Mechanisms underlying the inhibitory effects of tachykinin receptor antagonists on eosinophil recruitment in an allergic pleurisy model in mice

The activation of tachykinin NK receptors by neuropeptides may induce the recruitment of eosinophils in vivo. The aim of the present study was to investigate the effects and underlying mechanism(s) of the action of tachykinin receptor antagonists on eosinophil recruitment in a model of allergic pleurisy in mice. Pretreatment of immunized mice with capsaicin partially prevented the recruitment of eosinophils after antigen challenge, suggesting the potential contribution of sensory nerves for the recruitment of eosinophils Local (10–50 nmol per pleural cavity) or systemic (100–300 nmol per animal) pretreatment with the tachykinin NK1 receptor antagonist SR140333 prevented the recruitment of eosinophils induced by antigen challenge of immunized mice. Neither tachykinin NK2 nor NK3 receptor antagonists suppressed eosinophil recruitment. Pretreatment with SR140333 failed to prevent the antigen-induced increase of interleukin-5 concentrations in the pleural cavity. Similarly, SR140333 failed to affect the bone marrow eosinophilia observed at 48 h after antigen challenge of immunized mice. SR140333 induced a significant increase in the concentrations of antigen-induced eotaxin at 6 h after challenge. Antigen challenge of immunized mice induced a significant increase of Leucotriene B4 (LTB4) concentrations at 6 h after challenge. Pretreatment with SR140333 prevented the antigen-induced increase of LTB4 concentrations. Our data suggest an important role for NK1 receptor activation with consequent LTB4 release and eosinophil recruitment in a model of allergic pleurisy in the mouse. Tachykinins appear to be released mainly from peripheral endings of capsaicin-sensitive sensory neurons and may act on mast cells to facilitate antigen-driven release of LTB4. Keywords: Eosinophil recruitment, LTB4, eotaxin, IL-5, bone marrow Introduction There is much evidence suggesting an important role for eosinophils in the pathophysiology of allergic diseases (Schroder et al., 1996; Giembycz & Lindsay, 1999). In these conditions, eosinophils may be a crucial source of cationic proteins, lipid mediators, oxygen-derived radicals, cytokines and chemokines that contribute to severity of disease (Cara et al., 2000). Thus, the understanding of the mechanisms underlying eosinophil recruitment in vivo may aid in the development of novel strategies for the treatment of allergic disorders. Leucotriene B4 (LTB4), the chemokine eotaxin and interleukin-5 (IL-5) are among the mediators of the inflammatory process known to play an important role in inducing eosinophil migration during allergic processes (Giembycz & Lindsay, 1999; Cara et al., 2000; Klein et al., 2000, 2001, 2002). Tachykinins are a group of neuropeptides that include substance P, neurokinin A and neurokinin B, and are released from peripheral endings of capsaicin-sensitive sensory nerves. These fibres are stimulated by a large variety of agents (Geppetti et al., 1991; Geppetti, 1993) and are depleted by pretreatment with capsaicin (Jancso et al., 1977; Holzer, 1991). The biological actions of tachykinins are mediated by the tachykinins receptors NK1, NK2 and NK3, and their release may cause, among other things, oedema formation (Walsh et al., 1995), vasodilatation (Holzer, 1998), mast cell degranulation (Lau et al., 2001) and recruitment of inflammatory cells (Maggi, 1997; Saban et al., 1997; Frode-Saleh et al., 1999). Several studies have investigated the ability of neuropeptides, especially substance P, to induce eosinophil chemotaxis in vitro and migration in vivo (Matsuda et al., 1989; Numao & Agrawal, 1992; Iwamoto et al., 1993; Smith et al., 1993; Baluk et al., 1995; Walsh et al., 1995; Saban et al., 1997; Dunzendorfer et al., 1998; Frode-Saleh et al., 1999). It is clear from these studies that neuropeptides may not only activate eosinophil recruitment directly, but also induce the release of mediators of the inflammatory process, especially LTB4, which in turn induce the recruitment of eosinophils (Iwamoto et al., 1993; Walsh et al., 1995: Saban et al., 1997). Moreover, it appears that activation of mast cells, either via NK1 receptor-dependent or -independent mechanisms, is a relevant mechanism for neuropeptide-induced eosinophil migration (Matsuda et al., 1989; Iwamoto et al., 1993; Walsh et al., 1995). The importance of endogenous neuropeptide release and action on tachykinin NK receptors for the recruitment of eosinophils in various models of inflammation has also been demonstrated. Thus, blockade of tachykinin receptors was associated with the inhibition of eosinophil influx after pulmonary administration of sephadex (Tramontana et al., 2002) or in models of allergic pulmonary inflammation (Schuiling et al., 1999a,b; Nenan et al., 2001). Few of the studies above have evaluated the comparative effect of drugs that inhibit each of the tachykinin NK receptors. Furthermore, we are not aware of studies investigating the effects of these drugs on the local release of mediators of inflammation known to participate in the cascade of events leading to eosinophil recruitment after antigen challenge of sensitized animals. Thus, the aim of the present study was to investigate the effects and underlying mechanism(s) of the action of tachykinin receptor antagonists on eosinophil recruitment in a model of allergic pleurisy in mice.