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HIGHLIGHTED TOPICS
Airway Hyperresponsiveness: From Molecules to Bedside

Selected Contribution: TNF- modulates murine tracheal rings responsiveness to G-protein-coupled receptor agonists and KCl

Pulmonary, Allergy and Critical Care Division, Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104

Submitted 10 February 2003 ; accepted in final form 16 April 2003

Although the mechanisms that underlie airway hyperresponsiveness in asthma are complex and involve a variety of factors, evidence now suggests that intrinsic abnormalities in airway smooth muscle (ASM) may play an important role. We previously reported that TNF-, a cytokine involved in asthma, augments G-protein-coupled receptor (GPCR) agonist-evoked calcium responses in cultured ASM cells. Here we have extended our previous studies by investigating whether TNF- also modulates the contractile and relaxant responses to GPCR activation using cultured murine tracheal rings. We found that in tracheal rings treated with 50 ng/ml TNF-, carbachol-induced isometric force was significantly increased by 30% compared with those treated with diluent alone (P < 0.05). TNF- also augmented KCl-induced force generation by 70% compared with rings treated with diluent alone (P < 0.01). The enhancing effect of TNF- on carbachol-induced isometric force generation was completely abrogated in the tracheal rings obtained from TNF- receptor (TNFR)1-deficient mice and in control rings treated with a TNF- mutant that solely activates TNFR2. TNF- also attenuated relaxation responsiveness to isoproterenol but not to PGE₂ or forskolin. TNF- modulatory effects on GPCR-induced ASM responsiveness were completely abrogated by pertussis toxin, an inhibitor of G_i proteins. Taken together, these data suggest that TNF- may participate in the development of airway hyperresponsiveness in asthma via the modulation of ASM responsiveness to both contractile and -adrenoceptor GPCR agonists.

asthma; airway smooth muscle; tumor necrosis factor-

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