Leukotriene D4-induced activation of smooth-muscle cells from human bronchi is partly Ca2+-independent

M. R. Accomazzo, G. E. Rovati, T. Viganò, A. Hernandez, A. Bonazzi, M. Bolla, F. Fumagalli, S. Viappiani, E. Galbiati, S. Ravasi, C. Albertoni, M. Di Luca, A. Caputi, P. Zannini, G. Chiesa, A. M. Villa, S. M. Doglia, G. Folco, S. Nicosia

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Abstract

Cysteine-containing leukotrienes (cysteinyl-LTs) are potent bronchoconstrictors and play a key role in asthma. We found that histamine and LTD4 markedly constrict strips of human bronchi (HB) with similar efficacy. However, in human airway smooth-muscle (HASM) cells, LTD4, at variance with histamine, elicited only a small, transient change in intracellular calcium ion concentration. HASM cells express both Ca2+-dependent and -independent isoforms of protein kinase C (PKC) (i.e., PKC-α and PKC-ε). Western blot analysis showed that PKC-α is activated by histamine and, to a lesser extent, by LTD4, whereas only LTD4 translocates PKC-ε. This translocation was specifically inhibited by the LTD4 antagonist pobilukast. Phorbol-dibutyrate ester (PDBu) (a PKC activator) contracted HB strips to the same extent in the presence as in the absence of extra- and intracellular Ca2+. In the absence of Ca2+, LTD4 contracted HB strips to the same extent as did PDBu, suggesting the involvement of a Ca2+-independent PKC in LTD4-mediated signal transduction. PDBu-induced desensitization and the PKC inhibitor H7 abolished the slow and sustained LTD4-triggered contraction of HB strips in the absence of Ca2+, although H7 did not greatly affect the response in the presence of the ion. Thus, in human airways, we identified a novel LTD4 transduction mechanism linked to bronchial smooth-muscle contraction, which is partly independent of Ca2+ and involves the activation of PKC-ε.

Original languageEnglish
Pages (from-to)266-272
Number of pages7
JournalAmerican Journal of Respiratory and Critical Care Medicine
Volume163
Issue number1
Publication statusPublished - 2001

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine

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    Accomazzo, M. R., Rovati, G. E., Viganò, T., Hernandez, A., Bonazzi, A., Bolla, M., Fumagalli, F., Viappiani, S., Galbiati, E., Ravasi, S., Albertoni, C., Di Luca, M., Caputi, A., Zannini, P., Chiesa, G., Villa, A. M., Doglia, S. M., Folco, G., & Nicosia, S. (2001). Leukotriene D4-induced activation of smooth-muscle cells from human bronchi is partly Ca2+-independent. American Journal of Respiratory and Critical Care Medicine, 163(1), 266-272.