Am. J. Respir. Crit. Care Med., Volume 163, Number 1, January 2001, 266-272

Leukotriene D₄-Induced Activation of Smooth-Muscle Cells From Human Bronchi Is Partly Ca²⁺-Independent

MARIA ROSA ACCOMAZZO, GIAN ENRICO ROVATI, TERESA VIGANÒ, ALICIA HERNANDEZ, ALBINO BONAZZI, MANLIO BOLLA, FRANCESCA FUMAGALLI, SERENA VIAPPIANI, ELISABETTA GALBIATI, SAULA RAVASI, CHIARA ALBERTONI, MONICA DI LUCA, ANTONIO CAPUTI, PIERO ZANNINI, GIUSEPPE CHIESA, ANNA MARIA VILLA, SILVIA MARIA DOGLIA, GIANCARLO FOLCO, and SIMONETTA NICOSIA

Institute of Pharmacological Sciences, and Department of Biotechnology and Biosciences, University of Milan, and Department of Thoracic Surgery, Scientific Institute, St. Raffaele Hospital, Milan, Italy

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- and PKC- ). Western blot analysis showed that PKC- is activated by histamine and, to a lesser extent, by LTD₄, whereas only LTD₄ translocates PKC- . 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- .

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