Tachykinins in Experimental Allergic Lung Disease

Abstract

The sensory innervation of the lung and airways is generally classified into three different classes of receptors: (1) slowly adapting stretch receptors which are mainly located in the airway smooth muscle and represent the afferent limb of the Hering-Breuer reflex, (2) rapidly adapting or “irritant receptors” located in more superficial layers of the airways and responding both to mechanical and chemical stimuli, and (3) less characterized C-fibers with slow conduction velocity (Widdicombe 1981). At least some if not all of the C-fibers in the airways do not only serve as afferent nerve fibers conveying information from the airways to the central nervous system but, in addition, fulfill a local effector function in that they release neuropeptides at their site of stimulation in the airway wall (Holzer 1988). These neuropeptides are calcitonin gene related peptide (CGRP) and members of the tachykinin family, in particular substance P (SP) and neurokinin A (NKA). The pharmacological actions of these peptides in the airways can be generally described as pro-inflammatory: NKA and, to a lesser extent, SP induce bronchoconstriction, SP acts as stimulator of glandular secretion, plasma extravasation and activates a variety of immune cells, and CGRP is a potent vasodilator. Together, the effects exerted by these peptides resemble the inflammation seen in asthma. This has led to the proposal of “asthma as an axon reflex”. According to this concept, this particular class of sensory axons is abnormally stimulated in the course of asthma, e. g., by epithelial shedding and mediators released from immune cells, so that they release proinflammatory neuropeptides in abnormal amounts and thereby exaggerate and perpetuate the inflammatory process (for review see Barnes 1994). Final proof for a crucial involvement of such mechanisms in the pathogenesis of human airway diseases, however, has yet not been obtained. A particular gap in our knowledge concerns the plasticity of neuropeptide expression in sensory neurons in the course of allergic inflammation. For example, remarkable alterations in the expression of tachykinins and also their receptors have been observed in experimentally induced inflammation of the skin, joints, and gut (Schoenen et al. 1985; Noguchi et al. 1988; Mantyh et al. 1989). Therefore, we first determined the location of sensory nerve cell bodies innervating the airways by neuroanatomical tracing techniques combined with immunohistochemistry and then investigated tachykinin expression in these neurons in an animal model of allergic airway inflammation, i. e., the actively ovalbumin-sensitized and inhalatively challenged guinea-pig. This well-characterized model shows many similarities to human asthma (see Table 1).