Roles of P2X receptors and Ca2+ sensitization in extracellular adenosine triphosphate-induced hyperresponsiveness in airway smooth muscle

T. Oguma, S. Ito, M. Kondo, Y. Makino, K. Shimokata, H. Honjo, K. Kamiya, H. Kume

Research output: Contribution to journalArticle

35 Citations (Scopus)

Abstract

Background: The release of adenosine triphosphate (ATP) from the airway epithelial cells during the inflammatory process is considered to play an important role in the pathophysiology of asthma and chronic obstructive pulmonary disease. Objective: This study was designed to determine whether extracellular ATP is involved in the bronchial hyperresponsiveness as an interaction between epithelium and smooth muscle in the airways. Methods: We examined the contractile response to methacholine (MCh) before and after exposure to low concentrations (≤10 μm) of ATP in isolated, epithelium-denuded guinea-pig tracheal smooth muscle by measuring isometric tension. Intracellular Ca2+ concentrations ([Ca2+] i) were assessed by fluorescent intensities of fura-2. Results: MCh-induced contractile force was increased with no change in [Ca 2+]i after exposure to 10 μm ATP for 15 min. The ability of ATP to enhance the MCh-induced contraction was markedly attenuated by suramin, a non-selective P2 receptor inhibitor. Pre-incubation with ATPγS, a non-hydrolysable analogue of ATP and α,β-meATP, a P2X agonist, also enhanced the MCh-induced contraction. In contrast, uracil triphosphate, a P2Y agonist, did not affect the MCh-induced contraction. Y-27632, a Rho-kinase inhibitor, suppressed the ability of ATP to enhance the MCh-induced contraction. Moreover, PP1 and PP2, Src tyrosin kinase inhibitors, suppressed the enhancement of MCh-induced contraction by ATP. Conclusion: Pre-treatment with ATP induces hyperresponsiveness to MCh mediated by Ca 2+ sensitization via the P2X receptor in airway smooth muscle. The present findings suggest the possible involvement of both the Rho-kinase and Src pathways in the intracellular mechanism of this phenomenon.

Original languageEnglish
Pages (from-to)893-900
Number of pages8
JournalClinical and Experimental Allergy
Volume37
Issue number6
DOIs
Publication statusPublished - 06-2007

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology

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