Ž . European Journal of Pharmacology 348 1998 297–304 Fenspiride inhibits histamine-induced responses in a lung epithelial cell line Fabio Quartulli a , Eric Pinelli b , Anne Broue-Chabbert a , Sandrine Gossart a , Valerie Girard c , ´ ´ Bernard Pipy a, ) a Laboratoire Macrophages-Mediateurs de l’Inflammation et Interactions Cellulaires, UPS EA 2405, INSERM Institut Federatif de Recherche 31 Louis ´ ´´ Bugnard, CHU Rangueil, 1 aÕenue Jean Poulhes, 31403 Toulouse Cedex 4, France ` ´ b Laboratoire de toxicologie, ENSAT, 145 aÕenue de Muret, 31000 Toulouse, France c Institut de Recherches Internationales, SerÕier, 6 place des Pleiades, 92415 CourbeÕoie cedex, France ´ Received 12 January 1998; revised 17 February 1998; accepted 20 February 1998 Abstract Using the human lung epithelial WI26VA4 cell line, we investigated the capacity of fenspiride, an anti-inflammatory drug with anti-bronchoconstrictor properties, to interfere with histamine-induced intracellular Ca 2q increase and eicosanoid formation. Histamine 2q Ž . and a histamine H receptor agonist elicited a rapid and transient intracellular Ca increase 0–60 s in fluo 3-loaded WI26VA4 cells. 1 This response was antagonized by the histamine H receptor antagonist, diphenhydramine, the histamine H receptor antagonist, 1 2 Ž y7 y5 . 2q cimetidine, having no effect. Fenspiride 10 –10 M inhibited the histamine H receptor-induced Ca increase. In addition, 1 Ž . histamine induced a biphasic increase in arachidonic acid release. The initial rise 0–30 s , a rapid and transient arachidonic acid release, 2q Ž . was responsible for the histamine-induced intracellular Ca increase. In the second phase release 15–60 min , a sustained arachidonic Ž y5 . acid release appeared to be associated with the formation of cyclooxygenase and lipoxygenase metabolites. Fenspiride 10 M abolished both phases of histamine-induced arachidonic acid release. These results suggest that anti-inflammatory and antibronchocon- strictor properties of fenspiride may result from the inhibition of these effects of histamine. q 1998 Elsevier Science B.V. All rights reserved. Keywords: Fenspiride; Histamine; Lung epithelial cell line; Ca 2q ; Phospholipase A ; Eicosanoid 2 1. Introduction Fenspiride is a non-steroidal agent with anti-broncho- Ž . constrictor properties Advenier, 1988 . It exerts an anti- inflammatory effect that is attributed to inhibition of phos- pholipase A activity and subsequent release of eicosanoids 2 Ž . De Castro et al., 1995; Carre et al., 1991 . It also has been ´ shown that fenspiride may influence histamine-induced Ž bronchoconstriction and airway allergic responses Evrard . et al., 1991; Lima et al., 1988 . Airway epithelial cells that may produce inflammatory mediators are often implicated in the initiation and the Ž continuation of inflammation of airways Levine et al., . 1995 . Histamine released by mast cells during airway Ž allergic diseases Jarjour et al., 1991; Djukanovic et al., . 2q 1990 increases intracellular Ca concentration and the ) Corresponding author. Tel.: q33-5-61-32-29-67; fax: q33-5-61-32- 22-93; e-mail: pipy@rangueil.inserm.fr production of various inflammatory mediators, such as Ž eicosanoids, in airway epithelial cells Harris and Hanra- . han, 1993; Vignola et al., 1993; Noah et al., 1991 . The signal transduction mediated by the histamine H receptor, 1 which belongs to the superfamily of receptors coupled to G proteins, involves phospholipase C andror phospholi- Ž pase A pathways Arrang et al., 1995; Leurs et al., 1995; 2 . Murayama et al., 1990 . Among the active mediators released by epithelial cells in the lung, eicosanoids play an important role in the Ž . pathogenesis of airway inflammation Holtzman, 1991 . Eicosanoids are metabolites of arachidonic acid oxygena- tion by two main groups of enzymes, cyclooxygenases and Ž . lipoxygenases Goetzl et al., 1995 . Arachidonic acid liber- ated by phospholipase A , that hydrolyzes the sn-2-ester 2 bond of phospholipids, is metabolized by cyclooxygenases to prostaglandins and thromboxanes, by 5-lipoxygenase to leukotrienes and by 5- or 15-lipoxygenases to 5- or 15-hy- droxyeicosatetraenoic acid. Eicosanoids may regulate com- 0014-2999r98r$19.00 q 1998 Elsevier Science B.V. All rights reserved.