title: Role of capsaicin-sensitive afferents and sensory neuropeptides in endotoxin-induced airway inflammation and consequent bronchial hyperreactivity in the mouse.
abstract: Substance P (SP) and calcitonin gene-related peptide (CGRP) released from capsaicin-sensitive afferents induce neurogenic inflammation via NK(1), NK(2) and CGRP1 receptor activation. This study examines the role of capsaicin-sensitive fibres and sensory neuropeptides in endotoxin-induced airway inflammation and consequent bronchial hyperreactivity with functional, morphological and biochemical techniques in mice. Carbachol-induced bronchoconstriction was measured with whole body plethysmography 24 h after intranasal lipopolysaccharide administration. SP and CGRP were determined with radioimmunoassay, myeloperoxidase activity with spectrophotometry, interleukin-1beta with ELISA and histopathological changes with semiquantitative scoring from lung samples. Treatments with resiniferatoxin for selective destruction of capsaicin-sensitive afferents, NK(1) antagonist SR 140333, NK(2) antagonist SR 48968, their combination, or CGRP1 receptor antagonist CGRP(8-37) were performed. Lipopolysaccharide significantly increased lung SP and CGRP concentrations, which was prevented by resiniferatoxin pretreatment. Resiniferatoxin-desensitization markedly enhanced inflammation, but decreased bronchoconstriction. CGRP(8-37) or combination of SR 140333 and SR 48968 diminished neutrophil accumulation, MPO levels and IL-1beta production, airway hyperresponsiveness was inhibited only by SR 48968. This is the first evidence that capsaicin-sensitive afferents exert a protective role in endotoxin-induced airway inflammation, but contribute to increased bronchoconstriction. Activation of CGRP1 receptors or NK(1)+NK(2) receptors participate in granulocyte accumulation, but NK(2) receptors play predominant role in enhanced airway resistance.
authors.affiliation: Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, University of Pécs, H-7624 Pécs, Szigeti u. 12., Hungary.
authors.forename: Krisztián
authors.initials: K
authors.lastname: Elekes
authors.forename: Zsuzsanna
authors.initials: Z
authors.lastname: Helyes
authors.forename: József
authors.initials: J
authors.lastname: Németh
authors.forename: Katalin
authors.initials: K
authors.lastname: Sándor
authors.forename: Gábor
authors.initials: G
authors.lastname: Pozsgai
authors.forename: László
authors.initials: L
authors.lastname: Kereskai
authors.forename: Rita
authors.initials: R
authors.lastname: Börzsei
authors.forename: Erika
authors.initials: E
authors.lastname: Pintér
authors.forename: Arpád
authors.initials: A
authors.lastname: Szabó
authors.forename: János
authors.initials: J
authors.lastname: Szolcsányi
mesh_terms: D000818:Animals; D016535:Bronchial Hyperreactivity / Q000139:chemically induced / Q000276:immunology*; D015740:Calcitonin Gene-Related Peptide / Q000032:analysis; D002211:Capsaicin / Q000494:pharmacology*; D004731:Endotoxins / Q000633:toxicity*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006651:Histocytochemistry; D007249:Inflammation / Q000139:chemically induced / Q000473:pathology; D053583:Interleukin-1beta / Q000032:analysis; D008168:Lung / Q000201:enzymology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D009475:Neurons, Afferent / Q000187:drug effects*; D009479:Neuropeptides / Q000378:metabolism*; D009195:Peroxidase / Q000032:analysis; D011863:Radioimmunoassay; D013004:Somatostatin / Q000097:blood; D013053:Spectrophotometry; D013373:Substance P / Q000032:analysis
chemical_list: D004731:Endotoxins; D053583:Interleukin-1beta; D009479:Neuropeptides; D013373:Substance P; D013004:Somatostatin; D009195:Peroxidase; D015740:Calcitonin Gene-Related Peptide; D002211:Capsaicin