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Keywords:

  • airway smooth muscle;
  • β-agonists;
  • cAMP;
  • Smad;
  • tolerance

Summary

Background Transforming growth factor-β1 (TGF-β1) is generally considered to play an important role in the pathogenesis of chronic inflammation and fibrosis.

Objective and methods This study was designed to determine mechanisms of reduced responsiveness of guinea-pig tracheal smooth muscle to β-adrenoceptor agonists by TGF-β1, using isometric tension records and tissue cAMP measurement. Moreover, we examined the involvement of the signal transduction processes of TGF-β superfamily in the desensitization of β-adrenoceptors.

Results After exposure to 0.2–2000 pm TGF-β1 for 4–8 h, the inhibitory effects of 1 µm isoprenaline (ISO) and 10 µm forskolin on 1 µm MCh-induced contraction were markedly reduced in a concentration-dependent fashion. The desensitization by TGF-β1 was greater against ISO than for forskolin. The values of EC75 for the curves for ISO after exposure to the normal bathing solution and TGF-β1 were 0.039 ± 0.02 and 0.38 ± 0.28 µm, respectively. The values of EC50 for the curves for forskolin under these conditions were 0.50 ± 0.12 and 0.89 ± 0.21 µm, respectively. On the other hand, the inhibitory effects of phosphodiesterase inhibitors such as theophylline and rolipram were not attenuated after exposure to TGF-β1. Concentration–inhibition curve for ISO was shifted to the right after exposure to 2000 pm TGF-β1 for 8 h more than that curve for forskolin. In contrast, the curve for theophylline was not shifted to the right by TGF-β1. When the tissues were incubated with TGF-β1 in the presence of IFN-γ, an intracellular antagonist of TGF-β signalling, IFN-γ inhibited the reduced response to ISO and forskolin after exposure to TGF-β1 in a concentration-dependent fashion. After exposure to TGF-β1, the effects of cAMP accumulation of ISO was significantly reduced, however, neither forskolin-nor theophylline-induced cAMP accumulation was affected. IFN-γ had no significant effect on cAMP accumulation either to ISO or forskolin.

Conclusions Impairment of the β-adrenoceptors/adenylyl cyclase pathway are involved in heterologous desensitization of β-adrenoceptors induced by TGF-β1 in airway smooth muscle. IFN-γ functionally suppresses this phenomenon via cAMP-independent processes. Phosphodiesterase is still intact under this condition.