϫ/Ϫ mice, exogenous administration of somatostatin-14 (4 ϫ 100 g/kg ip) diminished inflammation and hyperreactivity. Furthermore, in wildtype mice, antagonizing somatostatin receptors by cyclo-somatostatin (4 ϫ 250 g/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 THE AIRWAYS ARE DENSELY INNERVATED by capsaicin-sensitive sensory nerves (54), which play an important regulatory role in inflammatory processes via the release of sensory neuropeptides. The transient receptor potential vanilloid 1 (TRPV1) receptor, also known as capsaicin receptor, is a nonselective cation channel expressed selectively in the cell membrane of thin afferent (C and A␦) fibers, which is activated/sensitized by noxious heat and a variety of inflammatory mediators such as protons, lipoxygenase products, bradykinin, or prostaglandins (7, 9, 10, 52). Therefore, its involvement in inflammatory and nociceptive processes has become an issue with pathophysiological relevance and important scopes for drug development (7, 52). The gene of the TRPV1 receptor was successfully deleted in mice (10), which enabled the studying of the functional roles of...