Document Detail

An assay to evaluate the long-term effects of inflammatory mediators on murine airway smooth muscle: evidence that TNFalpha up-regulates 5-HT(2A)-mediated contraction.
MedLine Citation:
PMID:  12429569     Owner:  NLM     Status:  MEDLINE    
1. Asthma research is arguably limited by an absence of appropriate animal models to study the pharmacology of inflammatory mediators that affect airway hyperresponsiveness and remodelling. Here we assessed an assay based on mouse tracheal segments cultured for 1-32 days, and investigated contractile responses mediated by muscarinic and 5-hydroxytryptamine (5-HT) receptors following long-term exposure to tumour necrosis factor-alpha (TNFalpha). 2. Following culture, in the absence of TNFalpha, maximum contractile responses to KCl and carbachol were similar, with an increase in response up to day two and a decrease to a stable level after 8 days. Maximal relaxations to isoprenaline were not affected by the culture procedure. The potency of KCl and isoprenaline increased throughout the study. DNA microarray data revealed that global gene expression changes were greater when tissues were introduced to culture than when they were maintained in culture. The morphology of smooth muscle cells was maintained throughout the culture period. 3. 5-HT induced a weak contraction in both fresh and cultured (up to 8 days) segments. Culture with TNFalpha produced a time- and concentration-dependent increase in the maximal contraction to 5-HT, evidently mediated by 5-HT(2A) receptors, whereas, the potency for carbachol was reduced. 4. In conclusion, the phenotype of airway smooth muscle remained largely intact during the culture period, even though minor changes were obtained during the first days of culture. The time-dependent effect of TNFalpha indicates the importance of studying the long-term effect of cytokines on the smooth muscle cells in relation to airway hyperresponsiveness and remodelling.
Mikael Adner; Andrew C Rose; Yaping Zhang; Karl Swärd; Mikael Benson; Rolf Uddman; Nigel P Shankley; Lars-Olaf Cardell
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  British journal of pharmacology     Volume:  137     ISSN:  0007-1188     ISO Abbreviation:  Br. J. Pharmacol.     Publication Date:  2002 Dec 
Date Detail:
Created Date:  2002-11-13     Completed Date:  2003-05-20     Revised Date:  2009-11-18    
Medline Journal Info:
Nlm Unique ID:  7502536     Medline TA:  Br J Pharmacol     Country:  England    
Other Details:
Languages:  eng     Pagination:  971-82     Citation Subset:  IM    
Department of Otorhinolaryngology, Malmö University Hospital, SE-20502 Malmö, Sweden.
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MeSH Terms
Atropine / pharmacology
Carbachol / pharmacology
Dose-Response Relationship, Drug
Gene Expression Profiling
Inflammation Mediators / pharmacology*
Isoproterenol / pharmacology
Mice, Inbred BALB C
Muscarinic Antagonists / pharmacology
Muscle Contraction / drug effects
Muscle, Smooth / drug effects*,  physiology
Oligonucleotide Array Sequence Analysis
Organ Culture Techniques
Potassium Chloride / pharmacology
Receptor, Serotonin, 5-HT2A
Receptors, Serotonin / drug effects,  physiology
Serotonin / pharmacology
Serotonin Agents / pharmacology
Serotonin Agonists / pharmacology
Serotonin Antagonists / pharmacology
Time Factors
Trachea / drug effects*,  metabolism,  physiology
Tumor Necrosis Factor-alpha / pharmacology
Reg. No./Substance:
0/Inflammation Mediators; 0/Muscarinic Antagonists; 0/Receptor, Serotonin, 5-HT2A; 0/Receptors, Serotonin; 0/Serotonin Agents; 0/Serotonin Agonists; 0/Serotonin Antagonists; 0/Tumor Necrosis Factor-alpha; 50-67-9/Serotonin; 51-55-8/Atropine; 51-83-2/Carbachol; 7447-40-7/Potassium Chloride; 7683-59-2/Isoproterenol
Comment In:
Br J Pharmacol. 2002 Dec;137(7):943-4   [PMID:  12429565 ]

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