Table of Contents
Journal of Allergy
Volume 2012, Article ID 494085, 10 pages
Research Article

Enhancement of Methacholine-Evoked Tracheal Contraction Induced by Bacterial Lipopolysaccharides Depends on Epithelium and Tumor Necrosis Factor

1Laboratory Molecular Immunology and Embryology, University of Orleans and CNRS, Orleans, France
2Department of Immunology, Institute of Biomedical Sciences, University of Sao Paulo, Avenue Prof. Lineu Prestes, 1730, 05508-000 São Paulo, SP, Brazil
3Cardiothoracic Pharmacology, Cardiothoracic and Stem Cell Pharmacology, National Heart and Lung Institute, Imperial College of London, London SW7 2AZ, UK
4Institute for Clinical and Biomedical Research Thurgau, Lauchefeld 31, CH-9548 Matzingen, Switzerland
5Institute of Infectious Disease and Molecular Medicine (IIDMM), University of Cape Town, Cape Town, South Africa

Received 5 October 2011; Revised 28 November 2011; Accepted 30 November 2011

Academic Editor: S. L. Johnston

Copyright © 2012 T. Secher et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


Inhaled bacterial lipopolysaccharides (LPSs) induce an acute tumour necrosis factor-alpha (TNF-α-) dependent inflammatory response in the murine airways mediated by Toll-like receptor 4 (TLR4) via the myeloid differentiation MyD88 adaptor protein pathway. However, the contractile response of the bronchial smooth muscle and the role of endogenous TNFα in this process have been elusive. We determined the in vivo respiratory pattern of C57BL/6 mice after intranasal LPS administration with or without the presence of increasing doses of methacholine (MCh). We found that LPS administration altered the basal and MCh-evoked respiratory pattern that peaked at 90 min and decreased thereafter in the next 48 h, reaching basal levels 7 days later. We investigated in controlled ex vivo condition the isometric contraction of isolated tracheal rings in response to MCh cholinergic stimulation. We observed that preincubation of the tracheal rings with LPS for 90 min enhanced the subsequent MCh-induced contractile response (hyperreactivity), which was prevented by prior neutralization of TNFα with a specific antibody. Furthermore, hyperreactivity induced by LPS depended on an intact epithelium, whereas hyperreactivity induced by TNFα was well maintained in the absence of epithelium. Finally, the enhanced contractile response to MCh induced by LPS when compared with control mice was not observed in tracheal rings from TLR4- or TNF- or TNF-receptor-deficient mice. We conclude that bacterial endotoxin-mediated hyperreactivity of isolated tracheal rings to MCh depends upon TLR4 integrity that signals the activation of epithelium, which release endogenous TNFα.